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

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

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.

Study Overview

• Status: Completed
• Conditions: Beta-Thalassemia
• Intervention / Treatment: Drug: Bitopertin

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Liguria
    • Genova, Liguria, Italy, 16128
      • Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Ospedale Maggiore di Milano; Cardio-Metabolic Diseases
• Lebanon
  • Baabda, Lebanon, 1003
    • Chronic Care Center
• Thailand
  • Bangkok Noi, Thailand, 10700
    • Siriraj Hospital; Division of Haematology-Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Bitopertin; Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).; Other Names: RO4917838

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2017
• Primary Completion (Actual): June 29, 2018
• Study Completion (Actual): June 29, 2018

Study Registration Dates

• First Submitted: September 1, 2017
• First Submitted That Met QC Criteria: September 1, 2017
• First Posted (Actual): September 5, 2017

Study Record Updates

• Last Update Posted (Actual): October 5, 2018
• Last Update Submitted That Met QC Criteria: October 4, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: BP39642; 2016-004799-23 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No