Clinical trial NCT03271541: A Study of Bitopertin (RO4917838) in Adults With Non-Transfusion-Dependent (NTD) Beta-Thalassemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Beta-Thalassemia
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-09-05
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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)

Primary outcomes:
measure: Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only
timeFrame: 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
timeFrame: Baseline to Week 16
measure: Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only
timeFrame: Baseline to 19 Months
Secondary outcomes:
measure: Apparent Clearance of Bitopertin
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: 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
timeFrame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Serum Lactate Dehydrogenase Level
timeFrame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Serum Bilirubin Level
timeFrame: Part 1: Baseline, Week 16. Part 2: Up to Week 65
measure: Change from Baseline in Absolute Red Blood Cell Count
timeFrame: 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
timeFrame: Baseline, 19 Months
Other outcomes:
Locations:
city: Genova
country: Italy
facility: Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia
state: Liguria
city: Milano
country: Italy
facility: Ospedale Maggiore di Milano; Cardio-Metabolic Diseases
state: Lombardia
city: Baabda
country: Lebanon
facility: Chronic Care Center
city: Bangkok Noi
country: Thailand
facility: Siriraj Hospital; Division of Haematology-Oncology
Study officials:
References:
citation: Taher AT, Viprakasit V, Cappellini MD, Kraus D, Cech P, Volz D, Winter E, Nave S, Dukart J, Khwaja O, Koerner A, Hermosilla R, Brugnara C. Haematological effects of oral administration of bitopertin, a glycine transport inhibitor, in patients with non-transfusion-dependent beta-thalassaemia. Br J Haematol. 2021 Jul;194(2):474-477. doi: 10.1111/bjh.17479. Epub 2021 Apr 30. No abstract available.