A Study of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent (NTD) Beta-Thalassemia

Study Overview
=================
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.

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

Conditions
-----------------
Beta-Thalassemia

Intervention / Treatment
-----------------
* Drug: Bitopertin


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bitopertin<br>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. | Drug: Bitopertin<br>* Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).<br>* Other names: RO4917838;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |