An Efficacy and Safety Study of Luspatercept (ACE-536) Ve... | NCT02604433

Name	Class
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA	INDUSTRY

Label	Type	Description	Intervention Names
Luspatercept (ACE-536) plus Best Supportive Care (BSC)	Experimental	Luspatercept, subcutaneous(ly) (SC) once every 21 days	Drug: Luspatercept
Placebo plus Best Supportive Care (BSC)	Placebo Comparator	normal saline solution subcutaneous(ly) (SC) once every 21 days	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Luspatercept	Drug	Subjects will start with luspatercept at 1 mg/kg dose level.	Luspatercept (ACE-536) plus Best Supportive Care (BSC)

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

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

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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

Male or female, ≥18 years of age at the time of signing the informed consent document (ICF).
Subject must understand and voluntarily sign an Inform Consent Form prior to any study-related assessments/procedures being conducted.
Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia. (β-thalassemia with mutation and/or multiplication of alpha globin is allowed).
Regularly transfused, defined as: 6-20 Red Blood Cell (RBC) units* in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.

* Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL. (i) sites who use transfusion bags within this range, or ≥ 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, (ii) sites who use transfusion bags < 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.
Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
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.
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:

Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
Any condition that confounds the ability to interpret data from the study.
A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H);
Evidence of active hepatitis C (HCV) infection as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B as demonstrated by the presence of HBsAg and/or HBVDNA-positive,, or known positive human immunodeficiency virus (HIV).

Note: Subjects receiving antiviral therapies should have 2 negative HCVRNA tests 3 months apart.(ie, one test at the end of the antiviral therapy and a second test 3 months following the first test).
Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
Use of chronic anticoagulant therapy is excluded, unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
Platelet count > 1000 x 109/L
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).
Treatment with another investigational drug or device ≤ 28 days prior to randomization.
Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization.
Iron chelation therapy, if initiated ≤ 24 weeks prior to randomization (allowed if initiated > 24 weeks before or during treatment).
Hydroxyurea treatment ≤ 24 weeks prior to randomization.
Pregnant or lactating females.
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).
Major organ damage, including:
1. Liver disease with alanine aminotransferase (ALT) > 3 x the upper limit of normal (ULN) or history of evidence of cirrhosis;
2. Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization.
3. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant ie, ≥ Grade 3 NCI CTCAE version 4.0 (current active minor version).
4. Creatinine clearance < 60 mL/min (per Cockroft-Gault formula).
Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).
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).
Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
Cytotoxic agents, immunosuppressants ≤ 28 days prior to randomization (ie, antithymocite globulin (ATG) or cyclosporine)
History of malignancy with the exception of:
1. Curatively resected nonmelanoma skin cancer.
2. Curatively treated cervical carcinoma in situ.
3. Other solid tumor with no known active disease in the opinion of the investigator.

Name	Affiliation	Role
Bristol-Myers Squibb	Bristol-Myers Squibb	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Children's Hospital of Los Angeles		Los Angeles	California	90027	United States
Children's Hospital and Research Center at Oakland

PubMed Identifier	Type	Citation	Retractions
30504333	Result	Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361-370. doi: 10.1182/asheducation-2018.1.361.
30617198	Result	Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

Label	URL
BMS Clinical Trial Information	View source

ID	Title	Description
FG000	Luspatercept + BSC	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

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 11, 2018	Dec 4, 2019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Participants Who Achieved Erythroid Response - Week 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.

All randomized participants

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000224 OG001112

Title

Denominators

Categories

Title	Measurements
	OG00021.0 OG0014.5

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Cochran-Mantel-Haenszel		<0.0001	Significance level of 0.050 for 2-sided tests.	Odds Ratio (OR)	5.62			2-Sided	95	2.17	14.53					Superiority

Secondary

Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 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.

All randomized participants

Posted

Number

Percentage of participants

Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 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.

All randomized participants

Posted

Number

Percentage of participants

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

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - 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.

All randomized participants

Posted

Number

Percentage of participants

Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Mean Change From Baseline in Transfusion Burden - Week 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.

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

RBC units

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

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Mean Change From Baseline In Liver Iron Concentration (LIC) At 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.

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

mg/g dry weight

Baseline: Week -12 to Day -1; Treatment: Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48

Three different types of Iron Chelation Therapy (ICT) were analyzed: 1. Deferasirox 2. Deferiprone 3. 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.

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Mean Change From Baseline In Mean Serum Ferritin At 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.

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

μg/L

Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At 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.

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

gm/cm^2

Baseline: Day 1; Treatment: Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Mean Change From Baseline In Myocardial Iron At 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).

All randomized participants with available measurements at the specified timepoints

Posted

Mean

Standard Deviation

Baseline: Day 1; Treatment: Week 48

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At 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.

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

Posted

Mean

Standard Deviation

Score on a scale

Baseline: 4 weeks prior to Day 1; Treatment: Week 24

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At 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: 1. Physical Functioning (Range of possible T-scores is 19.26 - 57.54) 2. General Health (Range of possible T-scores is 18.95 - 66.50) 3. Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.

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

Posted

Mean

Standard Deviation

T-score

Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC

Secondary

Number of Participants Who Utilized Healthcare Resources During Study

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

All randomized participants

Posted

Count of Participants

Participants

From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Number of Days Spent in Higher Care Hospital Units

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

All randomized participants who spent time in higher care hospital units

Posted

Mean

Standard Deviation

Days

From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment

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.

All randomized participants

Posted

Number

Percentage of participants

From first dose through 3 weeks post last dose (up to approximately 218 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Duration of Reduction in Transfusion Burden

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

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

Posted

Mean

Standard Deviation

Days

From first dose to end of study treatment (up to approximately 215 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts

Secondary

Longest Duration of Transfusion Independence

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.

All randomized participants who were transfusion independent for ≥ 8 weeks

Posted

Median

95% Confidence Interval

Days

From first dose through 3 weeks post last dose (up to approximately 218 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts

Secondary

Time to Erythroid Response

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.

All randomized participants who achieved erythroid response

Posted

Mean

Standard Deviation

Days

From first dose to 48 weeks following first dose

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units

Secondary

Post-Baseline Transfusion Event Frequency

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

All randomized participants who received transfusions

Posted

Mean

Standard Deviation

Number of transfusions

From first dose through 3 weeks post last dose (up to approximately 218 weeks)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

L/day

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

Liters

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

days

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

All randomized participants with available PK measurements for Luspatercept

Posted

Median

Full Range

Days

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

μg/mL

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

μg/mL

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants	OG000

Secondary

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)

All randomized participants with available PK measurements for Luspatercept

Posted

Geometric Mean

Geometric Coefficient of Variation

day*μg/mL

Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Units	Counts
Participants

Secondary

Participants With Treatment-Emergent Adverse Events (TEAE)

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

All treated participants

Posted

Count of Participants

Participants

From first dose to 90 days following last dose (up to approximately 52 months)

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC

Secondary

Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

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."

All treated participants with available measurements

Posted

Count of Participants

Participants

Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316

ID	Title	Description
OG000	Luspatercept + BSC	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
OG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0004 affected223 at risk EG0010 affected109 at risk
Extramedullary haemopoiesis	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pancytopenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Cardiac arrest	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Cardiac iron overload	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Left ventricular dysfunction	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Colitis	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Food poisoning	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Hyperpyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pain	General disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Cholangitis	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0003 affected223 at risk EG0012 affected109 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Drug-induced liver injury	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Gallbladder obstruction	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Hepatitis acute	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Portal vein thrombosis	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Acute sinusitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Appendicitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Bacteraemia	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Cellulitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0003 affected223 at risk EG0010 affected109 at risk
Dengue fever	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Epstein-Barr virus infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Gallbladder empyema	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Gastroenteritis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Large intestine infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Neutropenic sepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Parotid abscess	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pharyngitis bacterial	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pneumonia	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Pulmonary sepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pyelonephritis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Septic shock	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Splenic abscess	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Tonsillitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Urinary tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0011 affected109 at risk
Urosepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Vestibular neuronitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Viral infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Viral sepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0002 affected223 at risk EG0010 affected109 at risk
Wound infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Radius fracture	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Thermal burn	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Thoracic vertebral fracture	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Traumatic fracture	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Blood uric acid increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Coombs direct test positive	Investigations	MedDRA 23.0	Systematic Assessment	EG0000 affected223 at risk EG0011 affected109 at risk
Urine albumin/creatinine ratio increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Acute erythroid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Hepatocellular carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Meningioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Cerebral venous sinus thrombosis	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Dizziness	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Haemorrhage intracranial	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Intracranial aneurysm	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Neuritis	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Spinal cord compression	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Thrombotic stroke	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0003 affected223 at risk EG0010 affected109 at risk
Nephrolithiasis	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Renal colic	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Renal injury	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Pulmonary hypertension	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0003 affected223 at risk EG0010 affected109 at risk
Hypertension	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk
Thrombophlebitis superficial	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0001 affected223 at risk EG0010 affected109 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00030 affected223 at risk EG0017 affected109 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00025 affected223 at risk EG0018 affected109 at risk
Constipation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0014 affected109 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00041 affected223 at risk EG00114 affected109 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00019 affected223 at risk EG0011 affected109 at risk
Nausea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00029 affected223 at risk EG0016 affected109 at risk
Toothache	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00015 affected223 at risk EG0015 affected109 at risk
Vomiting	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00030 affected223 at risk EG0018 affected109 at risk
Asthenia	General disorders	MedDRA 23.0	Systematic Assessment	EG00026 affected223 at risk EG00111 affected109 at risk
Fatigue	General disorders	MedDRA 23.0	Systematic Assessment	EG00038 affected223 at risk EG00116 affected109 at risk
Influenza like illness	General disorders	MedDRA 23.0	Systematic Assessment	EG00021 affected223 at risk EG0018 affected109 at risk
Injection site pain	General disorders	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0013 affected109 at risk
Pain	General disorders	MedDRA 23.0	Systematic Assessment	EG00014 affected223 at risk EG0014 affected109 at risk
Pyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG00047 affected223 at risk EG00124 affected109 at risk
Gastroenteritis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00018 affected223 at risk EG0019 affected109 at risk
Influenza	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00025 affected223 at risk EG0018 affected109 at risk
Nasopharyngitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00017 affected223 at risk EG0014 affected109 at risk
Pharyngitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00036 affected223 at risk EG00115 affected109 at risk
Tonsillitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00016 affected223 at risk EG0012 affected109 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00093 affected223 at risk EG00143 affected109 at risk
Urinary tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG00013 affected223 at risk EG0016 affected109 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0008 affected223 at risk EG0018 affected109 at risk
Transfusion reaction	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0015 affected109 at risk
Alanine aminotransferase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0014 affected109 at risk
Liver iron concentration increased	Investigations	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0012 affected109 at risk
Hyperuricaemia	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG00016 affected223 at risk EG0010 affected109 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00051 affected223 at risk EG00115 affected109 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00072 affected223 at risk EG00133 affected109 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00050 affected223 at risk EG0019 affected109 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG0008 affected223 at risk EG0018 affected109 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00021 affected223 at risk EG00111 affected109 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00028 affected223 at risk EG00111 affected109 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00014 affected223 at risk EG0019 affected109 at risk
Osteoporosis	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00013 affected223 at risk EG0017 affected109 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00033 affected223 at risk EG00112 affected109 at risk
Spinal pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0015 affected109 at risk
Dizziness	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00029 affected223 at risk EG0015 affected109 at risk
Headache	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00078 affected223 at risk EG00127 affected109 at risk
Lethargy	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0014 affected109 at risk
Menstruation irregular	Reproductive system and breast disorders	MedDRA 23.0	Systematic Assessment	EG00012 affected223 at risk EG0016 affected109 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG00048 affected223 at risk EG00113 affected109 at risk
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG00021 affected223 at risk EG0013 affected109 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG00041 affected223 at risk EG00113 affected109 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG00017 affected223 at risk EG0014 affected109 at risk
Hypertension	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG00023 affected223 at risk EG0013 affected109 at risk

ID	Term
D013789	Thalassemia
D000745	Anemia, Hemolytic, Congenital
D000743	Anemia, Hemolytic
D000740	Anemia
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D006453	Hemoglobinopathies
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities

ID	Title	Description
BG000	Luspatercept + BSC	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
BG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Luspatercept + BSC	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	4	223	53	223	211	223
EG001	Placebo + BSC	Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care	1	109	8	109	95	109