BEYOND: A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia

• Sponsor: Celgene (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03342404
• Collaborator: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
• Enrollment: 145
• Locations: 17
• Arms: 2
• Anticipated Duration (Months): 57.1
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in adults with non-transfusion dependent beta (β)-thalassemia. The study is divided into the Screening Period, Double-blind Treatment Period (DBTP) and Post-Treatment Follow-up Period (PTFP).

It is planned to randomize approximately 150 subjects at a 2:1 ratio of luspatercept versus placebo.

Condition or Disease	Intervention/Treatment	Phase
Thalassemia	Drug: Luspatercept; Other: Placebo; Other: Best Supportive Care (BSC)	Phase 2

Detailed Description

The primary objective is:

• To evaluate the effect of luspatercept in non-transfusion dependent β-thalassemia-patient versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval, from Week 13 to Week 24, compared to baseline.

The secondary objectives are:

• To evaluate the effect of luspatercept versus placebo on β-thalassemia related symptoms, as measured by non transfusion dependent β-thalassemia-patient reported outcome (NTDT-PRO) over a continuous 12-week intervals (from Weeks 13 to 24 and from Weeks 37 to

1. compared to baseline.

• To evaluate the effect of luspatercept versus placebo on functional and health-related quality of life (QoL) as measured by Medical Outcomes Study 36-Item Short Form (SF-36) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaires

• To evaluate the long-term effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval from Week 37 to Week 48, compared to baseline

• To evaluate the effect of luspatercept versus placebo on iron overload, as measured by liver iron concentration (LIC) and iron chelation therapy (ICT) daily dose

• To evaluate the effect of luspatercept versus placebo on iron overload, as measured by serum ferritin

• To evaluate the duration of erythroid response

• To evaluate the effect of luspatercept versus placebo on physical activity measured by 6-minute walk test (6MWT)

Safety and Pharmacokinetics (PK) Objectives

• To evaluate safety and tolerability of luspatercept, including immunogenicity

• To evaluate population pharmacokinetics (PK) of luspatercept in subjects with β- thalassemia

The exploratory objectives are:

• To evaluate the effect of luspatercept versus placebo on measures of extra-medullary hematopoietic (EMH) masses, bone mineral density, splenomegaly, pulmonary hypertension, and leg ulcers, when present

• To evaluate the effect of luspatercept versus placebo on the β-thalassemia severity as measured by the NTDT severity score system

• To examine the relationship of baseline and change in serum Growth Differentiation Factor 11 (GDF11) and other related biomarkers with response to treatment with luspatercept

• To examine the effect of luspatercept on fetal hemoglobin (HbF)

• To examine the effect of luspatercept on Health Resource Utilization (HRU)

Study Design

• Study Type: Interventional
• Actual Enrollment: 145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Adults With Non-Transfusion Dependent Beta (B)-Thalassemia
• Actual Study Start Date: Feb 1, 2018
• Actual Primary Completion Date: Sep 14, 2020
• Anticipated Study Completion Date: Nov 4, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC) Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days	Drug: Luspatercept; Subjects will start with luspatercept at 1 mg/kg dose level every 3 weeks and can be dose escalated up to 1.25 mg/kg.; Other Names: ACE-536 ; Other: Best Supportive Care (BSC); Best Supportive Care (BSC)
Placebo Comparator: Placebo plus Best Supportive Care (BSC) normal saline solution subcutaneous(ly) (SC) once every 21 days	Other: Placebo; Placebo, Subcutaneous, every 21 days; Other Names: normal saline ; Other: Best Supportive Care (BSC); Best Supportive Care (BSC)

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24) [From Week 13 to Week 24 of study treatment]

   Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 13 to 24 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.

Secondary Outcome Measures

1. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24) [Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment]

   The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the T/W Domain Score at baseline.

2. Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24) [From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)]

   Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.

3. Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48) [From Week 37 to Week 48 of study treatment]

   Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 37 to 48 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.

4. Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) [Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment]

   The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much"). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 13 to Week 24 is compared to the FS score at baseline (last score available before start of study treatment).

5. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24) [Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment]

   The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the SoB Domain Score at baseline.

6. Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48) [From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)]

   Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.

7. Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) [Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment]

   The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much"). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 37 to Week 48 is compared to the FS score at baseline (last score available before start of study treatment).

8. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 37 to Week 48) [Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment]

   The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the T/W Domain Score at baseline.

9. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 37 to Week 48) [Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment]

   The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the SoB Domain Score at baseline.

10. Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) [From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)]

    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose.

11. Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) [From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)]

    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose.

12. Mean Change From Baseline in the Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of the Medical Outcomes Study 36-Item Short Form (SF-36) [From baseline to Week 24 and from baseline to Week 48 of study treatment]

    The SF-36v2 is a 36-item generic PRO questionnaire used to assess patient-reported outcomes. The SF-36 yields scores for 8 domains of health: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH) as well as physical component summary (PCS) and mental component summary (MCS) scores. Scores from each of the 8 domains of health are first normalized based on US general population means, then aggregated and transformed (according to specific standardization formulas detailed in the Statistical Protocol Analysis), so that the scores from each of the 8 domains of health will contribute differently to the determination of PCS and MCS summary scores. PCS and MCS scores range from 0 to 100, with higher scores indicating a better quality of life.

13. Percentage of Participants With Improvement of Iron Overload [Week 24 and Week 48 of study treatment]

    Iron overload was measured by Liver Iron Concentration (LIC) and Iron Chelation Therapy (ICT) daily dose. Improvement is defined as: For participants with baseline LIC ≥3 mg/g: ≥20% reduction in LIC or ≥ 33% decrease in ICT daily dose For participants with baseline LIC <3 mg/g: no increase in LIC >1 mg/g and not starting treatment with ICT, or no increase in ICT daily dose ≥ 33% (if on ICT at baseline)

14. Mean Change From Baseline in Serum Ferritin [From baseline to Week 24 and from baseline to Week 48 of study treatment]

    Baseline mean serum ferritin is calculated during the 24 weeks on or prior to dose 1 day 1. Post-baseline mean serum ferritin is calculated as mean of ferritin values during the last 24 weeks on or prior to the end date of the first 24 week or 48 week treatment

15. Mean Change From Baseline in Liver Iron Concentration (LIC) [From baseline to Week 24 and from baseline to Week 48 of study treatment]

    LIC was measured by Magnetic Resonance Imaging (MRI). Baseline is defined as the last value on or before the first dose of study drug is administered; Postbaseline is defined as the closest visit at Week 24 or Week 48. Participants with LIC value >43 are not included in the analysis.

16. Percentage of Participants Who Are Transfusion-Free Over 24 Weeks [From start of treatment to 24 weeks following start of treatment]

    Transfusion free is defined as the absence of any transfusion during Week 1-24 of study treatment. Participants who discontinued treatment prior to Week 24 were not considered as transfusion free during Week 1-24.

17. Percentage of Participants Who Are Transfusion-Free Over 48 Weeks [From start of treatment to 48 weeks following start of treatment]

    Transfusion free is defined as the absence of any transfusion during Week 1-48 of study treatment. Participants who discontinued treatment prior to Week 48 were not considered as transfusion free during Week 1-48.

18. Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL [From first to last Hemoglobin measurement with increase from baseline ≥1.0 g/dL (up to approximately 20 months)]

    The duration of increase is defined as Last Day of mean hemoglobin increase by >=1.0g/dL - First Day of increase +1.

19. Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance [From baseline to Week 24 and from baseline to Week 48 of study treatment]

    The 6MWT is typically used to objectively assess functional exercise capacity and response to medical interventions in patients with various moderate to severe diseases. Subjects are asked to walk as quickly as possible without running along a 30-meter corridor for six minutes, and the total distance covered during that time is measured. Baseline is defined as the last value on or before the first dose of study drug is administered. Postbaseline is defined as the closest visit at Week 24 or Week 48.

20. Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion [From Week 13 to Week 24 of study treatment]

    Percentage of participants who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.

21. Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score [From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment]

    The RD for the NTDT-PRO T/W domain score was defined as ≥ 1-point decrease (ie, RD = -1) from baseline over the time from Week 13 to Week 24 or from Week 37 to Week 48. Subjects with missing NTDT-PRO T/W scores at the indicated 12-week period are classified as non-responders in the analysis.

22. Number of Participants Experiencing Adverse Events [From first dose to 63 days after last dose (up to approximately 50 months)]

    Number of participants experiencing different types (any grade) of adverse events

23. Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept [From first dose and up to 2 years following last dose]

    Presence of anti-drug (ACE-536/Luspatercept) antibodies was assessed every 24 weeks from serum samples. A participant is counted as 'positive' if there is any positive result captured during the study. A participant is counted as 'negative' if there is no positive result captured during the study.

24. Apparent Clearance (CL/F) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Apparent Clearance (CL/F) of Luspatercept

25. Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept

26. Time to Reach Maximum Concentration (Tmax) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Time to Reach Maximum Concentration (Tmax) of Luspatercept

27. Maximum Concentration (Cmax) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Maximum Concentration (Cmax) of Luspatercept

28. Maximum Concentration From Steady State (Cmax,ss) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Maximum Concentration From Steady State (Cmax,ss) of Luspatercept

29. Area Under the Curve From Steady State (AUCss) of Luspatercept [At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)]

    Area Under the Curve From Steady State (AUCss) of Luspatercept

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

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

1. Subjects must be ≥ 18 years of age at the time of signing the informed consent document (ICF).

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

3. Subject is willing and able to adhere to the study visit schedule (eg, not scheduled to receive hematopoietic stem cell transplantation) and other protocol requirements.

4. Subject must have documented diagnosis of β-thalassemia or hemoglobin E/ β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.

5. Subject must be non-transfusion dependent, defined as 0 to 5 units of RBCs received during the 24-week period prior to randomization. Note: 1 unit defined for this entry criterion as approximately 200 to 350 mL of transfused packed RBCs.

6. Subject must not be on a regular transfusion program and must be RBC transfusion-free for at least ≥ 8 weeks prior to randomization

7. Subject must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.

8. Subject must have performance status: Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.

9. 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). A FCBP participating in the study must:

1. Have 2 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 during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple dose pharmacokinetics [PK] data) after discontinuation of study therapy.

3. Male subjects must:

1. Practice true abstinence (which must be reviewed on a monthly basis) 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 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy

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. Diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg,Hemoglobin H).

5. Active hepatitis C (HCV) infection

6. Deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.

7. Subjects on chronic anticoagulant therapy are excluded, unless they stopped the treatment at least 28 days prior to randomization. Anticoagulant therapies for prophylaxis and for surgery or high-risk procedures as well as low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) and chronic aspirin are allowed before and during the study.

8. Treatment with another investigational drug or device ≤ 28 days prior to randomization.

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

10. Platelet count > 1000 x 109/L.

11. Subjects on iron chelation therapy (ICT) at the time of ICF signature must have initiated the treatment with ICT at least 24 weeks before the predicted randomization date. ICT can be initiated at any time during treatment and should be used according to the label.

12. Subject had Hydroxyurea and ESA treatment ≤ 24 weeks prior to randomization, and no prior gene therapy.

13. Subject is pregnant or a lactating female.

14. Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) version 4.0 (current active minor version).

15. Subject has major organ damage, including:

16. Liver disease with alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) or history/evidence of cirrhosis, as well as presence of masses/tumor detected by ultrasound at screening.

17. 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 (MI) within 6 months of randomization.

18. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie, ≥G3 NCI CTCAE version 4.0 (current active minor version).

19. Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 (per Modification of Diet in Renal Disease [MDRD] formula).

20. Subject has received chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed).

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

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

23. Subject has received immunosuppressants ≤ 28 days prior to randomization.

24. History or current malignancies (solid tumors and hematological malignancies) unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
2	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609
3	Ann & Robert H Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
4	Local Institution - 503	Chicago	Illinois	United States	60611
5	Laiko General Hospital of Athens	Athens		Greece	115 27
6	Aghia Sofia Children's Hospital	Athens		Greece	11527
7	Universita degli Studi di Cagliari - ASL8	Cagliari		Italy	09121
8	Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite	Genoa		Italy	16128
9	Fondazione Ca Granda IRCCS Ospedale Maggiore	Milan		Italy	20122
10	Seconda Universita Degli Studi Di Napoli	Naples		Italy	80131
11	AORN A Cardarelli	Napoli		Italy	80131
12	Azienda Ospedaliero Universitaria S. Luigi Gonzaga	Orbassano		Italy	10043
13	Local Institution - 301	Hazmieh		Lebanon	00961
14	Chronic Care Center	Hazmieh		Lebanon	1003
15	Local Institution - 401	Bangkok		Thailand	10700
16	Siriraj Hospital Mahidol University	Bangkok		Thailand	10700
17	University College London Hospitals NHS Foundation Trust - University College Hospital	London Bloomsbury		United Kingdom	WC1E 6AU

Sponsors and Collaborators

• Celgene
• Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Investigators

• Study Director: Jeevan Shetty, MD, Celgene Corporation

Study Documents (Full-Text)

• Study Protocol - Jun 12, 2020
• Statistical Analysis Plan - Nov 5, 2020

More Information

Additional Information:

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls
• Investigator Inquiry Form

Publications

• Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT03342404
• Other Study ID Numbers: ACE-536-B-THAL-002; U1111-1202-7068; 2015-003225-33
• First Posted: Nov 17, 2017
• Last Update Posted: Aug 18, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Celgene: (β)-Thalassemia; Beta-Thalassemia; Phase 2; Luspatercept; ACE-536; Safety; Efficacy; Placebo; Red Blood Cell Transfusions; Erythrocyte transfusion; Hb increase; NTDT
• Additional relevant MeSH terms: Thalassemia; Luspatercept

Study Results

Participant Flow

Pre-assignment Detail	145 participants were randomized and treated.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Period Title: Overall Study
STARTED	96	49
COMPLETED	81	18
NOT COMPLETED	15	31

Baseline Characteristics

Arm/Group Title	Luspatercept	Placebo	Total
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W	Total of all reporting groups
Overall Participants	96	49	145
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.3 (13.24)	41.1 (11.90)	39.9 (12.79)
Sex: Female, Male (Count of Participants)
Female	56 58.3%	26 53.1%	82 56.6%
Male	40 41.7%	23 46.9%	63 43.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.1%	1 2%	3 2.1%
Not Hispanic or Latino	94 97.9%	48 98%	142 97.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	31 32.3%	13 26.5%	44 30.3%
White	59 61.5%	28 57.1%	87 60%
Other	6 6.3%	8 16.3%	14 9.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)
Description	Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 13 to 24 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.
Time Frame	From Week 13 to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Number (95% Confidence Interval) [Percent of Participants]	77.1 80.3%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The Estimated Odds Ratio (OR) is Infinite (INF)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	77.1
	Confidence Interval	(2-Sided) 95%; 63.4 to 87.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in proportions (luspatercept - placebo) and 95% CI were estimated from the exact unconditional test

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	77.1
	Confidence Interval	(2-Sided) 95%; 68.7 to 85.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	The common risk difference (luspatercept - placebo) and 95% CI were estimated from the CMH test stratified by baseline Hb category and baseline NTDT-PRO T/W domain score category

2. Secondary Outcome

Title	Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24)
Description	The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the T/W Domain Score at baseline.
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and from Week 13 to Week 24

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	94	48
Mean (Standard Deviation) [Score on a scale]	-0.92 (1.862)	-0.47 (1.356)

3. Secondary Outcome

Title	Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24)
Description	Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
Time Frame	From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and From Week 13 to Week 24

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	47
Mean (Standard Deviation) [g/dL]	1.54 (0.820)	0.13 (0.450)

4. Secondary Outcome

Title	Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48)
Description	Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 37 to 48 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.
Time Frame	From Week 37 to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Number (95% Confidence Interval) [Percentage of Participants]	70.8 73.8%	2.0 4.1%

5. Secondary Outcome

Title	Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)
Description	The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much"). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 13 to Week 24 is compared to the FS score at baseline (last score available before start of study treatment).
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	90	43
Mean (Standard Deviation) [Score on a scale]	1.95 (7.937)	0.31 (5.964)

6. Secondary Outcome

Title	Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24)
Description	The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the SoB Domain Score at baseline.
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and From Week 13 to Week 24

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	94	48
Mean (Standard Deviation) [Score on a scale]	-0.65 (1.693)	-0.18 (1.246)

7. Secondary Outcome

Title	Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48)
Description	Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
Time Frame	From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and From Week 37 to Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	91	34
Mean (Standard Deviation) [g/dL]	1.57 (0.812)	0.07 (0.503)

8. Secondary Outcome

Title	Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)
Description	The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much"). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 37 to Week 48 is compared to the FS score at baseline (last score available before start of study treatment).
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	83	33
Mean (Standard Deviation) [Score on a scale]	2.46 (7.785)	0.09 (5.559)

9. Secondary Outcome

Title	Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 37 to Week 48)
Description	The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the T/W Domain Score at baseline.
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at Week 37 to Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	72	28
Mean (Standard Deviation) [Score on a scale]	-1.00 (2.117)	-0.16 (1.427)

10. Secondary Outcome

Title	Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 37 to Week 48)
Description	The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the SoB Domain Score at baseline.
Time Frame	Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and From Week 37 to Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	72	28
Mean (Standard Deviation) [Score on a scale]	-0.82 (1.851)	0.29 (1.262)

11. Secondary Outcome

Title	Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)
Description	The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose.
Time Frame	From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	94	47
Number (95% Confidence Interval) [Percent of Participants]	40.4 42.1%	27.7 56.5%

12. Secondary Outcome

Title	Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)
Description	The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose.
Time Frame	From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	94	47
Number (95% Confidence Interval) [Percent of Participants]	36.2 37.7%	21.3 43.5%

13. Secondary Outcome

Title	Mean Change From Baseline in the Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of the Medical Outcomes Study 36-Item Short Form (SF-36)
Description	The SF-36v2 is a 36-item generic PRO questionnaire used to assess patient-reported outcomes. The SF-36 yields scores for 8 domains of health: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH) as well as physical component summary (PCS) and mental component summary (MCS) scores. Scores from each of the 8 domains of health are first normalized based on US general population means, then aggregated and transformed (according to specific standardization formulas detailed in the Statistical Protocol Analysis), so that the scores from each of the 8 domains of health will contribute differently to the determination of PCS and MCS summary scores. PCS and MCS scores range from 0 to 100, with higher scores indicating a better quality of life.
Time Frame	From baseline to Week 24 and from baseline to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline, at Week 24 and at Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	92	46
Physical Component Summary (PCS) at Week 24	0.85 (7.149)	-1.18 (5.503)
Physical Component Summary (PCS) at Week 48	1.03 (5.277)	0.48 (5.367)
Mental Component Summary (MCS) at Week 24	0.98 (8.816)	-0.76 (6.901)
Mental Component Summary (MCS) at Week 48	0.98 (7.882)	-2.53 (6.538)

14. Secondary Outcome

Title	Percentage of Participants With Improvement of Iron Overload
Description	Iron overload was measured by Liver Iron Concentration (LIC) and Iron Chelation Therapy (ICT) daily dose. Improvement is defined as: For participants with baseline LIC ≥3 mg/g: ≥20% reduction in LIC or ≥ 33% decrease in ICT daily dose For participants with baseline LIC <3 mg/g: no increase in LIC >1 mg/g and not starting treatment with ICT, or no increase in ICT daily dose ≥ 33% (if on ICT at baseline)
Time Frame	Week 24 and Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Week 24	44.8 46.7%	49.0 100%
Week 48	34.4 35.8%	49.0 100%

15. Secondary Outcome

Title	Mean Change From Baseline in Serum Ferritin
Description	Baseline mean serum ferritin is calculated during the 24 weeks on or prior to dose 1 day 1. Post-baseline mean serum ferritin is calculated as mean of ferritin values during the last 24 weeks on or prior to the end date of the first 24 week or 48 week treatment
Time Frame	From baseline to Week 24 and from baseline to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at week 24 or week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Week 24	33.32 (249.820)	0.90 (98.457)
Week 48	80.21 (236.406)	58.26 (211.064)

16. Secondary Outcome

Title	Mean Change From Baseline in Liver Iron Concentration (LIC)
Description	LIC was measured by Magnetic Resonance Imaging (MRI). Baseline is defined as the last value on or before the first dose of study drug is administered; Postbaseline is defined as the closest visit at Week 24 or Week 48. Participants with LIC value >43 are not included in the analysis.
Time Frame	From baseline to Week 24 and from baseline to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at week 24 or week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Week 24	-0.27 (0.930)	-0.18 (1.375)
Week 48	-0.26 (1.540)	-0.91 (2.950)

17. Secondary Outcome

Title	Percentage of Participants Who Are Transfusion-Free Over 24 Weeks
Description	Transfusion free is defined as the absence of any transfusion during Week 1-24 of study treatment. Participants who discontinued treatment prior to Week 24 were not considered as transfusion free during Week 1-24.
Time Frame	From start of treatment to 24 weeks following start of treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Number [Percent of Participants]	89.6 93.3%	67.3 137.3%

18. Secondary Outcome

Title	Percentage of Participants Who Are Transfusion-Free Over 48 Weeks
Description	Transfusion free is defined as the absence of any transfusion during Week 1-48 of study treatment. Participants who discontinued treatment prior to Week 48 were not considered as transfusion free during Week 1-48.
Time Frame	From start of treatment to 48 weeks following start of treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Number [Percent of Participants]	82.3 85.7%	44.9 91.6%

19. Secondary Outcome

Title	Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL
Description	The duration of increase is defined as Last Day of mean hemoglobin increase by >=1.0g/dL - First Day of increase +1.
Time Frame	From first to last Hemoglobin measurement with increase from baseline ≥1.0 g/dL (up to approximately 20 months)

Outcome Measure Data

Analysis Population Description

All participants with a mean hemoglobin increase ≥1.0 g/dL

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	88	11
Mean (Standard Deviation) [Days]	611.7 (243.29)	176.5 (132.89)

20. Secondary Outcome

Title	Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance
Description	The 6MWT is typically used to objectively assess functional exercise capacity and response to medical interventions in patients with various moderate to severe diseases. Subjects are asked to walk as quickly as possible without running along a 30-meter corridor for six minutes, and the total distance covered during that time is measured. Baseline is defined as the last value on or before the first dose of study drug is administered. Postbaseline is defined as the closest visit at Week 24 or Week 48.
Time Frame	From baseline to Week 24 and from baseline to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at Week 24 or Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
24 Weeks	10.44 (58.748)	-3.36 (85.094)
48 Weeks	8.99 (63.281)	0.87 (52.712)

21. Secondary Outcome

Title	Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion
Description	Percentage of participants who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
Time Frame	From Week 13 to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Number (95% Confidence Interval) [Percentage of Participants]	52.1 54.3%	0.0 0%

22. Secondary Outcome

Title	Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score
Description	The RD for the NTDT-PRO T/W domain score was defined as ≥ 1-point decrease (ie, RD = -1) from baseline over the time from Week 13 to Week 24 or from Week 37 to Week 48. Subjects with missing NTDT-PRO T/W scores at the indicated 12-week period are classified as non-responders in the analysis.
Time Frame	From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at Baseline and at the indicated 12-week periods

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Week 13 to week 24	37.5 39.1%	28.6 58.4%
Week 37 to week 48	31.3 32.6%	18.4 37.6%

23. Secondary Outcome

Title	Number of Participants Experiencing Adverse Events
Description	Number of participants experiencing different types (any grade) of adverse events
Time Frame	From first dose to 63 days after last dose (up to approximately 50 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Treatment-emergent adverse-event (TEAE)	96 100%	48 98%
Serious TEAE	11 11.5%	12 24.5%
Treatment-related TEAE	73 76%	18 36.7%
Treatment-related Serious TEAE	1 1%	0 0%
TEAE Leading to Death	0 0%	0 0%
TEAE Leading to Dose Reduction	10 10.4%	0 0%
TEAE Leading to Dose Delay	23 24%	9 18.4%
TEAE Leading to Study Drug Discontinuation	3 3.1%	4 8.2%
Treatment-related TEAE Leading to Death	0 0%	0 0%
Treatment-related TEAE Leading to Dose Reduction	10 10.4%	0 0%
Treatment-related TEAE Leading to Dose Delay	8 8.3%	0 0%
Treatment-related TEAE Leading to Study Drug Discontinuation	2 2.1%	0 0%

24. Secondary Outcome

Title	Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept
Description	Presence of anti-drug (ACE-536/Luspatercept) antibodies was assessed every 24 weeks from serum samples. A participant is counted as 'positive' if there is any positive result captured during the study. A participant is counted as 'negative' if there is no positive result captured during the study.
Time Frame	From first dose and up to 2 years following last dose

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W	0.9% Sodium Chloride SC Q3W
Measure Participants	96	49
Count of Participants [Participants]	5 5.2%	3 6.1%

25. Secondary Outcome

Title	Apparent Clearance (CL/F) of Luspatercept
Description	Apparent Clearance (CL/F) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Geometric Mean (Geometric Coefficient of Variation) [L/day]	0.458 (33.8)

26. Secondary Outcome

Title	Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept
Description	Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Geometric Mean (Geometric Coefficient of Variation) [Liters]	7.79 (19.6)

27. Secondary Outcome

Title	Time to Reach Maximum Concentration (Tmax) of Luspatercept
Description	Time to Reach Maximum Concentration (Tmax) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Median (Full Range) [Days]	5.50

28. Secondary Outcome

Title	Maximum Concentration (Cmax) of Luspatercept
Description	Maximum Concentration (Cmax) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	5.55 (16.9)

29. Secondary Outcome

Title	Maximum Concentration From Steady State (Cmax,ss) of Luspatercept
Description	Maximum Concentration From Steady State (Cmax,ss) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	8.36 (27.7)

30. Secondary Outcome

Title	Area Under the Curve From Steady State (AUCss) of Luspatercept
Description	Area Under the Curve From Steady State (AUCss) of Luspatercept
Time Frame	At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months)

Outcome Measure Data

Analysis Population Description

All treated participants receiving the study drug

Arm/Group Title	Luspatercept
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W
Measure Participants	96
Geometric Mean (Geometric Coefficient of Variation) [day*μg/mL]	130 (34.4)

Adverse Events

Time Frame	From first dose to 63 days after last dose (up to approximately 50 months)
Arm/Group Title	Luspatercept		Placebo
Arm/Group Description	Luspatercept SC 1mg/Kg Q3W		0.9% Sodium Chloride SC Q3W
All Cause Mortality
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/49 (0%)
Serious Adverse Events
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/96 (11.5%)		12/49 (24.5%)
Blood and lymphatic system disorders
Extramedullary haemopoiesis	0/96 (0%)		1/49 (2%)
Splenomegaly	1/96 (1%)		0/49 (0%)
Hepatobiliary disorders
Biliary colic	0/96 (0%)		1/49 (2%)
Infections and infestations
Abscess limb	0/96 (0%)		1/49 (2%)
Dengue haemorrhagic fever	1/96 (1%)		0/49 (0%)
Gastroenteritis	0/96 (0%)		1/49 (2%)
Influenza	0/96 (0%)		1/49 (2%)
Pharyngitis	0/96 (0%)		1/49 (2%)
Pilonidal cyst	1/96 (1%)		0/49 (0%)
Pyelonephritis acute	0/96 (0%)		1/49 (2%)
Tonsillitis	0/96 (0%)		1/49 (2%)
Viral upper respiratory tract infection	0/96 (0%)		2/49 (4.1%)
Injury, poisoning and procedural complications
Pulmonary contusion	1/96 (1%)		0/49 (0%)
Traumatic fracture	5/96 (5.2%)		1/49 (2%)
Metabolism and nutrition disorders
Diabetes mellitus	1/96 (1%)		0/49 (0%)
Hyperglycaemia	1/96 (1%)		0/49 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse large B-cell lymphoma	0/96 (0%)		1/49 (2%)
Hepatocellular carcinoma	0/96 (0%)		1/49 (2%)
Nervous system disorders
Spinal cord compression	1/96 (1%)		0/49 (0%)
Renal and urinary disorders
Renal colic	0/96 (0%)		1/49 (2%)
Reproductive system and breast disorders
Ovarian cyst ruptured	0/96 (0%)		1/49 (2%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	0/96 (0%)		1/49 (2%)
Pleural effusion	1/96 (1%)		0/49 (0%)
Pulmonary arterial hypertension	1/96 (1%)		0/49 (0%)
Other (Not Including Serious) Adverse Events
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	96/96 (100%)		47/49 (95.9%)
Blood and lymphatic system disorders
Extramedullary haemopoiesis	6/96 (6.3%)		1/49 (2%)
Cardiac disorders
Palpitations	6/96 (6.3%)		6/49 (12.2%)
Ear and labyrinth disorders
Ear pain	2/96 (2.1%)		4/49 (8.2%)
Vertigo	3/96 (3.1%)		3/49 (6.1%)
Gastrointestinal disorders
Abdominal pain	9/96 (9.4%)		5/49 (10.2%)
Abdominal pain upper	9/96 (9.4%)		3/49 (6.1%)
Diarrhoea	16/96 (16.7%)		6/49 (12.2%)
Dyspepsia	7/96 (7.3%)		1/49 (2%)
Gastrooesophageal reflux disease	2/96 (2.1%)		3/49 (6.1%)
Nausea	10/96 (10.4%)		6/49 (12.2%)
Toothache	12/96 (12.5%)		1/49 (2%)
Vomiting	5/96 (5.2%)		0/49 (0%)
General disorders
Asthenia	13/96 (13.5%)		5/49 (10.2%)
Fatigue	16/96 (16.7%)		10/49 (20.4%)
Influenza like illness	16/96 (16.7%)		3/49 (6.1%)
Injection site erythema	5/96 (5.2%)		0/49 (0%)
Pyrexia	14/96 (14.6%)		9/49 (18.4%)
Infections and infestations
Gastroenteritis	10/96 (10.4%)		2/49 (4.1%)
Influenza	12/96 (12.5%)		5/49 (10.2%)
Nasopharyngitis	5/96 (5.2%)		0/49 (0%)
Pharyngitis	19/96 (19.8%)		6/49 (12.2%)
Rhinitis	8/96 (8.3%)		5/49 (10.2%)
Tonsillitis	2/96 (2.1%)		6/49 (12.2%)
Upper respiratory tract infection	20/96 (20.8%)		11/49 (22.4%)
Injury, poisoning and procedural complications
Muscle strain	5/96 (5.2%)		0/49 (0%)
Metabolism and nutrition disorders
Iron overload	10/96 (10.4%)		5/49 (10.2%)
Vitamin D deficiency	9/96 (9.4%)		4/49 (8.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	28/96 (29.2%)		7/49 (14.3%)
Back pain	27/96 (28.1%)		5/49 (10.2%)
Bone pain	35/96 (36.5%)		3/49 (6.1%)
Muscular weakness	2/96 (2.1%)		3/49 (6.1%)
Musculoskeletal pain	6/96 (6.3%)		3/49 (6.1%)
Myalgia	11/96 (11.5%)		5/49 (10.2%)
Neck pain	7/96 (7.3%)		2/49 (4.1%)
Pain in extremity	16/96 (16.7%)		5/49 (10.2%)
Spinal pain	5/96 (5.2%)		1/49 (2%)
Nervous system disorders
Dizziness	8/96 (8.3%)		4/49 (8.2%)
Headache	29/96 (30.2%)		10/49 (20.4%)
Migraine	6/96 (6.3%)		0/49 (0%)
Psychiatric disorders
Anxiety	5/96 (5.2%)		0/49 (0%)
Insomnia	11/96 (11.5%)		1/49 (2%)
Reproductive system and breast disorders
Menstruation irregular	12/96 (12.5%)		3/49 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	17/96 (17.7%)		1/49 (2%)
Epistaxis	9/96 (9.4%)		1/49 (2%)
Oropharyngeal pain	19/96 (19.8%)		6/49 (12.2%)
Rhinitis allergic	4/96 (4.2%)		3/49 (6.1%)
Rhinorrhoea	3/96 (3.1%)		3/49 (6.1%)
Skin and subcutaneous tissue disorders
Erythema	6/96 (6.3%)		0/49 (0%)
Skin ulcer	5/96 (5.2%)		1/49 (2%)
Vascular disorders
Hypertension	19/96 (19.8%)		1/49 (2%)
Prehypertension	22/96 (22.9%)		7/49 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.