<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/NCT03271541</url>
  </required_header>
  <id_info>
    <org_study_id>BP39642</org_study_id>
    <secondary_id>2016-004799-23</secondary_id>
    <nct_id>NCT03271541</nct_id>
  </id_info>
  <brief_title>A Study of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent (NTD) Beta-Thalassemia</brief_title>
  <official_title>A Phase II, Single Arm, Multicenter, Proof-of-Mechanism Study to Investigate the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent Βeta-Thalassemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hoffmann-La Roche</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This proof-of-mechanism study is being performed to investigate the safety, tolerability,&#xD;
      efficacy, pharmacokinetics, and pharmacodynamics of multiple oral doses of bitopertin in&#xD;
      adults with NTD beta-thalassemia.&#xD;
&#xD;
      This study consists of two parts:&#xD;
&#xD;
      Part 1 - The main study - 16 weeks in total: Participants will undergo a 6-week&#xD;
      dose-escalation period followed by 10 weeks of treatment at the attained target dose.&#xD;
&#xD;
      Part 2 - Open Label Extension (OLE) - up to an additional 12 months. Participants will be&#xD;
      given the option to enroll into the OLE once the 16-week treatment of Part 1 has been&#xD;
      completed. Participants who decide not to enroll in the OLE, at the end of Part 1 will enter&#xD;
      a 6-week follow-up period.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 26, 2017</start_date>
  <completion_date type="Actual">June 29, 2018</completion_date>
  <primary_completion_date type="Actual">June 29, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only</measure>
    <time_frame>Baseline, Week 16, up to Week 22</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy Outcome: Change in Total Hemoglobin (Hb) Level from Baseline to End of 16-Week Treatment Period in Part 1</measure>
    <time_frame>Baseline to Week 16</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only</measure>
    <time_frame>Baseline to 19 Months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Apparent Clearance of Bitopertin</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of Distribution of Bitopertin</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Concentration-Time Curve (AUC) of Bitopertin within a Dosing Interval</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum Observed Concentration (Cmin) of Bitopertin</measure>
    <time_frame>Part 1: Predose (0 H) on Days 2, 15, 29, 57, 85, 113; and at early withdrawal (up to 22 weeks overall). Part 2: Predose (0 H) and postdose (1, 4 H) on Days 183, 365; and at early withdrawal (up to 65 weeks overall)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Observed Concentration (Cmax) of Bitopertin</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Elimination Half-Life of Bitopertin</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation Ratio of Bitopertin</measure>
    <time_frame>Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Absolute Reticulocyte Count</measure>
    <time_frame>Part 1: Baseline, Week 16. Part 2: Up to Week 65</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Serum Lactate Dehydrogenase Level</measure>
    <time_frame>Part 1: Baseline, Week 16. Part 2: Up to Week 65</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Serum Bilirubin Level</measure>
    <time_frame>Part 1: Baseline, Week 16. Part 2: Up to Week 65</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Absolute Red Blood Cell Count</measure>
    <time_frame>Part 1: Baseline, Week 16. Part 2: Up to Week 65</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Total Hb Level from Baseline to the End of the Treatment Period in Part 2</measure>
    <time_frame>Baseline, 19 Months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Beta-Thalassemia</condition>
  <arm_group>
    <arm_group_label>Bitopertin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 1 - The main study - 16 weeks in total:&#xD;
Participants will undergo a 6-week dose-escalation period followed by 10 weeks of treatment at the attained target dose of bitopertin.&#xD;
Part 2 - Open Label Extension (OLE) - up to an additional 12 months:&#xD;
Participants will be given the option to enroll into the OLE once the 16-week treatment of Part 1 has been completed.&#xD;
Participants who decide not to enroll in the OLE, at the end of Part 1 will enter a 6-week follow-up period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bitopertin</intervention_name>
    <description>Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).</description>
    <arm_group_label>Bitopertin</arm_group_label>
    <other_name>RO4917838</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed diagnosis of beta-thalassemia&#xD;
&#xD;
          -  Clinically defined non-transfusion-dependent anemia (Part 1 only), defined as Hb&#xD;
             concentrations &gt;7.5 grams per deciliter (g/dL) and &lt;9.5 g/dL, less than or equal to 4&#xD;
             transfusions of red blood cell units within 1 year prior to study enrollment, and no&#xD;
             transfusion within 12 weeks prior to study enrollment&#xD;
&#xD;
          -  Completion of 16 weeks of treatment with bitopertin in Part 1 of this study with more&#xD;
             than 80% compliance from expected use of study medication (based on patient diary and&#xD;
             study drug accountability; Part 2 only)&#xD;
&#xD;
          -  A favorable benefit-risk ratio from treatment with bitopertin as assessed by the&#xD;
             Investigator (Part 2 only)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any history of gene therapy&#xD;
&#xD;
          -  History of hemolytic anemia except for beta-thalassemia&#xD;
&#xD;
          -  Severe symptomatic splenomegaly and/or hepatomegaly with hypersplenism (Part 1 only)&#xD;
&#xD;
          -  Any use of an erythropoiesis-stimulating agent within 24 weeks prior to enrollment.&#xD;
&#xD;
          -  Initiation of iron chelation therapy or hydroxyurea within 24 weeks prior to&#xD;
             enrollment (Part 1 only)&#xD;
&#xD;
          -  Depression, treatment with anti-depressants, or other psychiatric illnesses and/or&#xD;
             drug abuse&#xD;
&#xD;
          -  Clinically significant/uncontrolled comorbid disease&#xD;
&#xD;
          -  Pregnant or breastfeeding females&#xD;
&#xD;
          -  Use of cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks or CYP3A4 inducers within 4&#xD;
             weeks prior to study drug&#xD;
&#xD;
          -  Active hepatitis B or C or known positive human immunodeficiency virus (HIV) test&#xD;
             result&#xD;
&#xD;
          -  Diagnosis of cancer within previous 5 years unless treatment has resulted in complete&#xD;
             freedom from disease for at least 2 years&#xD;
&#xD;
          -  Any major illness within 1 month or febrile illness within 1 week prior to study drug&#xD;
&#xD;
          -  Pulmonary hypertension requiring oxygen therapy (Part 1 only)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia</name>
      <address>
        <city>Genova</city>
        <state>Liguria</state>
        <zip>16128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Maggiore di Milano; Cardio-Metabolic Diseases</name>
      <address>
        <city>Milano</city>
        <state>Lombardia</state>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chronic Care Center</name>
      <address>
        <city>Baabda</city>
        <zip>1003</zip>
        <country>Lebanon</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siriraj Hospital; Division of Haematology-Oncology</name>
      <address>
        <city>Bangkok Noi</city>
        <zip>10700</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>Lebanon</country>
    <country>Thailand</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>September 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 5, 2017</study_first_posted>
  <last_update_submitted>October 4, 2018</last_update_submitted>
  <last_update_submitted_qc>October 4, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
  </condition_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/NCT03271541
org study id: BP39642
secondary id: 2016-004799-23
nct id: NCT03271541
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This proof-of-mechanism study is being performed to investigate the safety, tolerability,
      efficacy, pharmacokinetics, and pharmacodynamics of multiple oral doses of bitopertin in
      adults with NTD beta-thalassemia.

      This study consists of two parts:

      Part 1 - The main study - 16 weeks in total: Participants will undergo a 6-week
      dose-escalation period followed by 10 weeks of treatment at the attained target dose.

      Part 2 - Open Label Extension (OLE) - up to an additional 12 months. Participants will be
      given the option to enroll into the OLE once the 16-week treatment of Part 1 has been
      completed. Participants who decide not to enroll in the OLE, at the end of Part 1 will enter
      a 6-week follow-up period.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only
time frame: Baseline, Week 16, up to Week 22
measure: Efficacy Outcome: Change in Total Hemoglobin (Hb) Level from Baseline to End of 16-Week Treatment Period in Part 1
time frame: Baseline to Week 16
measure: Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only
time frame: Baseline to 19 Months
measure: Apparent Clearance of Bitopertin
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Volume of Distribution of Bitopertin
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Area Under the Concentration-Time Curve (AUC) of Bitopertin within a Dosing Interval
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Minimum Observed Concentration (Cmin) of Bitopertin
time frame: Part 1: Predose (0 H) on Days 2, 15, 29, 57, 85, 113; and at early withdrawal (up to 22 weeks overall). Part 2: Predose (0 H) and postdose (1, 4 H) on Days 183, 365; and at early withdrawal (up to 65 weeks overall)
measure: Maximum Observed Concentration (Cmax) of Bitopertin
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Apparent Elimination Half-Life of Bitopertin
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Accumulation Ratio of Bitopertin
time frame: Part 1: 2,12 hours (H) postdose (PD) on Day 1; 0 H predose (PRD) on Day 2; 0H PRD and 3H PD on Days 15,29,57; 0H PRD and 1,4H PD on Day 85; 0H PRD on Day 113; early withdrawal (ED) up to 22 wks. Part 2: 0H PRD and 1,4H PD on Days 183,365; ED up to 65 wks
measure: Change from Baseline in Absolute Reticulocyte Count
time frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Serum Lactate Dehydrogenase Level
time frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Serum Bilirubin Level
time frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Absolute Red Blood Cell Count
time frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change in Total Hb Level from Baseline to the End of the Treatment Period in Part 2
time frame: Baseline, 19 Months
arm group label: Bitopertin
arm group type: Experimental
description: Part 1 - The main study - 16 weeks in total:
Participants will undergo a 6-week dose-escalation period followed by 10 weeks of treatment at the attained target dose of bitopertin.
Part 2 - Open Label Extension (OLE) - up to an additional 12 months:
Participants will be given the option to enroll into the OLE once the 16-week treatment of Part 1 has been completed.
Participants who decide not to enroll in the OLE, at the end of Part 1 will enter a 6-week follow-up period.
intervention type: Drug
intervention name: Bitopertin
description: Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).
arm group label: Bitopertin
other name: RO4917838
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
country: Italy
country: Lebanon
country: Thailand
responsible party type: Sponsor
mesh term: Thalassemia
mesh term: beta-Thalassemia