A Study of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent (NTD) Beta-Thalassemia
- Registration Number
- NCT03271541
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 12
Inclusion Criteria
- Confirmed diagnosis of beta-thalassemia
- Clinically defined non-transfusion-dependent anemia (Part 1 only), defined as Hb concentrations >7.5 grams per deciliter (g/dL) and <9.5 g/dL, less than or equal to 4 transfusions of red blood cell units within 1 year prior to study enrollment, and no transfusion within 12 weeks prior to study enrollment
- Completion of 16 weeks of treatment with bitopertin in Part 1 of this study with more than 80% compliance from expected use of study medication (based on patient diary and study drug accountability; Part 2 only)
- A favorable benefit-risk ratio from treatment with bitopertin as assessed by the Investigator (Part 2 only)
Exclusion Criteria
- Any history of gene therapy
- History of hemolytic anemia except for beta-thalassemia
- Severe symptomatic splenomegaly and/or hepatomegaly with hypersplenism (Part 1 only)
- Any use of an erythropoiesis-stimulating agent within 24 weeks prior to enrollment.
- Initiation of iron chelation therapy or hydroxyurea within 24 weeks prior to enrollment (Part 1 only)
- Depression, treatment with anti-depressants, or other psychiatric illnesses and/or drug abuse
- Clinically significant/uncontrolled comorbid disease
- Pregnant or breastfeeding females
- Use of cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks or CYP3A4 inducers within 4 weeks prior to study drug
- Active hepatitis B or C or known positive human immunodeficiency virus (HIV) test result
- Diagnosis of cancer within previous 5 years unless treatment has resulted in complete freedom from disease for at least 2 years
- Any major illness within 1 month or febrile illness within 1 week prior to study drug
- Pulmonary hypertension requiring oxygen therapy (Part 1 only)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Bitopertin Bitopertin 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.
- Primary Outcome Measures
Name Time Method Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only Baseline, Week 16, up to Week 22 Efficacy Outcome: Change in Total Hemoglobin (Hb) Level from Baseline to End of 16-Week Treatment Period in Part 1 Baseline to Week 16 Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only Baseline to 19 Months
- Secondary Outcome Measures
Name Time Method Apparent Clearance of Bitopertin 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 Volume of Distribution of Bitopertin 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 Area Under the Concentration-Time Curve (AUC) of Bitopertin within a Dosing Interval 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 Minimum Observed Concentration (Cmin) of Bitopertin 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) Maximum Observed Concentration (Cmax) of Bitopertin 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 Apparent Elimination Half-Life of Bitopertin 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 Accumulation Ratio of Bitopertin 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 Change from Baseline in Absolute Reticulocyte Count Part 1: Baseline, Week 16. Part 2: Up to Week 65 Change from Baseline in Serum Lactate Dehydrogenase Level Part 1: Baseline, Week 16. Part 2: Up to Week 65 Change from Baseline in Serum Bilirubin Level Part 1: Baseline, Week 16. Part 2: Up to Week 65 Change from Baseline in Absolute Red Blood Cell Count Part 1: Baseline, Week 16. Part 2: Up to Week 65 Change in Total Hb Level from Baseline to the End of the Treatment Period in Part 2 Baseline, 19 Months
Trial Locations
- Locations (4)
Ospedale Maggiore di Milano; Cardio-Metabolic Diseases
🇮🇹Milano, Lombardia, Italy
Siriraj Hospital; Division of Haematology-Oncology
🇹ðŸ‡Bangkok Noi, Thailand
Chronic Care Center
🇱🇧Baabda, Lebanon
Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia
🇮🇹Genova, Liguria, Italy