<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/NCT01678430</url>
  </required_header>
  <id_info>
    <org_study_id>OMB114578</org_study_id>
    <secondary_id>2011-000919-22</secondary_id>
    <secondary_id>009988575</secondary_id>
    <nct_id>NCT01678430</nct_id>
  </id_info>
  <brief_title>A Trial Looking at Ofatumumab for People With Chronic Lymphocytic Leukaemia Who Cannot Have More Intensive Treatment</brief_title>
  <acronym>RIAltO</acronym>
  <official_title>A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liverpool</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Napp Pharmaceuticals Limited</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chugai Pharma USA</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Liverpool</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare ofatumumab &amp; chlorambucil (O-Chl) versus ofatumumab &amp;&#xD;
      bendamustine (O-B) in patients with Chronic Lymphocytic Leukaemia who are considered not fit&#xD;
      enough for rituximab, fludarabine &amp; cyclophosphamide (R-FC).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chlorambucil (Chl) has been the mainstay of CLL treatment for half a century. However,&#xD;
      frontline treatment has improved considerably over the last decade, first by the advent of&#xD;
      fludarabine plus cyclophosphamide (FC), and more recently by the addition of the anti-CD20&#xD;
      antibody, rituximab, to FC. Although FC-based regimens are considerably more effective than&#xD;
      Chl, they are also associated with greater toxicity which makes them inappropriate for less&#xD;
      fit patients. This is an important consideration, given that CLL predominantly affects older&#xD;
      people who tend to have more co-morbidity. Although a single-arm phase II study (Roche&#xD;
      MO20927; NCRI CLL208) has shown that R-Chl is safe and effective, there are no phase III data&#xD;
      proving the benefit of adding an anti-CD20 antibody to Chl. This question is currently being&#xD;
      addressed by a phase III RCT of Chl with or without ofatumumab (GSK OMB110911 / COMPLEMENT-1&#xD;
      / NCRI CLL7). Ofatumumab is a fully human anti-CD20 antibody that binds to an epitope&#xD;
      distinct from that of rituximab and produces more complement-dependent cytotoxicity. The&#xD;
      RIAltO trial is a direct follow-on to the NCRI CLL7 phase III RCT trial in less fit patients&#xD;
      and therefore the Ofatumumab dose has been selected to mirror the regimen used in that trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>December 2011</start_date>
  <completion_date type="Anticipated">December 2017</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>There are three pre-planned analyses of the PFS primary endpoint: end recruitment (approx 150 events); 300 events (after a minimum 12 months follow up for all patients), 400 events (after a minimum 24 months follow up for all patients)</time_frame>
    <description>Calculated from the date of randomisation to the date of progression or death, or the censor date.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>6 years (after 2 years follow up of the last patient recruited)</time_frame>
    <description>Response duration is defined as the time from when the criteria for partial or complete response are met until the first documentation of relapse or progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>6 years (after 2 year follow up of the last patient recruited)</time_frame>
    <description>Overall survival is defined as the time from initiation of study treatment to death, irrespective of cause or subsequent treatment. Patients still alive at the time of analysis will be censored at the date last seen alive at last follow up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure</measure>
    <time_frame>6 years (after 2 year follow up of the last patient recruited)</time_frame>
    <description>Time to treatment failure is defined as the time from initiation of study treatment to death, disease progression, or initiation of alternative treatment due to failure to achieve a complete or partial response to the study treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity</measure>
    <time_frame>6 years (after 2 years follow up of the last patient recruited)</time_frame>
    <description>Haematological toxicity will be reported in accordance with the 2008 NCI/IWCLL guidelines. Non-haematological toxicity will be reported in accordance with the current Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment dose administered</measure>
    <time_frame>5 years (assuming last patient in receives 12 cycles of treatment)</time_frame>
    <description>The number of cycles of treatment and cumulative dose of individual drugs administered will be summarised for each treatment group separately and compared across treatment groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>6 years (after 2 years follow up of the last patient recruited)</time_frame>
    <description>Quality of life will be assessed using the EQ-5D; EQ-VAS; EORTC QLQ-C30 and EORTC QLQ-CLL16 questionnaires. To standardise the raw scores, they will be linearly transformed into 0-to-100 scores.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health Economic analysis</measure>
    <time_frame>6 years (after 2 years follow up of the last patient recruited)</time_frame>
    <description>The economic evaluation will take the form of a cost-effectiveness analysis with the differential cost of the alternative treatments will be related to their differential benefits in terms of quality-adjusted life years (QALYs). Incremental cost-utility ratios will be estimated based on QALY estimates.&#xD;
A range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis.&#xD;
The use of bootstrapping and cost-effectiveness acceptability curves will facilitate a measure of variability around cost-effectiveness estimates. Sensitivity analysis will be used to consider the importance of sources of uncertainty other than sample variation (e.g. unit costs, discount rates).&#xD;
A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment cost-effectiveness.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of frailty and co-morbidity</measure>
    <time_frame>Baseline, 2 months post treatment</time_frame>
    <description>Patients outcomes will be compared across patient subgroups defined by CIRS, performance status, Vulnerable Elders Survey-13, Groningen Frailty Index (GFI) questionnaires and the Timed 'Up and Go' test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Predictive value of biomarkers</measure>
    <time_frame>Baseline, every 6 months until 42 months from study entry, disease progression</time_frame>
    <description>Patient outcomes will be compared across patient subgroups defined by clinical (e.g. age, sex, stage) and laboratory (e.g. chromosomal, abnormalities, IGHV mutation status, TP53 mutation status).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response</measure>
    <time_frame>Baseline; 2 months post treatment; 6 months post treatment</time_frame>
    <description>Response following initial therapy will be assessed in accordance with the revised (2008) NCI/IWCLL response criteria applicable to CLL. Minimal residual disease will be assessed by multicolour flow cytometric analysis of bone marrow aspirate samples taken 2 months after completing treatment and of blood samples taken 2 and 6 months after completing treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">670</enrollment>
  <condition>Chronic Lymphocytic Leukaemia</condition>
  <arm_group>
    <arm_group_label>Ofatumumab-Chlorambucil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Chlorambucil: 10mg/m2 po days 1-7</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ofatumumab-Bendamustine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Bendamustine: 70mg/m2 iv days 1 and 2</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ofatumumab</intervention_name>
    <arm_group_label>Ofatumumab-Bendamustine</arm_group_label>
    <arm_group_label>Ofatumumab-Chlorambucil</arm_group_label>
    <other_name>Arzerra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chlorambucil</intervention_name>
    <arm_group_label>Ofatumumab-Chlorambucil</arm_group_label>
    <other_name>Leukeran</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bendamustine</intervention_name>
    <arm_group_label>Ofatumumab-Bendamustine</arm_group_label>
    <other_name>Levact</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. CLL/SLL requiring treatment by NCI/IWCLL 2008 criteria. At least one of the following&#xD;
             criteria:&#xD;
&#xD;
               1. Progressive marrow failure as manifested by the development of, or worsening of,&#xD;
                  anaemia and/or thrombocytopenia.&#xD;
&#xD;
               2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic&#xD;
                  splenomegaly.&#xD;
&#xD;
               3. Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic&#xD;
                  lymphadenopathy.&#xD;
&#xD;
               4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period&#xD;
                  or lymphocyte doubling time (LDT) of less than 6 months.&#xD;
&#xD;
          2. No prior cytotoxic or targeted therapy for CLL&#xD;
&#xD;
          3. Full-dose R-FC considered inappropriate for at least one of the following reasons&#xD;
&#xD;
               1. Age 75 or greater&#xD;
&#xD;
               2. WHO performance status 2 or 3&#xD;
&#xD;
               3. Cardiac impairment (NYHA class II)&#xD;
&#xD;
               4. Respiratory impairment (bronchiectasis or moderate COPD)&#xD;
&#xD;
               5. Renal impairment (estimated Glomerular Filtration Rate (eGFR) 10-30 ml/min)&#xD;
&#xD;
               6. Any other significant co-morbidity or factor that makes R-FC inappropriate&#xD;
&#xD;
          4. Considered able to tolerate Chl at the dose used in the LRF CLL4 trial (10mg/m2 d1-7)&#xD;
&#xD;
          5. Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Neutrophil count less than 1.0 x 109/l or platelet count less than 50 x 109/l unless&#xD;
             due to CLL&#xD;
&#xD;
          2. Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia&#xD;
&#xD;
          3. Active infection&#xD;
&#xD;
          4. Seropositivity for HIV, HCV or HBV (surface antigen or and core antibody)&#xD;
&#xD;
          5. Severe renal impairment (eGFR less than 10ml/min)&#xD;
&#xD;
          6. Severe hepatic impairment (serum bilirubin more than twice the upper limit of normal)&#xD;
             unless due to CLL or Gilbert's syndrome.&#xD;
&#xD;
          7. Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od&#xD;
&#xD;
          8. Prior treatment with monoclonal antibody therapy within the last 3 months.&#xD;
&#xD;
          9. Yellow fever vaccination within 4 weeks prior to treatment start&#xD;
&#xD;
         10. Known hypersensitivity to ofatumumab, bendamustine or chlorambucil or any of their&#xD;
             excipients&#xD;
&#xD;
         11. CNS involvement with CLL&#xD;
&#xD;
         12. History of Richter transformation&#xD;
&#xD;
         13. Concomitant malignancies within the last 3 years except successfully treated&#xD;
             non-melanoma skin cancer or carcinoma in situ.&#xD;
&#xD;
         14. Major surgery within 28 days prior to randomisation&#xD;
&#xD;
         15. WHO performance status 4&#xD;
&#xD;
         16. Severe cardiac disease including unstable angina, acute myocardial infarction within&#xD;
             six months prior to randomization, congestive heart failure (NYHA III-IV), and&#xD;
             arrhythmia (excluding extra systoles or minor conduction abnormalities) unless&#xD;
             controlled by therapy.&#xD;
&#xD;
         17. Any serious underlying medical or psychological conditions, which could impair the&#xD;
             ability of the patient to participate in the trial or compromise ability to give&#xD;
             informed consent&#xD;
&#xD;
         18. Treatment within a clinical trial within 30 days prior to trial entry.&#xD;
&#xD;
         19. Adult patient under tutelage (not competent to sign informed consent).&#xD;
&#xD;
         20. Pregnant or lactating women.&#xD;
&#xD;
         21. Women of childbearing potential, including women whose last menstrual period was less&#xD;
             than one year prior to screening, unable or unwilling to use adequate contraception&#xD;
             from study start to one year after the last dose of protocol therapy. Adequate&#xD;
             contraception is defined as hormonal birth control, intrauterine device, double&#xD;
             barrier method or total abstinence.&#xD;
&#xD;
         22. Male subjects unable or unwilling to use adequate contraception methods from study&#xD;
             start to one year after the last dose of protocol therapy.&#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_contact>
    <last_name>Kathryn Marley</last_name>
    <phone>+44 151 895 5287</phone>
    <email>kathryn.marley@liv.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Countess of Chester Hospital</name>
      <address>
        <city>Chester</city>
        <state>Cheshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Salaheddin Tueger</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Derriford Hospital</name>
      <address>
        <city>Plymouth</city>
        <state>Devon</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Simon Rule</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Torbay Hospital</name>
      <address>
        <city>Torquay</city>
        <state>Devon</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Deborah Turner</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Bournemouth Hospital</name>
      <address>
        <city>Bournemouth</city>
        <state>Dorset</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Helen McCarthy</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dorset County Hospital</name>
      <address>
        <city>Dorchester</city>
        <state>Dorset</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Akeel Moosa</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Colchester General Hospital</name>
      <address>
        <city>Colchester</city>
        <state>Essex</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Mike Hamblin</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Basingstoke and North Hampshire Hospital</name>
      <address>
        <city>Basingstoke</city>
        <state>Hampshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Sylwia Simpson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Southampton General Hospital</name>
      <address>
        <city>Southampton</city>
        <state>Hampshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Andrew Duncombe</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Barnet and Chase Farm Hospitals</name>
      <address>
        <city>Enfield</city>
        <state>Hertfordshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Andres Virchis</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kent and Canterbury Hospital</name>
      <address>
        <city>Canterbury</city>
        <state>Kent</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Christopher Pocock</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Maidstone Hospital</name>
      <address>
        <city>Maidstone</city>
        <state>Kent</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Saad Rassam</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Princess Royal Hospital</name>
      <address>
        <city>Orpington</city>
        <state>Kent</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Corrine De Lord</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Woolwich</city>
        <state>London</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Corrine De Lord</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>West Middlesex University Hospital</name>
      <address>
        <city>Isleworth</city>
        <state>Middlesex</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Magda Alobaidi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ealing Hospital</name>
      <address>
        <city>Southall</city>
        <state>Middlesex</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Richard Kaczmarski</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hillingdon Hospital</name>
      <address>
        <city>Uxbridge</city>
        <state>Middlesex</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Richard Kaczmarski</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Belfast City Hospital</name>
      <address>
        <city>Belfast</city>
        <state>Northern Ireland</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Paul Kettle</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal United Hospital</name>
      <address>
        <city>Bath</city>
        <state>Somerset</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Christopher Knechtli</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Weston General Hospital</name>
      <address>
        <city>Weston-super-Mare</city>
        <state>Somerset</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Philip Robson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queens Hospital</name>
      <address>
        <city>Burton-upon-Trent</city>
        <state>Staffordshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Humayun Ahmad</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Gateshead</city>
        <state>Tyne and Wear</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Scott Marshall</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <state>West Midlands</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Paul Moss</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Bradford Royal Infirmary</name>
      <address>
        <city>Bradford</city>
        <state>West Yorkshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Adrian Williams</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Airdale General Hospital</name>
      <address>
        <city>Keighley</city>
        <state>West Yorkshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Chetan Patalappa</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>St James University Hospital</name>
      <address>
        <city>Leeds</city>
        <state>West Yorkshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Peter Hillmen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Salisbury District Hospital</name>
      <address>
        <city>Salisbury</city>
        <state>Wiltshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jonathan Cullis</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Arrowe Park Hospital</name>
      <address>
        <city>Upton</city>
        <state>Wirral</state>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Ranjit Dasgupta</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Liverpool Hospital</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Andrew Pettitt</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.controlled-trials.com/ISRCTN09988575/bendamustine</url>
    <description>ISRCTN</description>
  </link>
  <link>
    <url>http://cancerhelp.cancerresearchuk.org/trials/trials-search/a-trial-looking-ofatumumab-people-chronic-lymphocytic-leukaemia-who-cannot-have-more-intensive-treatment-rialto</url>
    <description>CancerHelp UK</description>
  </link>
  <verification_date>August 2012</verification_date>
  <study_first_submitted>August 30, 2012</study_first_submitted>
  <study_first_submitted_qc>September 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2012</study_first_posted>
  <last_update_submitted>October 12, 2012</last_update_submitted>
  <last_update_submitted_qc>October 12, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 15, 2012</last_update_posted>
  <keyword>Chronic Lymphocytic Leukaemia</keyword>
  <keyword>Less fit</keyword>
  <keyword>CD20 antibody</keyword>
  <keyword>Ofatumumab</keyword>
  <keyword>Chlorambucil</keyword>
  <keyword>Bendamustine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bendamustine Hydrochloride</mesh_term>
    <mesh_term>Chlorambucil</mesh_term>
    <mesh_term>Ofatumumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT01678430
org study id: OMB114578
secondary id: 2011-000919-22
secondary id: 009988575
nct id: NCT01678430
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this study is to compare ofatumumab & chlorambucil (O-Chl) versus ofatumumab &
      bendamustine (O-B) in patients with Chronic Lymphocytic Leukaemia who are considered not fit
      enough for rituximab, fludarabine & cyclophosphamide (R-FC).
Chlorambucil (Chl) has been the mainstay of CLL treatment for half a century. However,
      frontline treatment has improved considerably over the last decade, first by the advent of
      fludarabine plus cyclophosphamide (FC), and more recently by the addition of the anti-CD20
      antibody, rituximab, to FC. Although FC-based regimens are considerably more effective than
      Chl, they are also associated with greater toxicity which makes them inappropriate for less
      fit patients. This is an important consideration, given that CLL predominantly affects older
      people who tend to have more co-morbidity. Although a single-arm phase II study (Roche
      MO20927; NCRI CLL208) has shown that R-Chl is safe and effective, there are no phase III data
      proving the benefit of adding an anti-CD20 antibody to Chl. This question is currently being
      addressed by a phase III RCT of Chl with or without ofatumumab (GSK OMB110911 / COMPLEMENT-1
      / NCRI CLL7). Ofatumumab is a fully human anti-CD20 antibody that binds to an epitope
      distinct from that of rituximab and produces more complement-dependent cytotoxicity. The
      RIAltO trial is a direct follow-on to the NCRI CLL7 phase III RCT trial in less fit patients
      and therefore the Ofatumumab dose has been selected to mirror the regimen used in that trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival
time frame: There are three pre-planned analyses of the PFS primary endpoint: end recruitment (approx 150 events); 300 events (after a minimum 12 months follow up for all patients), 400 events (after a minimum 24 months follow up for all patients)
description: Calculated from the date of randomisation to the date of progression or death, or the censor date.
measure: Duration of response
time frame: 6 years (after 2 years follow up of the last patient recruited)
description: Response duration is defined as the time from when the criteria for partial or complete response are met until the first documentation of relapse or progression.
measure: Overall survival
time frame: 6 years (after 2 year follow up of the last patient recruited)
description: Overall survival is defined as the time from initiation of study treatment to death, irrespective of cause or subsequent treatment. Patients still alive at the time of analysis will be censored at the date last seen alive at last follow up.
measure: Time to treatment failure
time frame: 6 years (after 2 year follow up of the last patient recruited)
description: Time to treatment failure is defined as the time from initiation of study treatment to death, disease progression, or initiation of alternative treatment due to failure to achieve a complete or partial response to the study treatment.
measure: Toxicity
time frame: 6 years (after 2 years follow up of the last patient recruited)
description: Haematological toxicity will be reported in accordance with the 2008 NCI/IWCLL guidelines. Non-haematological toxicity will be reported in accordance with the current Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
measure: Treatment dose administered
time frame: 5 years (assuming last patient in receives 12 cycles of treatment)
description: The number of cycles of treatment and cumulative dose of individual drugs administered will be summarised for each treatment group separately and compared across treatment groups
measure: Quality of life
time frame: 6 years (after 2 years follow up of the last patient recruited)
description: Quality of life will be assessed using the EQ-5D; EQ-VAS; EORTC QLQ-C30 and EORTC QLQ-CLL16 questionnaires. To standardise the raw scores, they will be linearly transformed into 0-to-100 scores.
measure: Health Economic analysis
time frame: 6 years (after 2 years follow up of the last patient recruited)
description: The economic evaluation will take the form of a cost-effectiveness analysis with the differential cost of the alternative treatments will be related to their differential benefits in terms of quality-adjusted life years (QALYs). Incremental cost-utility ratios will be estimated based on QALY estimates.
A range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis.
The use of bootstrapping and cost-effectiveness acceptability curves will facilitate a measure of variability around cost-effectiveness estimates. Sensitivity analysis will be used to consider the importance of sources of uncertainty other than sample variation (e.g. unit costs, discount rates).
A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment cost-effectiveness.
measure: Analysis of frailty and co-morbidity
time frame: Baseline, 2 months post treatment
description: Patients outcomes will be compared across patient subgroups defined by CIRS, performance status, Vulnerable Elders Survey-13, Groningen Frailty Index (GFI) questionnaires and the Timed 'Up and Go' test.
measure: Predictive value of biomarkers
time frame: Baseline, every 6 months until 42 months from study entry, disease progression
description: Patient outcomes will be compared across patient subgroups defined by clinical (e.g. age, sex, stage) and laboratory (e.g. chromosomal, abnormalities, IGHV mutation status, TP53 mutation status).
measure: Response
time frame: Baseline; 2 months post treatment; 6 months post treatment
description: Response following initial therapy will be assessed in accordance with the revised (2008) NCI/IWCLL response criteria applicable to CLL. Minimal residual disease will be assessed by multicolour flow cytometric analysis of bone marrow aspirate samples taken 2 months after completing treatment and of blood samples taken 2 and 6 months after completing treatment.
arm group label: Ofatumumab-Chlorambucil
arm group type: Active Comparator
description: Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Chlorambucil: 10mg/m2 po days 1-7
arm group label: Ofatumumab-Bendamustine
arm group type: Experimental
description: Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Bendamustine: 70mg/m2 iv days 1 and 2
intervention type: Drug
intervention name: Ofatumumab
arm group label: Ofatumumab-Bendamustine
arm group label: Ofatumumab-Chlorambucil
other name: Arzerra
intervention type: Drug
intervention name: Chlorambucil
arm group label: Ofatumumab-Chlorambucil
other name: Leukeran
intervention type: Drug
intervention name: Bendamustine
arm group label: Ofatumumab-Bendamustine
other name: Levact
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kathryn Marley
phone: +44 151 895 5287
email: kathryn.marley@liv.ac.uk
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
country: United Kingdom
url: http://www.controlled-trials.com/ISRCTN09988575/bendamustine
description: ISRCTN
url: http://cancerhelp.cancerresearchuk.org/trials/trials-search/a-trial-looking-ofatumumab-people-chronic-lymphocytic-leukaemia-who-cannot-have-more-intensive-treatment-rialto
description: CancerHelp UK
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Bendamustine Hydrochloride
mesh term: Chlorambucil
mesh term: Ofatumumab