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

Beta-Thalassemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03271541
• Other study ID #: BP39642
• Secondary ID: 2016-004799-23
• Status: Completed
• Phase: Phase 2
• Start date: October 26, 2017
• Est. completion date: June 29, 2018

Study information

• Verified date: October 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 29, 2018
• Est. primary completion date: June 29, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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)

Related Conditions & MeSH terms

• Beta-Thalassemia
• Thalassemia

Intervention

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

Locations

Country	Name	City	State
Italy	Centro della Microcitemia e delle Anemie Congenite - Ospedale Galliera; Oncologia /Cardiologia	Genova	Liguria
Italy	Ospedale Maggiore di Milano; Cardio-Metabolic Diseases	Milano	Lombardia
Lebanon	Chronic Care Center	Baabda
Thailand	Siriraj Hospital; Division of Haematology-Oncology	Bangkok Noi

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Italy,  Lebanon,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Outcome: Percentage of Participants with Adverse Events (AEs) - Part 1 only		Baseline, Week 16, up to Week 22
Primary	Efficacy Outcome: Change in Total Hemoglobin (Hb) Level from Baseline to End of 16-Week Treatment Period in Part 1		Baseline to Week 16
Primary	Long-term Safety Outcome : Percentage of Participants with Adverse Events (AEs) - Part 2 only		Baseline to 19 Months
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	Change from Baseline in Absolute Reticulocyte Count		Part 1: Baseline, Week 16. Part 2: Up to Week 65
Secondary	Change from Baseline in Serum Lactate Dehydrogenase Level		Part 1: Baseline, Week 16. Part 2: Up to Week 65
Secondary	Change from Baseline in Serum Bilirubin Level		Part 1: Baseline, Week 16. Part 2: Up to Week 65
Secondary	Change from Baseline in Absolute Red Blood Cell Count		Part 1: Baseline, Week 16. Part 2: Up to Week 65
Secondary	Change in Total Hb Level from Baseline to the End of the Treatment Period in Part 2		Baseline, 19 Months