BELIEVE: An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (β) Thalassemia

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02604433
• Collaborator: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
• Enrollment: 336
• Locations: 73
• Arms: 2
• Actual Duration (Months): 56.1
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

The study is divided into the following periods:

• Historical Period,

• Screening/Run-in Period,

• Double-blind Treatment Period (48 weeks),

• Double-blind Long-term Treatment Period, (at the investigator's discretion an additional 48 weeks),

• Open-Label Phase post unblinding and upon Data Monitoring Committee positive recommendation

• Post-treatment Follow-up Period

Condition or Disease	Intervention/Treatment	Phase
Erythrocyte Transfusion; Beta-Thalassemia	Drug: Luspatercept; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 336 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: May 2, 2016
• Actual Primary Completion Date: Nov 24, 2017
• Actual Study Completion Date: Jan 5, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC) Luspatercept, subcutaneous(ly) (SC) once every 21 days	Drug: Luspatercept; Subjects will start with luspatercept at 1 mg/kg dose level.; Other Names: ACE-536
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.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24 [Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24]

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

Secondary Outcome Measures

1. Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48 [Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48]

   Percentage of participants who 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.

2. Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24 [Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24]

   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.

3. Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48 [Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48]

   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.

4. Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24 [Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24]

   Baseline was defined as the total number of Red Blood Cells (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.

5. Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48 [Baseline: Week -12 to Day -1; Treatment: Week 48]

   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 collected by magnetic resonance imaging. Participants with a LIC value > 43 mg/g were not included in the analysis.

6. Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48 [Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48]

   Three different types of Iron Chelation Therapy (ICT) were analyzed: Deferasirox Deferiprone Deferoxamine Mesilate/Deferoxamine 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.

7. Mean Change From Baseline In Mean Serum Ferritin At Week 48 [Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48]

   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.

8. Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48 [Baseline: Day 1; Treatment: Week 48]

   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.

9. Mean Change From Baseline In Myocardial Iron At Week 48 [Baseline: Day 1; Treatment: Week 48]

   Myocardial Iron levels were measured by Magnetic Resonance Imaging (MRI), using MRI parameter T2* (Unit: ms). T2* values correlates with heart failure (HF) risk (e.g. T2*<6ms: high HF risk).

10. Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24 [Baseline: 4 weeks prior to Day 1; Treatment: Week 24]

    The TranQol is a self-administered 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 specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.

11. Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24 [Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24]

    The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. 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. The domains/summaries reported are: Physical Functioning (Range of possible T-scores is 19.26 - 57.54) General Health (Range of possible T-scores is 18.95 - 66.50) Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.

12. Number of Participants Who Utilized Healthcare Resources During Study [From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)]

    Number of participants who had any of the following types of Healthcare Resource Utilization (HRU): a doctor office visit (non-study scheduled) an emergency department visit a hospitalization

13. Number of Days Spent in Higher Care Hospital Units [From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)]

    Types of hospitals units considered to be 'higher care' are: Intensive Care Unit Coronary Care Unit

14. Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment [From first dose through 3 weeks post last dose (up to approximately 218 weeks)]

    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.

15. Duration of Reduction in Transfusion Burden [From first dose to end of study treatment (up to approximately 215 weeks)]

    Responders were defined as subjects who achieved ≥ 33% reduction or ≥ 50% reduction in Red Blood Cells Transfusion (RBC-T) burden from baseline with a reduction of at least 2 RBC units during any rolling 12-week interval. The duration of reduction is calculated as Last Day of Response - First day of response +1

16. Longest Duration of Transfusion Independence [From first dose through 3 weeks post last dose (up to approximately 218 weeks)]

    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. Longest duration of transfusion independence was estimated based on Kaplan-Meier model.

17. Time to Erythroid Response [From first dose to 48 weeks following first dose]

    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.

18. Post-Baseline Transfusion Event Frequency [From first dose through 3 weeks post last dose (up to approximately 218 weeks)]

    The number of transfusion events after start of study treatment were evaluated. 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. Results are presented in 24-week intervals, up to 96 weeks after start of study treatment

19. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

20. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

21. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

22. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

23. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

24. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

25. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss) [Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337]

26. Participants With Treatment-Emergent Adverse Events (TEAE) [From first dose to 90 days following last dose (up to approximately 52 months)]

    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. 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

27. Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) [Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316]

    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."

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. 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 β-thalassemia or Hemoglobin E/β-thalassemia. (β-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.

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

2. 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.

1. 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.

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/β-thalassemia or alpha (α)-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).

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

2. 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.

3. Platelet count > 1000 x 109/L

4. 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).

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

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

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

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

9. Hydroxyurea treatment ≤ 24 weeks prior to randomization.

10. Pregnant or lactating females.

11. 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).

12. Major organ damage, including:

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

14. 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.

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

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

17. Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).

18. 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).

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

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

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

22. History of malignancy with the exception of:

23. Curatively resected nonmelanoma skin cancer.

24. Curatively treated cervical carcinoma in situ.

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

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 and Robert H Lurie Childrens Hospital of Chicago	Chicago	Illinois	United States	60611
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Weill Cornell Medical College	New York	New York	United States	10065
6	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
7	Prince of Wales Hospital	Randwick	New South Wales	Australia	2031
8	Mater Hospital Brisbane	South Brisbane	Queensland	Australia	4101
9	Royal Adelaide Hospital Institute of Medical and Veterinary Science	Adelaide	South Australia	Australia	5000
10	Monash Medical Centre	Clayton	Victoria	Australia	3168
11	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009
12	Royal Prince Alfred Hospital	Camperdown		Australia	2050
13	University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD	Plovdiv		Bulgaria	4002
14	Specialized Hospital for Active Treatment of Haematological Diseases - Sofia	Sofia		Bulgaria	1756
15	Multiprofile Hospital for Active Treatment Sveta Marina EAD	Varna		Bulgaria	9010
16	University Health Network	Toronto	Ontario	Canada	M5G 2C4
17	Hopital Henri Mondor	Creteil		France	94010
18	GH de Institut Catholique St. VincentHématologie	Lille		France	59000
19	Hopitaux de La Timone	Marseille Cedex 9		France	13385
20	Hospital of Necker	Paris		France	75015
21	Laiko General Hospital of Athens	Ampelokipi - Athens		Greece	115 26
22	General Children's Hospital "Agia Sophia"	Athens		Greece	115 27
23	General Hospital Georgios Gennimatas of Athens	Athens		Greece	11527
24	University General Hospital of Patras	Rio Patras		Greece	26500
25	Hippokration Hospital	Thessaloniki		Greece	54642
26	Soroka University Medical Centre	Beer Sheva		Israel	84101
27	Rambam Health Corporation	Haifa		Israel	3109601
28	HaEmek Medical Center	Haïfa (Afula)		Israel	18101
29	Shaare Zedek Medical Center	Jerusalem		Israel	91031
30	Hadassah Medical Center	Jerusalem		Israel	91120
31	Galilee Medical Center	Nahariya		Israel	22100
32	Rabin Medical Center	Petah Tikva		Israel	49100
33	Presidio Ospedaliero Antonio Perrino	Brindisi		Italy	72100
34	Universita degli Studi di Cagliari - ASL8	Cagliari		Italy	09121
35	Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna	Ferrara		Italy	44124
36	Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite	Genoa		Italy	16128
37	Fondazione Ca Granda IRCCS Ospedale Maggiore	Milan		Italy	20122
38	Seconda Universita Degli Studi Di Napoli	Naples		Italy	80131
39	AORN A Cardarelli	Napoli		Italy	80131
40	Azienda Ospedaliero Universitaria S. Luigi Gonzaga	Orbassano		Italy	10043
41	Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello	Palermo		Italy	90146
42	Azienda Ospedaliera Universitaria Integrata Di Verona	Verona		Italy	37134
43	Chronic Care Center	Beirut		Lebanon
44	Hospital Sultanah Aminah	Johor Bahru	Johor	Malaysia	80100
45	Hospital Sultanah Bahiyah	Alor Setar	Kedah	Malaysia	05460
46	Hospital Raja Permaisuri Bainun	Ipoh	Perak	Malaysia	30990
47	Queen Elizabeth Hospital	Kota Kinabalu	Sabah	Malaysia	88586
48	Hospital Umum Sarawak	Kuching	Sarawak	Malaysia	93586
49	University Malaya Medical Centre	Kuala Lumpur	Wilayah Persekutuan Kuala Lumpur	Malaysia	59100
50	Hospital Pulau Pinang c/o Penang Medical College	Georgetown		Malaysia	10990
51	Changhua Christian Hospital	Changhua City		Taiwan	500
52	Kaohsiung Medical University Hospital	Kaohsiung		Taiwan	807
53	China Medical University Hospital	Taichung		Taiwan	40447
54	National Taiwan University Hospital	Taipei, Zhongzheng Dist.		Taiwan	10002
55	Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital	Bangkok		Thailand	10330
56	Siriraj Hospital Mahidol University	Bangkok		Thailand	10700
57	Chiang Mai University - Maharaj Nakorn Chiang Mai Hospital	Chiang Mai		Thailand	50200
58	University Hospital Farhat Hached	Sousse		Tunisia	4031
59	Bone Marrow Transplant Center	Tunis		Tunisia	1006
60	Aziza Othmana Hospital	Tunis		Tunisia	1008
61	Military Hospital of Tunis	Tunis		Tunisia	1089
62	Acibadem Adana Hospital	Adana		Turkey	01130
63	Cukurova University Medical Faculty Balcali Hospital	Adana		Turkey	01330
64	Hacettepe Universitesi	Ankara		Turkey	01660
65	Antalya Egitim Arastirma	Antalya		Turkey	07100
66	Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi	Istanbul		Turkey	34093
67	Ege Universitesi Tip Fakultesi Hastanesi	Izmir		Turkey	35100
68	Mersin University Medical Faculty	Mersin		Turkey	33343
69	St James University Hospital	Leeds		United Kingdom	LS9 7TF
70	University College Hospital Trust	London Bloomsbury		United Kingdom	WC1E 6AU
71	Barts Health NHS Trust - The Royal London Hospital	London		United Kingdom	E1 1BB
72	Whittington Hospital	London		United Kingdom	N19 5NF
73	Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL

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: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol - Dec 11, 2018
• Statistical Analysis Plan - Mar 11, 2021

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02604433
• Other Study ID Numbers: ACE-536-B-THAL-001
• First Posted: Nov 13, 2015
• Last Update Posted: Jan 25, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Celgene: ACE-536; Safety; Efficacy; Placebo; Red Blood Cell Transfusions; Beta -Thalassemia
• Additional relevant MeSH terms: Thalassemia; beta-Thalassemia; Luspatercept

Study Results

Participant Flow

Pre-assignment Detail	336 participants were randomized, 332 participants were treated.

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Period Title: Overall Study
STARTED	224	112
Participants Treated	223	109
Completed 24 Weeks of Treatment	211	102
Completed 48 Weeks of Treatment	202	96
Completed 96 Weeks of Treatment	155	3
Completed 144 Weeks of Treatment	125	0
Completed 192 Weeks of Treatment	6	0
COMPLETED	6	6
NOT COMPLETED	218	106

Baseline Characteristics

Arm/Group Title	Luspatercept + BSC	Placebo + BSC	Total
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care	Total of all reporting groups
Overall Participants	224	112	336
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.2 (10.67)	31.9 (9.89)	32.1 (10.40)
Sex: Female, Male (Count of Participants)
Female	132 58.9%	63 56.3%	195 58%
Male	92 41.1%	49 43.8%	141 42%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 2.2%	2 1.8%	7 2.1%
Not Hispanic or Latino	218 97.3%	107 95.5%	325 96.7%
Unknown or Not Reported	1 0.4%	3 2.7%	4 1.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	81 36.2%	36 32.1%	117 34.8%
Black or African American	1 0.4%	0 0%	1 0.3%
White	122 54.5%	60 53.6%	182 54.2%
Not collected or reported	5 2.2%	5 4.5%	10 3%
Other	15 6.7%	11 9.8%	26 7.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
Description	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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Number [Percentage of participants]	21.4 9.6%	4.5 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.79
	Confidence Interval	(2-Sided) 95%; 2.24 to 14.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentages
	Estimated Value	17.0
	Confidence Interval	(2-Sided) 95%; 10.4 to 23.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Luspatercept - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Common Risk Difference
	Estimated Value	17.0
	Confidence Interval	() 95%; 10.4 to 23.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Luspatercept - Placebo

2. Secondary Outcome

Title	Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
Description	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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Number [Percentage of participants]	19.6 8.8%	3.6 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Odds ratio 95% CIs, and p-value were estimated from the CMH test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate for outcomes 2-4, the testing procedure was implemented strictly in order: the test for this outcome was only conducted when there was evidence showing that erythroid response was achieved in the luspatercept group from Week 13 to Week 24 (primary endpoint).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.44
	Confidence Interval	(2-Sided) 95%; 2.27 to 18.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24
Description	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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Number [Percentage of participants]	7.6 3.4%	1.8 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and 33% hematological improvement was achieved in the luspatercept group in outcome 2.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0303
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.55
	Confidence Interval	(2-Sided) 95%; 1.03 to 20.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
Description	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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Number [Percentage of participants]	10.3 4.6%	0.9 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and achievement of objective in the luspatercept group in outcomes 2+3.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	11.92
	Confidence Interval	(2-Sided) 95%; 1.65 to 86.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24
Description	Baseline was defined as the total number of Red Blood Cells (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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	210	102
Mean (Standard Deviation) [RBC units]	-0.67 (1.795)	0.66 (1.774)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Change from baseline at Week 48 LSM = least squares mean
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	ANCOVA
	Comments	Estimates were based on an ANCOVA model with geographical regions defined at randomization and baseline transfusion burden as covariates.
Method of Estimation	Estimation Parameter	LSM Difference
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95%; -1.77 to -0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

6. Secondary Outcome

Title	Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
Description	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 collected by magnetic resonance imaging. Participants with a LIC value > 43 mg/g were not included in the analysis.
Time Frame	Baseline: Week -12 to Day -1; Treatment: Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	185	99
Mean (Standard Deviation) [mg/g dry weight]	0.05 (5.770)	-0.00 (5.329)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Change from baseline at Week 48 P-value ANCOVA model with geographical regions defined at randomization and baseline LIC as covariates. LS = least square
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7598
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -1.10 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

7. Secondary Outcome

Title	Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
Description	Three different types of Iron Chelation Therapy (ICT) were analyzed: Deferasirox Deferiprone Deferoxamine Mesilate/Deferoxamine 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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	129	66
Deferasirox	-105.0 (378.67)	-60.4 (297.11)
Deferiprone	-229.1 (893.62)	-73.4 (614.80)
Deferoxamine Mesilate/Deferoxamine	84.9 (523.45)	274.2 (613.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Deferasirox: Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2552
	Comments	Significance level of 0.050 for 2-sided tests
	Method	ANCOVA
	Comments	Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-68.0
	Confidence Interval	(2-Sided) 95%; -185.8 to 49.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Deferiprone: Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7746
	Comments	Significance level of 0.050 for 2-sided tests
	Method	ANCOVA
	Comments	Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-76.4
	Confidence Interval	(2-Sided) 95%; -612.9 to 460.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Deferoxamine Mesilate / Deferoxamine: Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5186
	Comments	Significance level of 0.050 for 2-sided tests
	Method	ANCOVA
	Comments	Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-147.3
	Confidence Interval	(2-Sided) 95%; -673.1 to 378.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

8. Secondary Outcome

Title	Mean Change From Baseline In Mean Serum Ferritin At Week 48
Description	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.
Time Frame	Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	207	101
Mean (Standard Deviation) [μg/L]	-247.19 (713.767)	100.38 (522.047)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significance level of 0.050 for 2-sided tests
	Method	ANCOVA
	Comments	Estimates based on an ANCOVA model with geographical regions defined at randomization and baseline serum ferritin as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-342.59
	Confidence Interval	(2-Sided) 95%; -498.30 to -186.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

9. Secondary Outcome

Title	Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
Description	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.
Time Frame	Baseline: Day 1; Treatment: Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	190	97
Total Hip	0.01 (0.050)	0.01 (0.057)
Lumbar Spine	-0.00 (0.063)	0.00 (0.078)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Total Hip Bone Mineral Density: Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9201
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	ANCOVA
	Comments	Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline BMD measurement as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Lumbar Spine Bone Mineral Density: Change from baseline at Week 48 LS = least squares
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4620
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	ANCOVA
	Comments	Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline BMD measurement as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

10. Secondary Outcome

Title	Mean Change From Baseline In Myocardial Iron At Week 48
Description	Myocardial Iron levels were measured by Magnetic Resonance Imaging (MRI), using MRI parameter T2* (Unit: ms). T2* values correlates with heart failure (HF) risk (e.g. T2*<6ms: high HF risk).
Time Frame	Baseline: Day 1; Treatment: Week 48

Outcome Measure Data

Analysis Population Description

All randomized participants with available measurements at the specified timepoints

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	201	102
Mean (Standard Deviation) [ms]	-1.83 (15.084)	-0.01 (6.780)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Change from baseline at Week 48 LS = least square
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0543
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	ANCOVA
	Comments	Estimates were based on an ANCOVA model with geographical regions defined at randomization and baseline myocardial T2* as covariates.
Method of Estimation	Estimation Parameter	LS Mean of Difference
	Estimated Value	-2.22
	Confidence Interval	(2-Sided) 95%; -4.48 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

11. Secondary Outcome

Title	Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
Description	The TranQol is a self-administered 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 specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.
Time Frame	Baseline: 4 weeks prior to Day 1; Treatment: Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants with an evaluable TranQoL questionnaire at screening visit and at least one post-screening visit

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	200	94
Physical Health Domain Score - Change from Baseline	-1.5 (14.26)	-0.7 (14.24)
Total Score - Change from Baseline	0.8 (11.56)	-0.4 (11.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Physical Health Domain Score - Change from Baseline at Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.148
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Total Score - Change from Baseline at Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.318
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
Description	The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. 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. The domains/summaries reported are: Physical Functioning (Range of possible T-scores is 19.26 - 57.54) General Health (Range of possible T-scores is 18.95 - 66.50) Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.
Time Frame	Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24

Outcome Measure Data

Analysis Population Description

All randomized participants with an evaluable SF-36 questionnaire at screening visit and at least one post-screening visit

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	210	103
Physical Functioning Domain Score - Change from Baseline	-0.3 (6.93)	-0.2 (7.86)
General Health Domain Score - Change from Baseline	0.4 (7.18)	0.3 (7.03)
PCS - Change from Baseline	-0.4 (7.01)	-0.3 (7.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Physical Functioning Domain - Change from Baseline at Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.596
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	General Health Domain - Change from Baseline at Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.395
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	PCS - Change from Baseline at Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.373
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	Number of Participants Who Utilized Healthcare Resources During Study
Description	Number of participants who had any of the following types of Healthcare Resource Utilization (HRU): a doctor office visit (non-study scheduled) an emergency department visit a hospitalization
Time Frame	From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Doctor Office Visit	186 83%	69 61.6%
Emergency Department Visit	71 31.7%	22 19.6%
Hospital Admission	61 27.2%	5 4.5%

14. Secondary Outcome

Title	Number of Days Spent in Higher Care Hospital Units
Description	Types of hospitals units considered to be 'higher care' are: Intensive Care Unit Coronary Care Unit
Time Frame	From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who spent time in higher care hospital units

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	43	5
Mean (Standard Deviation) [Days]	8.0 (23.70)	0.6 (0.55)

15. Secondary Outcome

Title	Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment
Description	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.
Time Frame	From first dose through 3 weeks post last dose (up to approximately 218 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	224	112
Number [Percentage of participants]	12.1 5.4%	1.8 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.6
	Confidence Interval	(2-Sided) 95%; 1.8 to 32.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Duration of Reduction in Transfusion Burden
Description	Responders were defined as subjects who achieved ≥ 33% reduction or ≥ 50% reduction in Red Blood Cells Transfusion (RBC-T) burden from baseline with a reduction of at least 2 RBC units during any rolling 12-week interval. The duration of reduction is calculated as Last Day of Response - First day of response +1
Time Frame	From first dose to end of study treatment (up to approximately 215 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants with ≥ 33% reduction or ≥ 50% reduction in RBC-T burden

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	173	39
≥ 33% Transfusion Burden Reduction	627.3 (390.54)	224.0 (155.15)
≥ 50% Transfusion Burden Reduction	491.1 (386.37)	193.0 (142.51)

17. Secondary Outcome

Title	Longest Duration of Transfusion Independence
Description	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. Longest duration of transfusion independence was estimated based on Kaplan-Meier model.
Time Frame	From first dose through 3 weeks post last dose (up to approximately 218 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who were transfusion independent for ≥ 8 weeks

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	27	2
Median (95% Confidence Interval) [Days]	72.0	71.5

18. Secondary Outcome

Title	Time to Erythroid Response
Description	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.
Time Frame	From first dose to 48 weeks following first dose

Outcome Measure Data

Analysis Population Description

All randomized participants who achieved erythroid response

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	173	39
≥ 33% Transfusion Burden Reduction	96.3 (163.92)	163.5 (148.78)
≥ 50% Transfusion Burden Reduction	189.1 (257.69)	160.9 (160.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	≥ 33% Transfusion Burden Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0195
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-67.27
	Confidence Interval	(2-Sided) 95%; -123.63 to -10.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept + BSC, Placebo + BSC
	Comments	≥ 50% Transfusion Burden Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7473
	Comments	Significance level of 0.050 for 2-sided tests.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.24
	Confidence Interval	(2-Sided) 95%; -144.87 to 201.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	luspatercept - placebo

19. Secondary Outcome

Title	Post-Baseline Transfusion Event Frequency
Description	The number of transfusion events after start of study treatment were evaluated. 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. Results are presented in 24-week intervals, up to 96 weeks after start of study treatment
Time Frame	From first dose through 3 weeks post last dose (up to approximately 218 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants who received transfusions

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	210	102
Week 1 - 24	7.1 (2.03)	7.9 (1.65)
Week 25 - 48	7.0 (2.02)	7.6 (1.61)
Week 49 - 72	7.0 (2.04)	7.5 (1.28)
Week 73 - 96	7.0 (2.13)	7.0 (1.00)

20. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [L/day]	0.437 (38.5)

21. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [Liters]	7.08 (26.7)

22. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [days]	11.2 (25.7)

23. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Median (Full Range) [Days]	5.48

24. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	5.64 (25.1)

25. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	8.31 (30.1)

26. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)
Time Frame	Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

Outcome Measure Data

Analysis Population Description

All randomized participants with available PK measurements for Luspatercept

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	0
Geometric Mean (Geometric Coefficient of Variation) [day*μg/mL]	129 (36.0)

27. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAE)
Description	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. 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
Time Frame	From first dose to 90 days following last dose (up to approximately 52 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	223	109
≥ 1 Treatment-emergent adverse event (TEAE)	219 97.8%	102 91.1%
Serious TEAE	53 23.7%	8 7.1%
Grade ≥ 3 TEAE	84 37.5%	19 17%
Treatment-related TEAE	135 60.3%	31 27.7%
Treatment-related Serious TEAE	13 5.8%	0 0%
Treatment-related TEAE ≥ Grade 3	27 12.1%	1 0.9%
TEAE leading to death	2 0.9%	1 0.9%
Trt-related TEAE leading to death	0 0%	0 0%
TEAE leading to dose reduction	10 4.5%	3 2.7%
TEAE leading to dose delay	46 20.5%	11 9.8%
TEAE leading to drug discontinuation	25 11.2%	2 1.8%
Trt-related TEAE leading to dose reduction	9 4%	2 1.8%
Trt-related TEAE leading to dose delay	15 6.7%	3 2.7%
Trt-related TEAE leading to drug discontinuation	20 8.9%	1 0.9%

28. Secondary Outcome

Title	Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
Description	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."
Time Frame	Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements

Arm/Group Title	Luspatercept + BSC	Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
Measure Participants	221	109
Pre-existing	2 0.9%	1 0.9%
Treatment-emergent	4 1.8%	2 1.8%

Adverse Events

Time Frame	All-cause mortality was assessed from first dose to study completion (approximately 56 months) SAEs and NSAEs were assessed from first dose to 90 days following last dose (up to approximately 52 months)
Adverse Event Reporting Description	Adverse events were collected in all participants who received at least 1 dose of study drug.
Arm/Group Title	Luspatercept + BSC		Placebo + BSC
Arm/Group Description	Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care		Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
All Cause Mortality
	Luspatercept + BSC		Placebo + BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/223 (1.8%)		1/109 (0.9%)
Serious Adverse Events
	Luspatercept + BSC		Placebo + BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/223 (23.8%)		8/109 (7.3%)
Blood and lymphatic system disorders
Anaemia	4/223 (1.8%)		0/109 (0%)
Extramedullary haemopoiesis	2/223 (0.9%)		0/109 (0%)
Febrile neutropenia	1/223 (0.4%)		0/109 (0%)
Neutropenia	1/223 (0.4%)		0/109 (0%)
Pancytopenia	1/223 (0.4%)		0/109 (0%)
Thrombocytopenia	1/223 (0.4%)		0/109 (0%)
Cardiac disorders
Cardiac arrest	1/223 (0.4%)		0/109 (0%)
Cardiac failure congestive	1/223 (0.4%)		0/109 (0%)
Cardiac iron overload	0/223 (0%)		1/109 (0.9%)
Left ventricular dysfunction	1/223 (0.4%)		0/109 (0%)
Myocardial ischaemia	1/223 (0.4%)		0/109 (0%)
Gastrointestinal disorders
Abdominal pain	2/223 (0.9%)		0/109 (0%)
Colitis	1/223 (0.4%)		0/109 (0%)
Food poisoning	1/223 (0.4%)		0/109 (0%)
Pancreatitis acute	1/223 (0.4%)		0/109 (0%)
General disorders
Hyperpyrexia	1/223 (0.4%)		0/109 (0%)
Pain	1/223 (0.4%)		0/109 (0%)
Pyrexia	2/223 (0.9%)		0/109 (0%)
Hepatobiliary disorders
Cholangitis	2/223 (0.9%)		0/109 (0%)
Cholecystitis acute	3/223 (1.3%)		2/109 (1.8%)
Cholelithiasis	1/223 (0.4%)		0/109 (0%)
Drug-induced liver injury	1/223 (0.4%)		0/109 (0%)
Gallbladder obstruction	1/223 (0.4%)		0/109 (0%)
Hepatitis acute	1/223 (0.4%)		0/109 (0%)
Portal vein thrombosis	1/223 (0.4%)		0/109 (0%)
Infections and infestations
Acute sinusitis	1/223 (0.4%)		0/109 (0%)
Appendicitis	1/223 (0.4%)		0/109 (0%)
Bacteraemia	0/223 (0%)		1/109 (0.9%)
Cellulitis	3/223 (1.3%)		0/109 (0%)
Dengue fever	1/223 (0.4%)		0/109 (0%)
Epstein-Barr virus infection	0/223 (0%)		1/109 (0.9%)
Gallbladder empyema	1/223 (0.4%)		0/109 (0%)
Gastroenteritis	1/223 (0.4%)		0/109 (0%)
Large intestine infection	0/223 (0%)		1/109 (0.9%)
Neutropenic sepsis	1/223 (0.4%)		0/109 (0%)
Parotid abscess	1/223 (0.4%)		0/109 (0%)
Pharyngitis bacterial	1/223 (0.4%)		0/109 (0%)
Pneumonia	2/223 (0.9%)		0/109 (0%)
Pulmonary sepsis	1/223 (0.4%)		0/109 (0%)
Pyelonephritis	1/223 (0.4%)		0/109 (0%)
Septic shock	2/223 (0.9%)		0/109 (0%)
Splenic abscess	1/223 (0.4%)		0/109 (0%)
Tonsillitis	1/223 (0.4%)		0/109 (0%)
Upper respiratory tract infection	1/223 (0.4%)		0/109 (0%)
Urinary tract infection	1/223 (0.4%)		1/109 (0.9%)
Urosepsis	0/223 (0%)		1/109 (0.9%)
Vestibular neuronitis	1/223 (0.4%)		0/109 (0%)
Viral infection	1/223 (0.4%)		0/109 (0%)
Viral sepsis	1/223 (0.4%)		0/109 (0%)
Viral upper respiratory tract infection	2/223 (0.9%)		0/109 (0%)
Wound infection	1/223 (0.4%)		0/109 (0%)
Injury, poisoning and procedural complications
Femur fracture	1/223 (0.4%)		0/109 (0%)
Radius fracture	1/223 (0.4%)		0/109 (0%)
Thermal burn	1/223 (0.4%)		0/109 (0%)
Thoracic vertebral fracture	1/223 (0.4%)		0/109 (0%)
Traumatic fracture	1/223 (0.4%)		0/109 (0%)
Investigations
Blood uric acid increased	1/223 (0.4%)		0/109 (0%)
Coombs direct test positive	0/223 (0%)		1/109 (0.9%)
Urine albumin/creatinine ratio increased	1/223 (0.4%)		0/109 (0%)
Metabolism and nutrition disorders
Dehydration	1/223 (0.4%)		0/109 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/223 (0.4%)		0/109 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute erythroid leukaemia	1/223 (0.4%)		0/109 (0%)
Hepatocellular carcinoma	1/223 (0.4%)		0/109 (0%)
Meningioma	1/223 (0.4%)		0/109 (0%)
Nervous system disorders
Cerebral venous sinus thrombosis	1/223 (0.4%)		0/109 (0%)
Depressed level of consciousness	1/223 (0.4%)		0/109 (0%)
Dizziness	1/223 (0.4%)		0/109 (0%)
Haemorrhage intracranial	1/223 (0.4%)		0/109 (0%)
Intracranial aneurysm	1/223 (0.4%)		0/109 (0%)
Neuritis	1/223 (0.4%)		0/109 (0%)
Spinal cord compression	1/223 (0.4%)		0/109 (0%)
Thrombotic stroke	1/223 (0.4%)		0/109 (0%)
Transient ischaemic attack	3/223 (1.3%)		0/109 (0%)
Renal and urinary disorders
Nephrolithiasis	1/223 (0.4%)		0/109 (0%)
Renal colic	1/223 (0.4%)		0/109 (0%)
Renal injury	1/223 (0.4%)		0/109 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/223 (0.4%)		0/109 (0%)
Pulmonary hypertension	1/223 (0.4%)		0/109 (0%)
Vascular disorders
Deep vein thrombosis	3/223 (1.3%)		0/109 (0%)
Hypertension	1/223 (0.4%)		0/109 (0%)
Thrombophlebitis superficial	1/223 (0.4%)		0/109 (0%)
Other (Not Including Serious) Adverse Events
	Luspatercept + BSC		Placebo + BSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	211/223 (94.6%)		95/109 (87.2%)
Gastrointestinal disorders
Abdominal pain	30/223 (13.5%)		7/109 (6.4%)
Abdominal pain upper	25/223 (11.2%)		8/109 (7.3%)
Constipation	12/223 (5.4%)		4/109 (3.7%)
Diarrhoea	41/223 (18.4%)		14/109 (12.8%)
Dyspepsia	19/223 (8.5%)		1/109 (0.9%)
Nausea	29/223 (13%)		6/109 (5.5%)
Toothache	15/223 (6.7%)		5/109 (4.6%)
Vomiting	30/223 (13.5%)		8/109 (7.3%)
General disorders
Asthenia	26/223 (11.7%)		11/109 (10.1%)
Fatigue	38/223 (17%)		16/109 (14.7%)
Influenza like illness	21/223 (9.4%)		8/109 (7.3%)
Injection site pain	12/223 (5.4%)		3/109 (2.8%)
Pain	14/223 (6.3%)		4/109 (3.7%)
Pyrexia	47/223 (21.1%)		24/109 (22%)
Infections and infestations
Gastroenteritis	18/223 (8.1%)		9/109 (8.3%)
Influenza	25/223 (11.2%)		8/109 (7.3%)
Nasopharyngitis	17/223 (7.6%)		4/109 (3.7%)
Pharyngitis	36/223 (16.1%)		15/109 (13.8%)
Tonsillitis	16/223 (7.2%)		2/109 (1.8%)
Upper respiratory tract infection	93/223 (41.7%)		43/109 (39.4%)
Urinary tract infection	13/223 (5.8%)		6/109 (5.5%)
Injury, poisoning and procedural complications
Fall	8/223 (3.6%)		8/109 (7.3%)
Transfusion reaction	12/223 (5.4%)		5/109 (4.6%)
Investigations
Alanine aminotransferase increased	12/223 (5.4%)		4/109 (3.7%)
Liver iron concentration increased	12/223 (5.4%)		2/109 (1.8%)
Metabolism and nutrition disorders
Hyperuricaemia	16/223 (7.2%)		0/109 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	51/223 (22.9%)		15/109 (13.8%)
Back pain	72/223 (32.3%)		33/109 (30.3%)
Bone pain	50/223 (22.4%)		9/109 (8.3%)
Musculoskeletal chest pain	8/223 (3.6%)		8/109 (7.3%)
Musculoskeletal pain	21/223 (9.4%)		11/109 (10.1%)
Myalgia	28/223 (12.6%)		11/109 (10.1%)
Neck pain	14/223 (6.3%)		9/109 (8.3%)
Osteoporosis	13/223 (5.8%)		7/109 (6.4%)
Pain in extremity	33/223 (14.8%)		12/109 (11%)
Spinal pain	12/223 (5.4%)		5/109 (4.6%)
Nervous system disorders
Dizziness	29/223 (13%)		5/109 (4.6%)
Headache	78/223 (35%)		27/109 (24.8%)
Lethargy	12/223 (5.4%)		4/109 (3.7%)
Reproductive system and breast disorders
Menstruation irregular	12/223 (5.4%)		6/109 (5.5%)
Respiratory, thoracic and mediastinal disorders
Cough	48/223 (21.5%)		13/109 (11.9%)
Nasal congestion	21/223 (9.4%)		3/109 (2.8%)
Oropharyngeal pain	41/223 (18.4%)		13/109 (11.9%)
Skin and subcutaneous tissue disorders
Urticaria	17/223 (7.6%)		4/109 (3.7%)
Vascular disorders
Hypertension	23/223 (10.3%)		3/109 (2.8%)

Limitations/Caveats

[Not Specified]

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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.