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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 4
- 主要终点
- Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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)
研究组 & 干预措施
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.
干预措施: Bitopertin (Drug)
结局指标
主要结局
Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only
时间窗: 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
时间窗: Baseline to Week 16
Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only
时间窗: Baseline to 19 Months
次要结局
- 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)