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

NCT03271541 | Completed Phase 2

• 2 other identifiers: BP396422016-004799-23
• Study Type: interventional
• Target: 12
• Locations: 3 countries
• Sites: 4

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.

Conditions

Beta-Thalassemia

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (12)

• 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

Study Arms (1)

Bitopertin

EXPERIMENTAL

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

Interventions

Bitopertin DRUG

Bitopertin will be administered orally once daily at doses up to 120 milligrams (mg).

Also known as: RO4917838

Bitopertin

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (4)

Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia

Genoa, Liguria, 16128, Italy

Location

Ospedale Maggiore di Milano; Cardio-Metabolic Diseases

Milan, Lombardy, 20122, Italy

Location

Chronic Care Center

Baabda, 1003, Lebanon

Location

Siriraj Hospital; Division of Haematology-Oncology

Bangkok Noi, 10700, Thailand

Location

Related Publications (1)

• 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.

  PMID: 33931857 DERIVED

MeSH Terms

Conditions

beta-Thalassemia

Interventions

(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2017
• First Posted: September 5, 2017
• Study Start: October 26, 2017
• Primary Completion: June 29, 2018
• Study Completion: June 29, 2018
• Last Updated: October 5, 2018

Record last verified: 2018-10

Locations

TH (1); IT (2); LE (1)