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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02604433




Registration number
NCT02604433
Ethics application status
Date submitted
21/10/2015
Date registered
13/11/2015
Date last updated
27/01/2020

Titles & IDs
Public title
An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (ß) Thalassemia
Scientific title
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
Secondary ID [1] 0 0
ACE-536-B-THAL-001
Universal Trial Number (UTN)
Trial acronym
BELIEVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Erythrocyte Transfusion 0 0
Beta-Thalassemia 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Luspatercept
Other interventions - Placebo

Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC) - Luspatercept, subcutaneous(ly) (SC) once every 21 days

Placebo Comparator: Placebo plus Best Supportive Care (BSC) - normal saline solution subcutaneous(ly) (SC) once every 21 days


Treatment: Drugs: Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.

Other interventions: Placebo
Placebo, Subcutaneous, every 21 days.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants Who Achieved Erythroid Response From Week 13 to Week 24 (Data Cut-off Date: 11 May 2018) - 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. Transfusion records collected up to a minimum of (death date, study discontinuation date, last dose date + 20 days or 11 May 2018) were used for the analysis.
Timepoint [1] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [1] 0 0
Percentage Of Participants Who Achieve >=33% Reduction From Baseline in Transfusion Burden From Week 37 to Week 48 (Data Cut-off Date: 11 May 2018) - This hematological improvement outcome was defined as the percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline = 33% with a reduction of at least 2 units during Weeks 37 - 48 compared to the 12-week interval on or prior to Dose 1 Day 1. Transfusion records collected up to a minimum of (death date, study discontinuation date, last dose date + 20 days or 11 May 2018) were used for the analysis.
Timepoint [1] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48
Secondary outcome [2] 0 0
Percentage Of Participants Who Achieve >=50% Reduction From Baseline in Transfusion Burden From Week 13 to Week 24 (Data Cut-off Date: 11 May 2018) - This hematological improvement outcome was defined as the percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline = 50% with a reduction of at least 2 units during Weeks 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1. Transfusion records collected up to a minimum of (death date, study discontinuation date, last dose date + 20 days or 11 May 2018) were used for the analysis.
Timepoint [2] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [3] 0 0
Percentage Of Participants Who Achieve >=50% Reduction From Baseline in Transfusion Burden From Week 37 to Week 48 (Data Cut-off Date: 11 May 2018) - This hematological improvement outcome was defined as the percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline = 50% with a reduction of at least 2 units during Week 37 to Week 48 compared to the 12-week interval on or prior to Dose 1 Day 1. Transfusion records collected up to a minimum of (death date, study discontinuation date, last dose date + 20 days or 11 May 2018) were used for the analysis.
Timepoint [3] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [4] 0 0
Baseline Values and Mean Change From Baseline in Transfusion Burden (RBC Units) to the Fixed Week 13 to Week 24 Interval (Data Cut-off Date: 11 May 2018) - Baseline was defined as the total number of RBC units transfused during the 12-week interval on or prior to Dose 1 Day 1. This is compared to the total number of RBC units transfused during the 12-week interval from treatment weeks 13-24.
Timepoint [4] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [5] 0 0
Baseline Values and Mean Change From Baseline At Week 48 In Derived Liver Iron Concentration (LIC) By Magnetic Resonance Imaging (MRI) (Data Cut-off Date: 11 May 2018) - In ß-thalassemia adult patients who are transfused, iron overload occurs mainly as a result of accumulation of iron from transfusions and, to a lesser extent, increased intestinal absorption of iron due to hepcidin suppression. Baseline was defined as the last value on or before the first dose of study drug was administered; if multiple values were present for the same date, the average of these values was used. If a participant had 1 postbaseline assessment, it was used as the Week 48 value. If a participant had multiple postbaseline assessments, the last one was used as the Week 48 value. The value of LIC was either the value collected from the electronic case report form or the value derived from the T2*, R2*, or R2 parameter, depending on which techniques and software were used for magnetic resonance imaging LIC acquisition. Participants with an LIC value > 43 mg/g were not included in the analysis.
Timepoint [5] 0 0
Baseline: Week -12 to Day -1; Treatment: Week 48
Secondary outcome [6] 0 0
Baseline Values and Mean Change From Baseline At Week 48 In Mean Daily Dose Of Iron Chelation Therapies (ICT) Deferasirox, Deferiprone and Deferoxamine Mesilate/Deferoxamine (Data Cut-off Date: 11 May 2018) - This outcome tests the hypothesis that reducing the transfusion burden will likely reduce ICT daily dosage requirements, which will provide a number of benefits to the participants. The baseline mean daily dose was calculated using the ICT dosage during the 12 weeks prior to first study drug administration and the postbaseline mean daily dose was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or the last 12 weeks of the study treatment for early discontinued participants. DM/D = Deferoxamine Mesilate / Deferoxamine
Timepoint [6] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [7] 0 0
Baseline Values and Mean Change From Baseline At Week 48 In Mean Serum Ferritin (Data Cut-off Date: 11 May 2018) - For each participant, the baseline mean serum ferritin level was calculated during the 12 weeks prior to first study drug administration. The postbaseline mean serum ferritin level was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or last 12 weeks of study treatment, if discontinued early. The change was calculated as the difference of post baseline mean serum ferritin level and baseline mean serum ferritin level.
Timepoint [7] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [8] 0 0
Baseline Values and Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48 By Dual Energy X-Ray Absorptiometry (DXA) (Data Cut-off Date: 11 May 2018) - For BMD, the lumbar spine and total hip were measured at baseline and 48 weeks by dual energy x-ray absorptiometry (DXA). Baseline was defined as the last value on or before the first dose of study drug is administered; if multiple values are present for the same date, the average of these values was used. If during the 48 week double-blinded treatment period, a participant has only one assessment, it is counted as 'Week 48' visit; if a participant has multiple assessments, the last one is used as 'Week 48' visit. The analysis was done on the population that had at least 2 measurements.
Timepoint [8] 0 0
Baseline: Day 1; Treatment: Week 48
Secondary outcome [9] 0 0
Baseline Values and Mean Change From Baseline In Myocardial Iron By T2* Magnetic Resonance Imaging (MRI) at Week 48 (Data Cut-off Date: 11 May 2018) - MRI parameter T2* (Unit: ms) is considered as the most reliable way to assess cardiac iron overload and heart failure (HF) risk compared to other methods in Beta-Thalassemia patients, clinical management being nowadays based on it (e.g. T2*<6ms: high HF risk)
Timepoint [9] 0 0
Baseline: Day 1; Treatment: Week 48
Secondary outcome [10] 0 0
Baseline Values and Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire Total Score at Weeks 24 and 48 - The TranQol is a disease-specific, self-administered, well-validated health-related quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 36 questions assessed on a 5-point response, that are grouped into 5 domains (Physical Health, Emotional Health, Sexual Health, Family Functioning, School/Career Functioning). Scores are calculated according to author's guidelines and scoring rules. The total score ranges from 0 (worst) to 100 (best). The TranQoL was considered completed at a given visit when = 75% of all items were answered (ie, = 27 items of the 36 items or a nonmissing total score). Positive change from baseline values indicate improvement.
Timepoint [10] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24 and 48
Secondary outcome [11] 0 0
Baseline Values and Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire Physical Health Domain at Weeks 24 and 48 (Data Cut-off Date: 11 May 2018) - The TranQol is a disease-specific, self-administered, well-validated health-related quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 10 questions concerning physical assessed on a 5-point response scale. Scores are calculated according to author's guidelines and scoring rules. The Physical Health Domain ranges from 0 (worst) to 100 (best). The TranQoL was considered completed at a given visit when = 75% of all items were answered (ie, = 27 items of the 36 items or a nonmissing total score). Positive change from baseline values indicate improvement.
Timepoint [11] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24 and 48
Secondary outcome [12] 0 0
Baseline Values and Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire Physical Functioning Domain at Weeks 24 and 48 (Data Cut-off Date: 11 May 2018) - The SF-36 is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. Survey items 3a-3j comprise the Physical Functioning domain which is reported here. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0-100 scale score for each health domain is further converted to normbased scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL, based on data from a nationally representative sample of adults from the US. The range of possible T-scores for the Physical Functioning domain is 19.26 - 57.54 and the minimally important differences between readings is considered 3.0. The completion of the SF-36 for a given visit was defined as = 50% of all items being answered (ie, = 18 items of the 36 items). Positive change from baseline values indicate improvement.
Timepoint [12] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24 and 48
Secondary outcome [13] 0 0
Baseline Values and Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire General Health Domain at Weeks 24 and 48 (Data Cut-off Date: 11 May 2018) - The SF-36 is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. Survey items 1, 11a-11d comprise the General Health domain which is reported here. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0-100 scale score for each health domain is further converted to norm-based scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL, based on data from a nationally representative sample of adults from the US. The range of possible T-scores for the General Health domain is 18.95 - 66.50 and the minimally important differences between readings is considered 2.0. The completion of the SF-36 for a given visit was defined as = 50% of all items being answered (ie, = 18 items of the 36 items). Positive change from baseline values indicate improvement.
Timepoint [13] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24 and 48
Secondary outcome [14] 0 0
Baseline Values and Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire Physical Component Summary at Weeks 24 and 48 (Data Cut-off Date: 11 May 2018) - The SF-36 is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. The Physical Component Summary is one of two summary scales that summarize information from the 8 health scales. This information is also converted to norm-based scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL, based on data from a nationally representative sample of adults from the US. The range of possible T-scores for the Physical Component Summary is 5.02 - 79.78 and the minimally important differences between readings is considered 2.0. The completion of the SF-36 for a given visit was defined as = 50% of all items being answered (ie, = 18 items of the 36 items). Positive change from baseline values indicate improvement.
Timepoint [14] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24 and 48
Secondary outcome [15] 0 0
Percentage of Participants Who Utilized Healthcare Resources During Treatment [Healthcare Resource Utilization (HRU)] (Data Cut-off Date: 11 May 2018) - Percentage of participants who had a doctor office visit (non-study scheduled), or emergency room visit, or a hospitalization after signing informed consent.
Timepoint [15] 0 0
HRU data is collected continuously from Week-12 (informed consent) up to 9 weeks post last dose. Up to data cutoff date of 11 May 2018 (48 weeks post last participant enrolled day 1), median exposure is 64.1 weeks (Q1,Q3:52.5,70.0; Min, Max: 3,97)
Secondary outcome [16] 0 0
Number of Days in Higher Care Hospital Units; [Healthcare Resource Utilization (HRU)] (Data Cut-off Date: 11 May 2018) - Types of hospitals units considered to be 'higher care' are - Intensive Care Unit - Coronary Care Unit
Timepoint [16] 0 0
HRU data is collected continuously from Week-12 (informed consent) up to 9 weeks post last dose. Up to data cutoff date of 11 May 2018 (48 weeks post last participant enrolled day 1), median exposure is 64.1 weeks (Q1,Q3:52.5,70.0; Min, Max: 3,97)
Secondary outcome [17] 0 0
Percentage Of Participants Who Were Transfusion Independent For = 8 Weeks During Treatment (Data Cut-off Date: 11 May 2018) - Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, i.e, Days 1 to 56, Days 2 to 57 and so on. Participants discontinued from double-blind treatment for lack of therapeutic effect or with less than 56 days of assessment during the double-blind treatment period were counted as nonresponders. Transfusion records were collected up to a minimum of (death date, or study discontinuation date, or last dose date + 20 days, or 11 May 2018) were used for the analysis.
Timepoint [17] 0 0
Transfusion data is collected continuously at week (wk) -24 (12 weeks pre ICF) up to 9 wks post last dose. Efficacy cutoff = defined as: death, study discontinuation, last dose+20, 11 May 18; median exposure is 64.1 wks (Q1, Q3: 52.5,70.0; Min, Max: 3,97)
Secondary outcome [18] 0 0
Mean Duration of Reduction in Transfusion Burden In Participants With a >= 33% Reduction and >=50% Reduction in Red Blood Cell (RBC) Transfusion Burden During Any Rolling 12-week Interval Up to the Efficacy Cutoff Date (11 May 2018) - The duration of response was defined as Last Day of Response - First Day of Response + 1. For participants who continued to respond at the efficacy cutoff, the end day of the response was censored at the date of efficacy cutoff and the duration of response was calculated as date of efficacy cutoff - first day of response + 1 day. The efficacy cutoff date was defined as the minimum date among death date, study discontinuation date, last dose date + 20, and 11 May 2018. The response of transfusion burden reduction was assessed based on rolling method.
Timepoint [18] 0 0
Transfusion data is collected continuously at week (wk) -24 (12 weeks pre ICF) up to 9 wks post last dose. Efficacy cutoff = defined as: death, study discontinuation, last dose+20, 11 May 18; median exposure is 64.1 wks (Q1, Q3: 52.5,70.0; Min, Max: 3,97)
Secondary outcome [19] 0 0
Kaplan-Meier Estimates for Duration of Transfusion Independence in Participants Who Were Transfusion Independent For = 8 Weeks (Data Cut-off Date: 11 May 2018) - Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, ie, Days 1 to 56, Days 2 to 57 and so on. Participants discontinued from double-blind treatment for lack of therapeutic effect or with less than 56 days of assessment during the double-blind treatment period were counted as nonresponders.
Timepoint [19] 0 0
Transfusion data is collected continuously at week (wk) -24 (12 weeks pre ICF) up to 9 wks post last dose. Efficacy cutoff = defined as: death, study discontinuation, last dose+20, 11 May 18; median exposure is 64.1 wks (Q1, Q3: 52.5,70.0; Min, Max: 3,97)
Secondary outcome [20] 0 0
Time to Erythroid Response in Participants With = 33% Reduction and = 50% Reduction in RBC Transfusion Burden (Data Cut-off Date: 11 May 2018) - Time to erythroid response was defined as the time from first dose of the study drug to first erythroid response. This is reported for participants with a = 33% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval., as well as participants with a = 50% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval.
Timepoint [20] 0 0
Transfusion data is collected continuously at week (wk) -24 (12 weeks pre ICF) up to 9 wks post last dose. Efficacy cutoff = defined as: death, study discontinuation, last dose+20, 11 May 18; median exposure is 64.1 wks (Q1, Q3: 52.5,70.0; Min, Max: 3,97)
Secondary outcome [21] 0 0
Post-Baseline Transfusion Event Frequency (Data Cut-off Date: 11 May 2018) - The number of transfusion events were evaluated, as these relate directly to hours or days devoted to receiving RBC transfusions that can impact patients' quality of life. For the definition of transfusion events, if multiple transfusions happen on the same date, they are counted as one event; if multiple transfusions happen on two consecutive dates, they are counted as one event; if multiple transfusions happen on three consecutive dates, they are counted as two events. Events are counted while on while on treatment inclusive of 3 weeks after the last treatment.
Timepoint [21] 0 0
Transfusion data is collected continuously at week (wk) -24 (12 weeks pre ICF) up to 9 wks post last dose. Efficacy cutoff = defined as: death, study discontinuation, last dose+20, 11 May 18; median exposure is 64.1 wks (Q1, Q3: 52.5,70.0; Min, Max: 3,97)
Secondary outcome [22] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F) (Data Cut-off Date: 11 May 2018)
Timepoint [22] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [23] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F) (Data Cut-off Date: 11 May 2018)
Timepoint [23] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [24] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2) (Data Cut-off Date: 11 May 2018)
Timepoint [24] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [25] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax) (Data Cut-off Date: 11 May 2018)
Timepoint [25] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [26] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) (Data Cut-off Date: 11 May 2018)
Timepoint [26] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [27] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss) (Data Cut-off Date: 11 May 2018)
Timepoint [27] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [28] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss) (Data Cut-off Date: 11 May 2018)
Timepoint [28] 0 0
Blood serum samples taken pre-dose on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337. Blood serum samples also taken on Days 135 and 142 (Days 8 + 15 after Dose 6)
Secondary outcome [29] 0 0
Participants With Treatment-Emergent Adverse Events (TEAE) (Data Cut-off Date: 11 May 2018) - An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A TEAE includes AEs between the first dose date of either study drug and 90 days after the last dose of study drug. A serious AE is any AE occurring at any dose that - Results in death - Is life-threatening - Requires or prolongs existing inpatient hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death
Timepoint [29] 0 0
Day 1 up to 97 weeks (maximum treatment as of data cut-off date)
Secondary outcome [30] 0 0
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) (Data Cut-off Date: 11 May 2018) - Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as "treatment-emergent" if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer = 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as "preexisting" if the baseline sample was ADA positive and the participant was not qualified for "treatment-emergent."
Timepoint [30] 0 0
Timeframe: predose Day 1, Days 22, 64, 106, 148, 232, 316

Eligibility
Key inclusion criteria
Subjects must satisfy the following criteria to be enrolled in the study:

1. Male or female, =18 years of age at the time of signing the informed consent document
(ICF).

2. Subject must understand and voluntarily sign an Inform Consent Form prior to any
study-related assessments/procedures being conducted.

3. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.

4. Documented diagnosis of ß-thalassemia or Hemoglobin E/ß-thalassemia. (ß-thalassemia
with mutation and/or multiplication of alpha globin is allowed).

5. 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.

6. Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.

7. 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:

1. 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.

2. Either commit to true abstinence** from heterosexual contact (which must be
reviewed on a monthly basis and source documented) If a FCBP engages in sexual
activity that may result in a pregnancy, she must agree to use, and be able to
comply with, effective*** contraception without interruption, 28 days prior to
starting investigational product, during the study therapy (including dose
interruptions), and for 12 weeks (approximately five times the mean terminal
half-life of luspatercept based on multiple-dose Pharmacokinetic PK) data) after
discontinuation of study therapy.

- True abstinence is acceptable when this is in line with the preferred and
usual lifestyle of the subject. [Periodic abstinence (eg, calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.] *** Agreement to use highly effective
methods of contraception that alone or in combination result in a failure
rate of a Pearl index of less than 1% per year when used consistently and
correctly throughout the course of the study.

Such methods include: Combined (estrogen and progesterone/progestin containing)
hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only
hormonal contraception associated with inhibition of ovulation: Oral; Injectable
hormonal contraception; Implantable hormonal contraception; Placement of an
intrauterine device (IUD); Placement of an intrauterine hormone-releasing system
(IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

8. Male subjects must:

- Practice true abstinence or agree to use a condom during sexual contact with a
pregnant female or a female of childbearing potential while participating in the
study, during dose interruptions and for at least 12 weeks (approximately five
times the mean terminal half-life of luspatercept based on multiple-dose PK data)
following investigational product discontinuation, even if he has undergone a
successful vasectomy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The presence of any of the following will exclude a subject from enrollment:

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from participating in the study.

2. Any condition including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.

3. Any condition that confounds the ability to interpret data from the study.

4. A diagnosis of Hemoglobin S/ß-thalassemia or alpha (a)-thalassemia (eg, Hemoglobin H);

5. 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).

6. Deep Vein Thrombosis (DVT) or stroke requiring medical intervention = 24 weeks prior
to randomization.

7. 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.

8. Platelet count > 1000 x 109/L

9. Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined
by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic
cardiovascular complications (eg, stroke or myocardial infarction).

10. Treatment with another investigational drug or device = 28 days prior to
randomization.

11. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).

12. Use of an erythropoiesis-stimulating agent (ESA) = 24 weeks prior to randomization.

13. Iron chelation therapy, if initiated = 24 weeks prior to randomization (allowed if
initiated > 24 weeks before or during treatment).

14. Hydroxyurea treatment = 24 weeks prior to randomization.

15. Pregnant or lactating females.

16. Uncontrolled hypertension. Controlled hypertension for this protocol is considered =
Grade 1 according to NCI Common Terminology Criteria for Adverse Events (CTCAE)
version 4.0 (current active minor version).

17. Major organ damage, including:

1. Liver disease with alanine aminotransferase (ALT) > 3 x the upper limit of normal
(ULN) or history of evidence of cirrhosis;

2. Heart disease, heart failure as classified by the New York Heart Association
(NYHA) classification 3 or higher, or significant arrhythmia requiring treatment,
or recent myocardial infarction within 6 months of randomization.

3. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are
clinically significant ie, = Grade 3 NCI CTCAE version 4.0 (current active minor
version).

4. Creatinine clearance < 60 mL/min (per Cockroft-Gault formula).

18. Proteinuria = Grade 3 according to NCI CTCAE version 4.0 (current active minor
version).

19. Chronic systemic glucocorticoids = 12 weeks prior to randomization (physiologic
replacement therapy for adrenal insufficiency is allowed). Single day glucocorticoid
treatment (eg, for prevention or treatment of transfusion reactions, is allowed).

20. Major surgery = 12 weeks prior to randomization (subjects must have completely
recovered from any previous surgery prior to randomization).

21. History of severe allergic or anaphylactic reactions or hypersensitivity to
recombinant proteins or excipients in the investigational product (see Investigator
Brochure).

22. Cytotoxic agents, immunosuppressants = 28 days prior to randomization (ie,
antithymocite globulin (ATG) or cyclosporine)

23. History of malignancy with the exception of:

1. Curatively resected nonmelanoma skin cancer.

2. Curatively treated cervical carcinoma in situ.

3. Other solid tumor with no known active disease in the opinion of the
investigator.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [2] 0 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [3] 0 0
Royal Adelaide Hospital Institute of Medical and Veterinary Science - Adelaide
Recruitment hospital [4] 0 0
Monash Medical Centre - Clayton
Recruitment hospital [5] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [6] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3168 - Clayton
Recruitment postcode(s) [5] 0 0
6009 - Nedlands
Recruitment postcode(s) [6] 0 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Pennsylvania
Country [6] 0 0
Bulgaria
State/province [6] 0 0
Plovdiv
Country [7] 0 0
Bulgaria
State/province [7] 0 0
Sofia
Country [8] 0 0
Bulgaria
State/province [8] 0 0
Varna
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
France
State/province [10] 0 0
Creteil
Country [11] 0 0
France
State/province [11] 0 0
Lille
Country [12] 0 0
France
State/province [12] 0 0
Marseille Cedex 9
Country [13] 0 0
France
State/province [13] 0 0
Paris
Country [14] 0 0
Greece
State/province [14] 0 0
Ampelokipi - Athens
Country [15] 0 0
Greece
State/province [15] 0 0
Athens
Country [16] 0 0
Greece
State/province [16] 0 0
Rio Patras
Country [17] 0 0
Greece
State/province [17] 0 0
Thessaloniki
Country [18] 0 0
Israel
State/province [18] 0 0
Beer Sheva
Country [19] 0 0
Israel
State/province [19] 0 0
Haifa
Country [20] 0 0
Israel
State/province [20] 0 0
Haïfa (Afula)
Country [21] 0 0
Israel
State/province [21] 0 0
Jerusalem
Country [22] 0 0
Israel
State/province [22] 0 0
Nahariya
Country [23] 0 0
Israel
State/province [23] 0 0
Petah Tikva
Country [24] 0 0
Italy
State/province [24] 0 0
Brindisi
Country [25] 0 0
Italy
State/province [25] 0 0
Cagliari
Country [26] 0 0
Italy
State/province [26] 0 0
Ferrara
Country [27] 0 0
Italy
State/province [27] 0 0
Genoa
Country [28] 0 0
Italy
State/province [28] 0 0
Milan
Country [29] 0 0
Italy
State/province [29] 0 0
Naples
Country [30] 0 0
Italy
State/province [30] 0 0
Napoli
Country [31] 0 0
Italy
State/province [31] 0 0
Orbassano
Country [32] 0 0
Italy
State/province [32] 0 0
Palermo
Country [33] 0 0
Italy
State/province [33] 0 0
Verona
Country [34] 0 0
Lebanon
State/province [34] 0 0
Beirut
Country [35] 0 0
Malaysia
State/province [35] 0 0
Johor
Country [36] 0 0
Malaysia
State/province [36] 0 0
Kedah
Country [37] 0 0
Malaysia
State/province [37] 0 0
Perak
Country [38] 0 0
Malaysia
State/province [38] 0 0
Sabah
Country [39] 0 0
Malaysia
State/province [39] 0 0
Sarawak
Country [40] 0 0
Malaysia
State/province [40] 0 0
Wilayah Persekutuan Kuala Lumpur
Country [41] 0 0
Malaysia
State/province [41] 0 0
Georgetown
Country [42] 0 0
Taiwan
State/province [42] 0 0
Changhua City
Country [43] 0 0
Taiwan
State/province [43] 0 0
Kaohsiung
Country [44] 0 0
Taiwan
State/province [44] 0 0
Taichung
Country [45] 0 0
Taiwan
State/province [45] 0 0
Taipei, Zhongzheng Dist.
Country [46] 0 0
Thailand
State/province [46] 0 0
Bangkok
Country [47] 0 0
Thailand
State/province [47] 0 0
Chiang Mai
Country [48] 0 0
Tunisia
State/province [48] 0 0
Sousse
Country [49] 0 0
Tunisia
State/province [49] 0 0
Tunis
Country [50] 0 0
Turkey
State/province [50] 0 0
Adana
Country [51] 0 0
Turkey
State/province [51] 0 0
Ankara
Country [52] 0 0
Turkey
State/province [52] 0 0
Antalya
Country [53] 0 0
Turkey
State/province [53] 0 0
Istanbul
Country [54] 0 0
Turkey
State/province [54] 0 0
Izmir
Country [55] 0 0
Turkey
State/province [55] 0 0
Mersin
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Leeds
Country [57] 0 0
United Kingdom
State/province [57] 0 0
London Bloomsbury
Country [58] 0 0
United Kingdom
State/province [58] 0 0
London
Country [59] 0 0
United Kingdom
State/province [59] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Celgene
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Acceleron Pharma, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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
(ß)-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
Trial website
https://clinicaltrials.gov/show/NCT02604433
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jeevan Shetty, MBCh.B , FRCP
Address 0 0
Celgene Corporation
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications