A Phase 3, Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Adults With Transfusion Dependent Beta (B)-Thalassemia

Celgene76 sites in 10 countries336 target enrollmentMay 2, 2016

ConditionsErythrocyte Transfusion Beta-Thalassemia

InterventionsLuspatercept Placebo

DrugsLuspatercept

Overview

Phase: Phase 3
Intervention: Luspatercept
Conditions: Erythrocyte Transfusion
Sponsor: Celgene
Enrollment: 336
Locations: 76
Primary Endpoint: Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
Status: Completed
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) plus Best supportive care (BSC) versus placebo plus BSC in adults who require regular red blood cell transfusion due to (β)-thalassemia.

The study is divided into the following periods:

Historical Period,
Screening/Run-in Period,
Double-blind Treatment Period (48 weeks),
Double-blind Long-term Treatment Period, (at the investigator's discretion an additional 48 weeks),
Open-Label Phase post unblinding and upon Data Monitoring Committee positive recommendation
Post-treatment Follow-up Period

Registry

clinicaltrials.gov

Start Date

May 2, 2016

End Date

January 5, 2021

Last Updated

3 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Celgene

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Subjects must satisfy the following criteria to be enrolled in the study:
•Male or female, ≥18 years of age at the time of signing the informed consent document (ICF).
•Subject must understand and voluntarily sign an Inform Consent Form prior to any study-related assessments/procedures being conducted.
•Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
•Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia. (β-thalassemia with mutation and/or multiplication of alpha globin is allowed).
•Regularly transfused, defined as: 6-20 Red Blood Cell (RBC) units\* in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.
•\* Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL. (i) sites who use transfusion bags within this range, or ≥ 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, (ii) sites who use transfusion bags \< 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.
•Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or
•A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:
•Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence \*\* from heterosexual contact.

Exclusion Criteria

•The presence of any of the following will exclude a subject from enrollment:
•Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
•Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
•Any condition that confounds the ability to interpret data from the study.
•A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H);
•Evidence of active hepatitis C (HCV) infection as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B as demonstrated by the presence of HBsAg and/or HBVDNA-positive,, or known positive human immunodeficiency virus (HIV).
•Note: Subjects receiving antiviral therapies should have 2 negative HCVRNA tests 3 months apart.(ie, one test at the end of the antiviral therapy and a second test 3 months following the first test).
•Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
•Use of chronic anticoagulant therapy is excluded, unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
•Platelet count \> 1000 x 109/L

Arms & Interventions

Luspatercept (ACE-536) plus Best Supportive Care (BSC)

Luspatercept, subcutaneous(ly) (SC) once every 21 days

Intervention: Luspatercept

Placebo plus Best Supportive Care (BSC)

normal saline solution subcutaneous(ly) (SC) once every 21 days

Intervention: Placebo

Outcomes

Primary Outcomes

Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24

Time Frame: Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

Erythroid Response was defined as red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Week 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.

Secondary Outcomes

Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48(Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48)
Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24(Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24)
Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24(Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24)
Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48(Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48)
Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48(Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48)
Number of Participants Who Utilized Healthcare Resources During Study(From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks))
Number of Days Spent in Higher Care Hospital Units(From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks))
Longest Duration of Transfusion Independence(From first dose through 3 weeks post last dose (up to approximately 218 weeks))
Time to Erythroid Response(From first dose to 48 weeks following first dose)
Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48(Baseline: Week -12 to Day -1; Treatment: Week 48)
Mean Change From Baseline In Mean Serum Ferritin At Week 48(Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48)
Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48(Baseline: Day 1; Treatment: Week 48)
Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24(Baseline: 4 weeks prior to Day 1; Treatment: Week 24)
Mean Change From Baseline In Myocardial Iron At Week 48(Baseline: Day 1; Treatment: Week 48)
Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment(From first dose through 3 weeks post last dose (up to approximately 218 weeks))
Duration of Reduction in Transfusion Burden(From first dose to end of study treatment (up to approximately 215 weeks))
Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24(Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24)
Post-Baseline Transfusion Event Frequency(From first dose through 3 weeks post last dose (up to approximately 218 weeks))
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)(Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337)
Participants With Treatment-Emergent Adverse Events (TEAE)(From first dose to 90 days following last dose (up to approximately 52 months))
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)(Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316)