Beta-Thalassemia
Conditions
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.
Interventions
DRUGBitopertin
Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
| 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 |
| Change from Baseline in Absolute Reticulocyte Count | Part 1: Baseline, Week 16. Part 2: Up to Week 65 |
| 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 |
Countries
Italy, Lebanon, Thailand
Outcome results
None listed