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

• ClinicalTrials.gov Identifier: NCT03271541
• Recruitment Status: Completed
• First Posted: September 5, 2017
• Last Update Posted: October 5, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 1, 2017
• First Posted Date: September 5, 2017
• Last Update Posted Date: October 5, 2018
• Actual Study Start Date: October 26, 2017
• Actual Primary Completion Date: June 29, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 8, 2018)

• Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only [ Time Frame: 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 [ Time Frame: Baseline to Week 16 ]
• Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only [ Time Frame: Baseline to 19 Months ]

Original Primary Outcome Measures (submitted: September 1, 2017)

• Safety Outcome: Percentage of Participants with Adverse Events (AEs) [ Time Frame: Baseline to Week 22 ]
• Efficacy Outcome: Change in Total Hemoglobin (Hb) Level from Baseline to End of 16-Week Treatment Period [ Time Frame: Baseline, Week 16 ]

Current Secondary Outcome Measures (submitted: March 8, 2018)

• Apparent Clearance of Bitopertin [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65 ]
• Change from Baseline in Serum Lactate Dehydrogenase Level [ Time Frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65 ]
• Change from Baseline in Serum Bilirubin Level [ Time Frame: Part 1: Baseline, Week 16. Part 2: Up to Week 65 ]
• Change from Baseline in Absolute Red Blood Cell Count [ Time Frame: 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 [ Time Frame: Baseline, 19 Months ]

Original Secondary Outcome Measures (submitted: September 1, 2017)

• Apparent Clearance of Bitopertin [ Time Frame: Postdose (2, 12 hours [H]) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Volume of Distribution of Bitopertin [ Time Frame: Postdose (2, 12 H) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Area Under the Concentration-Time Curve (AUC) of Bitopertin within a Dosing Interval [ Time Frame: Postdose (2, 12 H) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Minimum Observed Concentration (Cmin) of Bitopertin [ Time Frame: Predose (0 H) on Days 2, 15, 29, 57, 85, 113; and at early withdrawal (up to 22 weeks overall) ]
• Maximum Observed Concentration (Cmax) of Bitopertin [ Time Frame: Postdose (2, 12 H) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Apparent Elimination Half-Life of Bitopertin [ Time Frame: Postdose (2, 12 H) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Accumulation Ratio of Bitopertin [ Time Frame: Postdose (2, 12 H) on Day 1; predose (0 H) on Day 2; predose (0 H) and postdose (3 H) on Days 15, 29, 57; predose (0 H) and postdose (1, 4 H) on Day 85; predose (0 H) on Day 113; and at early withdrawal (up to 22 weeks overall) ]
• Change from Baseline in Absolute Reticulocyte Count [ Time Frame: Baseline, Week 16 ]
• Change from Baseline in Serum Lactate Dehydrogenase Level [ Time Frame: Baseline, Week 16 ]
• Change from Baseline in Serum Bilirubin Level [ Time Frame: Baseline, Week 16 ]
• Change from Baseline in Absolute Red Blood Cell Count [ Time Frame: Baseline, Week 16 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Beta-Thalassemia

Intervention

Drug: Bitopertin

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

Other Name: RO4917838

Study Arms

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.

Intervention: Drug: Bitopertin

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 13, 2018): 12
• Original Estimated Enrollment (submitted: September 1, 2017): 16
• Actual Study Completion Date: June 29, 2018
• Actual Primary Completion Date: June 29, 2018 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Lebanon, Thailand

Administrative Information

• NCT Number: NCT03271541
• Other Study ID Numbers: BP39642; 2016-004799-23 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Hoffmann-La Roche
• Verification Date: October 2018