<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01660451</url>
  </required_header>
  <id_info>
    <org_study_id>16349</org_study_id>
    <secondary_id>2012-002602-52</secondary_id>
    <nct_id>NCT01660451</nct_id>
  </id_info>
  <brief_title>Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas</brief_title>
  <official_title>Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bayer</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of the study (part A) is to evaluate the efficacy and safety of BAY80-6946 in&#xD;
      patients with indolent or aggressive Non-Hodgkin's Lymphoma, who have progressed after&#xD;
      standard therapy. 30 patients will be enrolled to both indolent and aggressive disease group.&#xD;
      The objective of the study part B (CHRONOS-1) is to evaluate the efficacy and safety of&#xD;
      BAY80-6946 in patients with relapsed/refractory follicular lymphoma. 120 patients will be&#xD;
      enrolled in the part B of the study. Further objectives are to evaluate the pharmacokinetics&#xD;
      and biomarkers. Quality of life will be a further objective of part B of the study.&#xD;
&#xD;
      In a cohort of 20 patients (enrolled both in part A and B) an ECG substudy will be performed&#xD;
      to assess the potential for cardiac toxicity and QT/QTc interval prolongation of BAY80-6946.&#xD;
&#xD;
      After an up to 28-day screening period, eligible patients will start treatment with&#xD;
      BAY80-6946 at a dose of 0.8 mg/kg (Part A) and at a dose of 60 mg (Part B).&#xD;
&#xD;
      Treatment will be continued until disease has progressed or until another criterion is met&#xD;
      for withdrawal from study. An end-of-treatment visit will be performed within 7 days after&#xD;
      discontinuation of study treatment. Thirty to 35 days after last study drug administration, a&#xD;
      safety followup visit will be performed for the collection of adverse events (AEs) and&#xD;
      concomitant medication data. Patients will be contacted quarterly to determine overall&#xD;
      survival status up to 4 years after last patient completed treatment. Patients who&#xD;
      discontinue study drug for reasons other than disease progression will enter the Active&#xD;
      Assessment Follow-up period. The end of study notification to Health Authorities will be&#xD;
      based on the completion of the collection of survival data.&#xD;
&#xD;
      The efficacy is measured by the decrease in tumor size. Tumor assessments will be done at&#xD;
      Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months&#xD;
      during Year 3. Blood samples will be collected for pharmacokinetic analysis. Archival tumor&#xD;
      tissue and blood samples will be collected for biomarker analysis (mandatory) and for central&#xD;
      pathology review (part B), fresh biopsy tissue will also be collected if available.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 19, 2012</start_date>
  <completion_date type="Actual">May 18, 2023</completion_date>
  <primary_completion_date type="Actual">June 22, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate (ORR) Based on Independent Review-Part A</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Rate (ORR) Based on Independent Review-Part B</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ORR Based on Investigator Assessment-Part A</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ORR Based on Investigator Assessment-Part B</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR) Based on Independent Review</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DOR Based on Investigator Assessment</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) Based on Independent Review</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS Based on Investigator Assessment</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B</measure>
    <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
    <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">227</enrollment>
  <condition>Lymphoma, Non-Hodgkin</condition>
  <arm_group>
    <arm_group_label>Copanlisib (indolent NHL)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part A: Participants in this arm will be patients with indolent NHL.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Copanlisib (aggressive NHL)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part A: Participants in this arm will be patients with aggressive NHL.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Copanlisib (indolent B-cell NHL)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part B: Participants in this arm will be patients with indolent B-cell NHL.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Copanlisib (Aliqopa, BAY80-6946)</intervention_name>
    <description>BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).&#xD;
Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.&#xD;
Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.</description>
    <arm_group_label>Copanlisib (aggressive NHL)</arm_group_label>
    <arm_group_label>Copanlisib (indolent B-cell NHL)</arm_group_label>
    <arm_group_label>Copanlisib (indolent NHL)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Indolent NHL:&#xD;
&#xD;
               -  Histologically confirmed diagnosis of follicular lymphoma (FL) grades 1, 2 or 3a,&#xD;
                  marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma&#xD;
                  and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic&#xD;
                  lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).&#xD;
&#xD;
               -  Relapsed after ≥ 2 prior chemotherapy- or immunotherapy-based regimens for&#xD;
                  indolent NHL, or refractory to 2 prior chemotherapy and/ or immunotherapy-based&#xD;
                  regimens.&#xD;
&#xD;
          -  Aggressive NHL:&#xD;
&#xD;
               -  Histologically confirmed diagnosis of grade 3b follicular lymphoma (FL),&#xD;
                  transformed indolent lymphoma, diffuse large B-cell lymphoma (DLBCL), mediastinal&#xD;
                  large B-cell lymphoma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma&#xD;
                  unspecified, or anaplastic large cell lymphoma primary systemic type, or&#xD;
                  angioimmunoblastic T cell lymphoma.&#xD;
&#xD;
               -  Relapsed after ≥ 2 prior chemotherapy regimens, including the following:&#xD;
                  First-line treatment with standard anthracycline-containing regimen (e.g.,&#xD;
                  cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At&#xD;
                  least 1 additional combination chemotherapy regimen. Patients relapsed after or&#xD;
                  refractory to first prior chemotherapy- and/or immunotherapy-based regimen for&#xD;
                  aggressive NHL and not eligible for high-dose regimen followed by transplant.&#xD;
                  High-dose chemotherapy, or chemoradiotherapy with autologous stem cell&#xD;
                  transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic&#xD;
                  cells must have received prior rituximab, if available.&#xD;
&#xD;
               -  Patients with transformed indolent lymphoma must have received at least 2 prior&#xD;
                  chemotherapy- and/or immunotherapy-based regimens&#xD;
&#xD;
               -  Consent to provide fresh tumor tissue during screening&#xD;
&#xD;
          -  Indolent B-cell NHL lymphoma (study part B):&#xD;
&#xD;
               -  Histologically confirmed diagnosis of indolent B-cell NHL, with histological&#xD;
                  subtype limited to the following:&#xD;
&#xD;
                    -  Follicular lymphoma (FL) grade 1-2-3a&#xD;
&#xD;
                    -  Small lymphocytic lymphoma (SLL) with absolute lymphocyte count &lt; 5 x 109/L&#xD;
                       at the time of diagnosis and at study entry&#xD;
&#xD;
                    -  Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)&#xD;
&#xD;
                    -  Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)&#xD;
&#xD;
               -  Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as&#xD;
                  not responding to a standard regimen or progressing within 6 months of the last&#xD;
                  course of a standard regimen). Patients must have received Rituximab and&#xD;
                  alkylating agents.&#xD;
&#xD;
          -  For all patients:&#xD;
&#xD;
               -  Male or female patients &gt; 18 years of age&#xD;
&#xD;
               -  ECOG performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group)&#xD;
&#xD;
               -  Life expectancy of at least 3 months&#xD;
&#xD;
               -  Adequate bone marrow, liver and renal function as assessed within 7 days before&#xD;
                  starting study treatment&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the&#xD;
                  Institution&#xD;
&#xD;
               -  Availability of archival tumor tissue&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical&#xD;
             management)&#xD;
&#xD;
          -  Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding&#xD;
             event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common&#xD;
             Terminology Criteria for Adverse Events).&#xD;
&#xD;
          -  History or concurrent condition of interstitial lung disease&#xD;
&#xD;
          -  Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any&#xD;
             prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute)&#xD;
&#xD;
          -  Prior treatment with PI3K inhibitors&#xD;
&#xD;
          -  Systemic corticosteroid therapy (ongoing)&#xD;
&#xD;
          -  Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days&#xD;
             prior to study drug start using the hepatitis virus panel laboratorial routine.&#xD;
             Subjects positive for HBsAg or HBcAb will be eligible if they are negative for&#xD;
             HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV&#xD;
             RNA.&#xD;
&#xD;
          -  For Part B:&#xD;
&#xD;
               -  Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed&#xD;
                  disease and chronic lymphocytic leukemia (CLL)&#xD;
&#xD;
               -  History or concurrent condition of interstitial lung disease or severely impaired&#xD;
                  pulmonary function&#xD;
&#xD;
          -  Excluded medical conditions:&#xD;
&#xD;
               -  Previous or concurrent cancer that is distinct in primary site or histology from&#xD;
                  indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively&#xD;
                  treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder&#xD;
                  tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades&#xD;
                  lamina propria)].&#xD;
&#xD;
               -  Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28&#xD;
                  days prior to study drug start using the hepatitis virus panel laboratorial&#xD;
                  routine. Subjects positive for HBsAg or HBcAb will be eligible if they are&#xD;
                  negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are&#xD;
                  negative for HCV-RNA.&#xD;
&#xD;
               -  Type I or II diabetes mellitus with HbA1c &gt; 8.5% or fasting plasma glucose &gt; 160&#xD;
                  mg/dL at screening.&#xD;
&#xD;
               -  Previous or concurrent cancer that is distinct in primary site or histology from&#xD;
                  indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively&#xD;
                  treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder&#xD;
                  tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades&#xD;
                  lamina propria)].&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bayer Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Bayer</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gilbert</city>
        <state>Arizona</state>
        <zip>85234</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Anaheim</city>
        <state>California</state>
        <zip>90801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Englewood</city>
        <state>Colorado</state>
        <zip>80113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Fort Collins</city>
        <state>Colorado</state>
        <zip>80528</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Port Saint Lucie</city>
        <state>Florida</state>
        <zip>34952</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Louis Park</city>
        <state>Minnesota</state>
        <zip>55426</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Westbury</city>
        <state>New York</state>
        <zip>11590</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Goldsboro</city>
        <state>North Carolina</state>
        <zip>27534</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44718</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99208-1129</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Garran</city>
        <state>Australian Capital Territory</state>
        <zip>2605</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Linz</city>
        <zip>4020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Anderlecht</city>
        <zip>1070</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bruxelles - Brussel</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Turnhout</city>
        <zip>2300</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wilrijk</city>
        <zip>2610</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint John</city>
        <state>New Brunswick</state>
        <zip>E2L 4L2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H1T 2M4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Helsinki</city>
        <zip>00290</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oulu</city>
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        <zip>650066</zip>
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      <address>
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      <address>
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        <state>Cambridgeshire</state>
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      <address>
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  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hong Kong</country>
    <country>Hungary</country>
    <country>Ireland</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Korea, Republic of</country>
    <country>New Zealand</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Russian Federation</country>
    <country>Singapore</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Turkey</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Chile</country>
    <country>China</country>
    <country>Colombia</country>
    <country>Denmark</country>
    <country>Japan</country>
    <country>Luxembourg</country>
    <country>Mexico</country>
    <country>Peru</country>
  </removed_countries>
  <link>
    <url>https://clinicaltrials.bayer.com/</url>
    <description>Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.</description>
  </link>
  <results_reference>
    <citation>Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, Linton K, Thieblemont C, Vitolo U, Hiemeyer F, Giurescu M, Garcia-Vargas J, Gorbatchevsky I, Liu L, Koechert K, Pena C, Neves M, Childs BH, Zinzani PL. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017 Sep 1;28(9):2169-2178. doi: 10.1093/annonc/mdx289.</citation>
    <PMID>28633365</PMID>
  </results_reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 6, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 8, 2012</study_first_posted>
  <results_first_submitted>October 13, 2017</results_first_submitted>
  <results_first_submitted_qc>December 8, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">January 8, 2018</results_first_posted>
  <last_update_submitted>June 12, 2023</last_update_submitted>
  <last_update_submitted_qc>June 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Clinical trial, phase II</keyword>
  <keyword>Phosphatidylinositol 3-Kinase</keyword>
  <keyword>Class I, Non-Hodgkin's lymphoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA &quot;Principles for responsible clinical trial data sharing&quot;. This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.&#xD;
Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Part A-Study enrolled participants from 41 study centers in 10 countries, between 19 NOV 2012 (first participant first visit [FPFV]) and 01 OCT 2015 (cut-off date for interim analysis).&#xD;
Part B-Study enrolled participants from 81 study centers in 24 countries, between 04 NOV 2013 (FPFV) and 22 JUN 2016 (cut-off date for primary analysis).</recruitment_details>
      <pre_assignment_details>Part A: Overall 125 participants were screened, of them 41 were screen failure. Total 84 were assigned to treatment.&#xD;
Part B: Overall 213 participants were screened, of them 70 were screen failure. Total 143 were assigned to treatment, of them 1 was suspected as fraudulent and excluded from analysis sets. Therefore 142 participants were evaluable.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Part A: Indolent NHL/CLL</title>
          <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="P2">
          <title>Part A: Aggressive NHL</title>
          <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="P3">
          <title>Part B: Indolent NHL</title>
          <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
                <participants group_id="P2" count="51"/>
                <participants group_id="P3" count="142"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="34"/>
                <participants group_id="P3" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="105"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event (AE) without Clinical PD</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="26"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>AE with Clinical PD</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="9"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Deviation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="16"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Ongoing with treatment</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="46"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Full Analysis Set (FAS) included all participants assigned to study treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Part A: Indolent NHL/CLL</title>
          <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="B2">
          <title>Part A: Aggressive NHL</title>
          <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="B3">
          <title>Part B: Indolent NHL</title>
          <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="33"/>
            <count group_id="B2" value="51"/>
            <count group_id="B3" value="142"/>
            <count group_id="B4" value="226"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>18 to 90 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="51"/>
                    <measurement group_id="B3" value="142"/>
                    <measurement group_id="B4" value="226"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="71"/>
                    <measurement group_id="B4" value="111"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="71"/>
                    <measurement group_id="B4" value="115"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate (ORR) Based on Independent Review-Part A</title>
        <description>Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. (In Part A, for CLL patients, there was no independent assessment. Instead, the investigator assessment had been used.)</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR) Based on Independent Review-Part A</title>
          <description>Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.</description>
          <population>Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. (In Part A, for CLL patients, there was no independent assessment. Instead, the investigator assessment had been used.)</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.75" lower_limit="28.73" upper_limit="59.68"/>
                    <measurement group_id="O2" value="27.08" lower_limit="16.83" upper_limit="39.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 5%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0001</p_value>
            <p_value_desc>0.0001</p_value_desc>
            <method>Exact binomial test</method>
            <param_type>Response rate</param_type>
            <param_value>45.45</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>30.49</ci_lower_limit>
            <ci_upper_limit>61.06</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 5%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0001</p_value>
            <p_value_desc>0.0001</p_value_desc>
            <method>Exact binominal test</method>
            <method_desc>P-value was based on the original patients in the aggressive arm (for the first 34 patients), not including the additional recruited patients.</method_desc>
            <param_type>Response rate</param_type>
            <param_value>27.08</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>16.83</ci_lower_limit>
            <ci_upper_limit>39.57</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate (ORR) Based on Independent Review-Part B</title>
        <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR) Based on Independent Review-Part B</title>
          <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
          <population>FAS included all patients assigned to study treatment.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.15" lower_limit="50.60" upper_limit="67.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 40%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>0.001</p_value_desc>
            <method>Exact binominal test</method>
            <param_type>Response rate</param_type>
            <param_value>59.15</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>50.60</ci_lower_limit>
            <ci_upper_limit>67.32</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>ORR Based on Investigator Assessment-Part A</title>
        <description>Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. Patients who were not evaluable for ORR and discontinued due to a drug-related toxicity, death / progression by clinical judgment before disease was re-evaluated and included.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>ORR Based on Investigator Assessment-Part A</title>
          <description>Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.</description>
          <population>Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. Patients who were not evaluable for ORR and discontinued due to a drug-related toxicity, death / progression by clinical judgment before disease was re-evaluated and included.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.88" lower_limit="31.54" upper_limit="62.66"/>
                    <measurement group_id="O2" value="31.25" lower_limit="20.35" upper_limit="43.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 5%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0001</p_value>
            <p_value_desc>0.0001</p_value_desc>
            <method>Exact binominal test</method>
            <param_type>Response rate</param_type>
            <param_value>46.88</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>31.54</ci_lower_limit>
            <ci_upper_limit>62.66</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 5%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0001</p_value>
            <p_value_desc>0.0001</p_value_desc>
            <method>Exact binominal test</method>
            <method_desc>P-value was based on the original patients in the aggressive arm (for the first 34 patients), not including the additional recruited patients.</method_desc>
            <param_type>Response rate</param_type>
            <param_value>31.25</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>20.35</ci_lower_limit>
            <ci_upper_limit>43.97</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>ORR Based on Investigator Assessment-Part B</title>
        <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>ORR Based on Investigator Assessment-Part B</title>
          <description>Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.</description>
          <population>FAS included all patients assigned to study treatment.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="142"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.41" lower_limit="42.88" upper_limit="59.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Response rate was statistically compared by exact binomial test if higher than 40%.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <p_value>0.0039</p_value>
            <p_value_desc>0.01</p_value_desc>
            <method>Exact binominal test</method>
            <param_type>Response rate</param_type>
            <param_value>51.41</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>42.88</ci_lower_limit>
            <ci_upper_limit>59.87</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response (DOR) Based on Independent Review</title>
        <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>PPS (for Part A) included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.&#xD;
FAS (for Part B) included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O3">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response (DOR) Based on Independent Review</title>
          <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
          <population>PPS (for Part A) included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.&#xD;
FAS (for Part B) included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="13"/>
                <count group_id="O3" value="84"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="390" lower_limit="63" upper_limit="NA">NA: Median or confidence limited not yet estimable.</measurement>
                    <measurement group_id="O2" value="166" lower_limit="61" upper_limit="434"/>
                    <measurement group_id="O3" value="687" lower_limit="225" upper_limit="687"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>DOR Based on Investigator Assessment</title>
        <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>PPS (for Part A) included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.&#xD;
FAS (for Part B) included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O3">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>DOR Based on Investigator Assessment</title>
          <description>Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason &quot;other&quot; or &quot;AE not related to disease progression.</description>
          <population>PPS (for Part A) included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.&#xD;
FAS (for Part B) included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="15"/>
                <count group_id="O3" value="73"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="287" lower_limit="63" upper_limit="574"/>
                    <measurement group_id="O2" value="166" lower_limit="112" upper_limit="NA">NA: Median or confidence limited not yet estimable.</measurement>
                    <measurement group_id="O3" value="370" lower_limit="226" upper_limit="NA">NA: Median or confidence limited not yet estimable.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) Based on Independent Review</title>
        <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O3">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) Based on Independent Review</title>
          <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
          <population>FAS included all patients assigned to study treatment.</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="51"/>
                <count group_id="O3" value="142"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="294" lower_limit="148" upper_limit="493"/>
                    <measurement group_id="O2" value="70" lower_limit="47" upper_limit="112"/>
                    <measurement group_id="O3" value="340" lower_limit="247" upper_limit="736"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PFS Based on Investigator Assessment</title>
        <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O3">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>PFS Based on Investigator Assessment</title>
          <description>PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).</description>
          <population>FAS included all patients assigned to study treatment.</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="51"/>
                <count group_id="O3" value="142"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="280" lower_limit="173" upper_limit="431"/>
                    <measurement group_id="O2" value="70" lower_limit="47" upper_limit="115"/>
                    <measurement group_id="O3" value="330" lower_limit="237" upper_limit="385"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Indolent NHL/CLL</title>
            <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Aggressive NHL</title>
            <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
          <group group_id="O3">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause.</description>
          <population>FAS included all patients assigned to study treatment.</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="51"/>
                <count group_id="O3" value="142"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="657" lower_limit="391" upper_limit="NA">NA: Median or confidence limited not yet estimable.</measurement>
                    <measurement group_id="O2" value="183" lower_limit="140" upper_limit="445"/>
                    <measurement group_id="O3" value="NA" lower_limit="NA" upper_limit="NA">NA: Median or confidence limited not yet estimable.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B</title>
        <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment. The analysis was performed by using last observation carried forward (LOCF) method.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B</title>
          <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
          <population>FAS included all patients assigned to study treatment. The analysis was performed by using last observation carried forward (LOCF) method.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.50" lower_limit="40.50" upper_limit="52.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Value at Week 16</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="141"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.00" lower_limit="42.00" upper_limit="54.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Hodges-Lehmann-estimate was used to calculate change to Week 16 and 95% confidence interval.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Hodges-Lehmann-estimate</param_type>
            <param_value>1.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.5</ci_lower_limit>
            <ci_upper_limit>2.5</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B</title>
        <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
        <time_frame>Baseline up to the last patient has completed the 16 weeks of treatment</time_frame>
        <population>FAS included all patients assigned to study treatment. The analysis was performed by using last LOCF method.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Indolent NHL</title>
            <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
          </group>
        </group_list>
        <measure>
          <title>Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B</title>
          <description>HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table &quot;n&quot; signifies evaluable participants for the respective category.</description>
          <population>FAS included all patients assigned to study treatment. The analysis was performed by using last LOCF method.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="141"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="127.50" lower_limit="113.75" upper_limit="145.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Value at Week 16</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="141"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="130.83" lower_limit="113.00" upper_limit="146.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Hodges-Lehmann-estimate was used to calculate change to Week 16 and 95% confidence interval.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Hodges-Lehmann-estimate</param_type>
            <param_value>0.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.5</ci_lower_limit>
            <ci_upper_limit>3.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From start of study treatment up to 35 days after the last dose of study medication, with updated AE data from FEB 2017.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Part A: Indolent NHL/CLL</title>
          <description>Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia [iNHL/CLL] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="E2">
          <title>Part A: Aggressive NHL</title>
          <description>Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
        <group group_id="E3">
          <title>Part B: Indolent NHL</title>
          <description>Participants with indolent B-cell NHL received copanlisib 60 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.1)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="51"/>
                <counts group_id="E3" subjects_affected="74" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Autoimmune haemolytic anaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Aortic valve incompetence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Melaena</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Haemorrhoidal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="9" subjects_affected="9" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>General physical health deterioration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Multiple organ dysfunction syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholangitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Gallbladder obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteraemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Bronchopulmonary aspergillosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Cryptococcosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="19" subjects_affected="16" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumonia pneumococcal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumonia viral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Progressive multifocal leukoencephalopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Septic shock</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Tooth abscess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Rectal abscess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Sinusitis aspergillus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Corona virus infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Klebsiella bacteraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumonia fungal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Device related infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumocystis jirovecii pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumocystis jirovecii infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Systemic infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Afferent loop syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Diabetes mellitus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hypercalcaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="9" subjects_affected="7" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Groin pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Psoriatic arthropathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Myelodysplastic syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Plasma cell myeloma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Tumour flare</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Tumour compression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Disorientation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Obstructive uropathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Scrotal swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Interstitial lung disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lung disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="8" subjects_affected="6" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pulmonary congestion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pulmonary oedema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Organising pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis exfoliative</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Preoperative care</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arteriovenous fistula</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Circulatory collapse</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Thrombophlebitis superficial</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (19.1)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="50" subjects_at_risk="51"/>
                <counts group_id="E3" subjects_affected="138" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="21" subjects_affected="11" subjects_at_risk="33"/>
                <counts group_id="E2" events="13" subjects_affected="12" subjects_at_risk="51"/>
                <counts group_id="E3" events="36" subjects_affected="22" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="16" subjects_affected="8" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="9" subjects_at_risk="33"/>
                <counts group_id="E2" events="25" subjects_affected="15" subjects_at_risk="51"/>
                <counts group_id="E3" events="86" subjects_affected="37" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="24" subjects_affected="20" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="10" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="15" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="11" subjects_affected="8" subjects_at_risk="51"/>
                <counts group_id="E3" events="20" subjects_affected="18" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="65" subjects_affected="13" subjects_at_risk="33"/>
                <counts group_id="E2" events="39" subjects_affected="21" subjects_at_risk="51"/>
                <counts group_id="E3" events="86" subjects_affected="48" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="17" subjects_affected="10" subjects_at_risk="33"/>
                <counts group_id="E2" events="22" subjects_affected="18" subjects_at_risk="51"/>
                <counts group_id="E3" events="45" subjects_affected="33" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="21" subjects_affected="12" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="10" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="7" subjects_affected="5" subjects_at_risk="51"/>
                <counts group_id="E3" events="23" subjects_affected="19" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="8" subjects_at_risk="33"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="51"/>
                <counts group_id="E3" events="14" subjects_affected="11" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="13" subjects_affected="12" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="20" subjects_affected="16" subjects_at_risk="33"/>
                <counts group_id="E2" events="15" subjects_affected="14" subjects_at_risk="51"/>
                <counts group_id="E3" events="40" subjects_affected="36" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="51"/>
                <counts group_id="E3" events="16" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="13" subjects_affected="11" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="14" subjects_affected="10" subjects_at_risk="33"/>
                <counts group_id="E2" events="22" subjects_affected="8" subjects_at_risk="51"/>
                <counts group_id="E3" events="51" subjects_affected="34" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="9" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="51"/>
                <counts group_id="E3" events="19" subjects_affected="14" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="6" subjects_affected="5" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="11" subjects_affected="8" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Oral candidiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="7" subjects_affected="6" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="11" subjects_affected="8" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="33" subjects_affected="20" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="33"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="51"/>
                <counts group_id="E3" events="7" subjects_affected="7" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="12" subjects_affected="9" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="42" subjects_affected="2" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Eosinophil count increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="8" subjects_affected="7" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="15" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="19" subjects_affected="7" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="14" subjects_affected="11" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="9" subjects_affected="9" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="88" subjects_affected="21" subjects_at_risk="33"/>
                <counts group_id="E2" events="55" subjects_affected="27" subjects_at_risk="51"/>
                <counts group_id="E3" events="269" subjects_affected="69" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="51"/>
                <counts group_id="E3" events="10" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="11" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="10" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="51"/>
                <counts group_id="E3" events="15" subjects_affected="15" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="10" subjects_affected="10" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="18" subjects_affected="14" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="33"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="15" subjects_affected="11" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="33"/>
                <counts group_id="E2" events="12" subjects_affected="9" subjects_at_risk="51"/>
                <counts group_id="E3" events="21" subjects_affected="13" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="8" subjects_affected="8" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="12" subjects_affected="6" subjects_at_risk="33"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="51"/>
                <counts group_id="E3" events="37" subjects_affected="27" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="51"/>
                <counts group_id="E3" events="11" subjects_affected="11" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Dyspnoea exertional</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="11" subjects_affected="9" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="18" subjects_affected="13" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="10" subjects_affected="7" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="51"/>
                <counts group_id="E3" events="30" subjects_affected="13" subjects_at_risk="142"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="51"/>
                <counts group_id="E3" events="25" subjects_affected="14" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="93" subjects_affected="23" subjects_at_risk="33"/>
                <counts group_id="E2" events="82" subjects_affected="24" subjects_at_risk="51"/>
                <counts group_id="E3" events="183" subjects_affected="42" subjects_at_risk="142"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Contract Partners (PI) shall provide to Bayer any proposed publication or oral presentation relating to the Study or the Results (&quot;Publication&quot;) at least sixty (60) days prior to the intended submission or presentation of the Publication in order to allow Bayer to review it.&#xD;
If Bayer does not notify PI within forty-five (45) days of Bayer's receipt of the intended Publication, PI shall remind Bayer. If Bayer does not provide any comments within the sixty day period, PI shall be free to publish.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Therapeutic Area Head</name_or_title>
      <organization>Bayer</organization>
      <phone>+1-888-8422937</phone>
      <email>clinical-trials-contact@bayer.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01660451
org study id: 16349
secondary id: 2012-002602-52
nct id: NCT01660451
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The objective of the study (part A) is to evaluate the efficacy and safety of BAY80-6946 in
      patients with indolent or aggressive Non-Hodgkin's Lymphoma, who have progressed after
      standard therapy. 30 patients will be enrolled to both indolent and aggressive disease group.
      The objective of the study part B (CHRONOS-1) is to evaluate the efficacy and safety of
      BAY80-6946 in patients with relapsed/refractory follicular lymphoma. 120 patients will be
      enrolled in the part B of the study. Further objectives are to evaluate the pharmacokinetics
      and biomarkers. Quality of life will be a further objective of part B of the study.

      In a cohort of 20 patients (enrolled both in part A and B) an ECG substudy will be performed
      to assess the potential for cardiac toxicity and QT/QTc interval prolongation of BAY80-6946.

      After an up to 28-day screening period, eligible patients will start treatment with
      BAY80-6946 at a dose of 0.8 mg/kg (Part A) and at a dose of 60 mg (Part B).

      Treatment will be continued until disease has progressed or until another criterion is met
      for withdrawal from study. An end-of-treatment visit will be performed within 7 days after
      discontinuation of study treatment. Thirty to 35 days after last study drug administration, a
      safety followup visit will be performed for the collection of adverse events (AEs) and
      concomitant medication data. Patients will be contacted quarterly to determine overall
      survival status up to 4 years after last patient completed treatment. Patients who
      discontinue study drug for reasons other than disease progression will enter the Active
      Assessment Follow-up period. The end of study notification to Health Authorities will be
      based on the completion of the collection of survival data.

      The efficacy is measured by the decrease in tumor size. Tumor assessments will be done at
      Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months
      during Year 3. Blood samples will be collected for pharmacokinetic analysis. Archival tumor
      tissue and blood samples will be collected for biomarker analysis (mandatory) and for central
      pathology review (part B), fresh biopsy tissue will also be collected if available.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate (ORR) Based on Independent Review-Part A
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.
measure: Objective Response Rate (ORR) Based on Independent Review-Part B
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
measure: ORR Based on Investigator Assessment-Part A
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.
measure: ORR Based on Investigator Assessment-Part B
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
measure: Duration of Response (DOR) Based on Independent Review
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason "other" or "AE not related to disease progression.
measure: DOR Based on Investigator Assessment
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: Duration of response (DOR) was defined as the time (in days) from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease [PD], first clinical progression or first adverse event [AE] associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason "other" or "AE not related to disease progression.
measure: Progression Free Survival (PFS) Based on Independent Review
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
measure: PFS Based on Investigator Assessment
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
measure: Overall Survival (OS)
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause.
measure: Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table "n" signifies evaluable participants for the respective category.
measure: Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B
time frame: Baseline up to the last patient has completed the 16 weeks of treatment
description: HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table "n" signifies evaluable participants for the respective category.
arm group label: Copanlisib (indolent NHL)
arm group type: Experimental
description: Part A: Participants in this arm will be patients with indolent NHL.
arm group label: Copanlisib (aggressive NHL)
arm group type: Experimental
description: Part A: Participants in this arm will be patients with aggressive NHL.
arm group label: Copanlisib (indolent B-cell NHL)
arm group type: Experimental
description: Part B: Participants in this arm will be patients with indolent B-cell NHL.
intervention type: Drug
intervention name: Copanlisib (Aliqopa, BAY80-6946)
description: BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22).
Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded.
Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.
arm group label: Copanlisib (aggressive NHL)
arm group label: Copanlisib (indolent B-cell NHL)
arm group label: Copanlisib (indolent NHL)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bayer Study Director
role: Study Director
affiliation: Bayer
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country: Australia
country: Austria
country: Belgium
country: Bulgaria
country: Canada
country: Finland
country: France
country: Germany
country: Greece
country: Hong Kong
country: Hungary
country: Ireland
country: Israel
country: Italy
country: Korea, Republic of
country: New Zealand
country: Poland
country: Portugal
country: Russian Federation
country: Singapore
country: Spain
country: Sweden
country: Turkey
country: United Kingdom
country: United States
country: Chile
country: China
country: Colombia
country: Denmark
country: Japan
country: Luxembourg
country: Mexico
country: Peru
url: https://clinicaltrials.bayer.com/
description: Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.
citation: Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, Linton K, Thieblemont C, Vitolo U, Hiemeyer F, Giurescu M, Garcia-Vargas J, Gorbatchevsky I, Liu L, Koechert K, Pena C, Neves M, Childs BH, Zinzani PL. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017 Sep 1;28(9):2169-2178. doi: 10.1093/annonc/mdx289.
PMID: 28633365
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Non-Hodgkin
sharing ipd: No
ipd description: Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.
Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 