MEDALIST: A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02631070
• Collaborator: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
• Enrollment: 229
• Locations: 74
• Arms: 2
• Actual Duration (Months): 57.6
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Luspatercept; Other: Placebo	Phase 3

Detailed Description

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 229 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, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions.
• Actual Study Start Date: Feb 9, 2016
• Actual Primary Completion Date: Jun 18, 2019
• Actual Study Completion Date: Nov 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Arm - Luspatercept (ACE-536) Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks	Drug: Luspatercept; Other Names: ACE-536
Placebo Comparator: Control Arm: Placebo Subcutaneous injection every 3 weeks	Other: Placebo

Outcome Measures

Primary Outcome Measures

1. Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24 [From Week 1 through Week 24 of study treatment]

   RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

Secondary Outcome Measures

1. Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24 [From Week 1 through Week 24 of study treatment]

   RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.

2. Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48 [From Week 1 through Week 48 of study treatment]

   RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.

3. Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48 [From Week 1 through Week 48 of study treatment]

   RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.

4. Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period [At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48]

   Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.

5. Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period [Week 1 through 24 or Week 1 Through Week 48]

   A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of <4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.

6. Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions [Week 1 though Week 24 and Week 1 through 48]

   A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).

7. Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24 [From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks]

   Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

8. Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48 [From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks]

   Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

9. Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score [Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.]

   The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.

10. Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period [Week 1 through Week 24 or Week 1 Through Week 48 of study treatment]

    Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase > 0.5 X 10^9/L.

11. Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period [Week 1 through Week 24 or Week 1 Through Week 48 of study treatment]

    Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as: Absolute increase of ≥ 30 X 10^9/L in platelets for participants starting with > 20 X 10^9/L platelets Increase in platelets from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%

12. Change From Baseline in Mean Serum Ferritin [Baseline and Week 9 through Week 24 and Week 33 through Week 48]

    Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.

13. Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT) [Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment]

    Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.

14. Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24 [From first dose to Week 24 of study treatment]

    Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24

15. Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48 [From first dose to Week 48 of study treatment]

    Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48

16. Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML) [From randomization to study completion (up to approximately 57 months)]

    Percentage of participants progressing to AML throughout the course of the study

17. Time to Acute Myeloid Leukemia (AML) Progression [From randomization to study completion (up to approximately 57 months)]

    Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML.

18. Overall Survival [From randomization to study completion (up to approximately 57 months)]

    Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.

19. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)]

    The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs). TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP. The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

20. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).

21. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.

22. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.

23. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Tmax was defined as the observed time to maximum plasma concentration of luspatercept.

24. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.

25. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.

26. Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss) [Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.]

    Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.

27. Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) [From randomization to 1 year post first dose]

    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. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

2. Documented diagnosis of MDS according to World Health Organization (WHO)/French American British (FAB) classification that meets IPSS R classification of very low, low, or intermediate risk disease, and:

Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present.

• < 5% blasts in bone marrow

• Peripheral blood white blood cell (WBC) count < 13,000/µL 3. Requires red blood cell RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5. Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating agents (ESA) treatment, defined as:

• Refractory to prior - erythropoietin stimulating agents treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with granulocyte colony stimulating factor (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent

• Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event

• ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Prior therapy with disease modifying agents for underlying MDS disease.

2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)

3. MDS associated with del 5q cytogenetic abnormality

4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.

5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

• iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate stain for iron).

1. Prior allogeneic or autologous stem cell transplant

2. Known history of diagnosis of acute myeloid leukemia (AML)

3. Use of any of the following within 5 weeks prior to randomization:

• anticancer cytotoxic chemotherapeutic agent or treatment

• corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS

• iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization

• other RBC hematopoietic growth factors (eg, Interleukin-3)

• investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to randomization or within 5 weeks, whichever is longer is excluded.

1. Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

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

1. Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Center	Stanford	California	United States	94305
2	Yale University School of Medicine	New Haven	Connecticut	United States	06510
3	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Emory University Hospital	Atlanta	Georgia	United States	30322
5	Ochsner Medical Institutions	New Orleans	Louisiana	United States	70123
6	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
7	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
8	Montefiore Medical Center Albert Einstein Cancer Center	Bronx	New York	United States	10467
9	Columbia-Presbyterian Medical Center	New York	New York	United States	10032
10	Gabrail Cancer Center	Canton	Ohio	United States	44718
11	Cleveland Clinic Taussig Cancer Institute	Cleveland	Ohio	United States	44195-0001
12	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
13	MD Anderson Cancer Center	Houston	Texas	United States	77030
14	Algemeen Ziekenhuis Klina	Brasschaat		Belgium	2930
15	AZ Sint-Jan AV Brugge	Brugge		Belgium	8000
16	UZ Brussels	Brussel		Belgium	1090
17	Grand Hopital de Charleroi	Charleroi		Belgium	6000
18	UZ Gent	Gent		Belgium	9000
19	UZ Leuven	Leuven		Belgium	3000
20	Cliniques Universitaires UCL de Mont-Godine	Yvoir		Belgium	5530
21	Tom Baker Cancer Center	Calgary	Alberta	Canada	T2N 4N2
22	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 1C3
23	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
24	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
25	CHU d'Angers	Angers		France	49033
26	CHU Hotel	Grenoble Cedex 09		France	38043
27	CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang	Lille		France	59037
28	Institut Paoli Calmettes	Marseille cedex		France	13273
29	CHU de Nice Archet I	Nice		France	06202
30	Hopital Saint Louis	Paris		France	75010
31	Hopital Haut Leveque	Pessac Cedex		France	33604
32	Centre hospitalier Lyon Sud Hematologie	Pierre-Bénite cedex		France	69495
33	Hopital civil	Strasbourg		France	67091
34	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse Cedex 9		France	31059
35	Hopital Bretonneau	Tours		France	37044
36	Universitatsklinikum Bonn	Bonn		Germany	53105
37	Universitatsklinikum Carl Gustav Carus an der TU Dresden	Dresden		Germany	01307
38	Marien Hospital	Dusseldorf		Germany	40479
39	Universitätsklinikum Düsseldorf	Düsseldorf		Germany	40225
40	Medizinische Hochschule Hannover	Hannover		Germany	30625
41	Klinikum rechts der Isar der Technischen Universität München	München		Germany	81675
42	Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo	Allessandria		Italy	15100
43	Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola Malpighi	Bologna		Italy	40138
44	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50121
45	Azienda Sanitaria Locale Lecce	Lecce		Italy	73100
46	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
47	Azienda Ospedaliera Bianchi Melacrino Morelli	Reggio, Calabria		Italy	89100
48	Fondazione Policlinico Universitario A Gemelli	Roma		Italy	00168
49	Fondazione PTV Policlinico Tor Vergata	Roma		Italy	00168
50	VU Medisch Centrum	Amsterdam		Netherlands	1081 HV
51	Universitair Medisch Centrum Groningen	Groningen		Netherlands	9713 GZ
52	Spaarne Ziekenhuis	Hoofddorp		Netherlands	2135
53	Hospital Universitario Cruces	Barakaldo		Spain	48903
54	Hospital Universitario Vall D hebron	Barcelona		Spain	08035
55	Instituto Catalan de Oncologia-Hospital Duran i Reynals	Barcelona		Spain	08908
56	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
57	Hospital Universitario Central de Asturias	Oviedo		Spain	33011
58	Hospital Universitario de Salamanca	Salamanca		Spain	37007
59	Hospital Universitario Virgen del Rocio	Seville		Spain	41013
60	Hospital Universitario La Fe	Valencia		Spain	46026
61	Sahlgrenska Universitetssjukhus	Göteborg		Sweden	SE-41685
62	Skanes Universitetssjukhus Lund	Lund		Sweden	222 41
63	Karolinska University Hospital	Stockholm		Sweden	SE-17176
64	Akademiska Sjukhuset	Uppsala		Sweden	75185
65	Cukurova University Medical Faculty Balcali Hospital	Adana		Turkey	01330
66	Ankara University Medical Faculty Cebeci Hospital	Ankara		Turkey	06590
67	Istanbul University Cerrahpasa Medical Faculty Hospital	Istanbul		Turkey	34098
68	Ege Universitesi Tip Fakultesi Hastanesi	Izmir		Turkey	35100
69	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
70	John Radcliffe Hospital	Headington		United Kingdom	OX3 9DU
71	St James University Hospital	Leeds		United Kingdom	LS1 3EX
72	Guys Hospital	London		United Kingdom	SE1 9RT
73	Kings College Hospital	London		United Kingdom	SE5 9RS
74	Kings Mill Hospital	Sutton in Ashfield		United Kingdom	NG17 4SL

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: Rodrigo Ito, MD, Celgene

Study Documents (Full-Text)

• Study Protocol - May 9, 2017
• Statistical Analysis Plan - May 31, 2018

More Information

Publications

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

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02631070
• Other Study ID Numbers: ACE-536-MDS-001; 2015-003454-41
• First Posted: Dec 15, 2015
• Last Update Posted: Dec 17, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Celgene: Luspatercept; Transfusion dependent; Lower risk; Low risk; Myelodysplastic Syndromes; ESA refractory; ESA intolerant; ESA ineligible; ACE-536; Anemia; Ring Sideroblasts; Require Red Blood Cell Transfusions; MEDALIST; MDS; IPSS-R very low/IPSS-R low/IPSS-R intermediate
• Additional relevant MeSH terms: Preleukemia; Anemia; Myelodysplastic Syndromes; Syndrome; Luspatercept

Study Results

Participant Flow

Pre-assignment Detail	229 participants were randomized and treated.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Period Title: Overall Study
STARTED	153	76
COMPLETED	4	12
NOT COMPLETED	149	64

Baseline Characteristics

Arm/Group Title	Luspatercept	Placebo	Total
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle	Total of all reporting groups
Overall Participants	153	76	229
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.5 (8.68)	70.7 (10.88)	70.6 (9.44)
Sex: Female, Male (Count of Participants)
Female	59 38.6%	26 34.2%	85 37.1%
Male	94 61.4%	50 65.8%	144 62.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 2%	4 5.3%	7 3.1%
Not Hispanic or Latino	115 75.2%	52 68.4%	167 72.9%
Unknown or Not Reported	35 22.9%	20 26.3%	55 24%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	1 0.7%	0 0%	1 0.4%
White	107 69.9%	51 67.1%	158 69%
Not Collected or Reported	44 28.8%	24 31.6%	68 29.7%
Other	1 0.7%	1 1.3%	2 0.9%

Outcome Measures

1. Primary Outcome

Title	Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
Description	RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.
Time Frame	From Week 1 through Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Number (95% Confidence Interval) [Percent of Participants]	37.91 24.8%	13.16 17.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Common Risk Difference on Response Rate
	Estimated Value	24.56
	Confidence Interval	(2-Sided) 95%; 14.48 to 34.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.065
	Confidence Interval	(2-Sided) 95%; 2.278 to 11.259
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
Description	RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.
Time Frame	From Week 1 through Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Number (95% Confidence Interval) [Percent of Participants]	28.10 18.4%	7.89 10.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Common Risk Difference on Response Rate
	Estimated Value	20.00
	Confidence Interval	(2-Sided) 95%; 10.92 to 29.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.071
	Confidence Interval	(2-Sided) 95%; 2.002 to 12.844
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
Description	RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.
Time Frame	From Week 1 through Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Number (95% Confidence Interval) [Percent of Participants]	33.33 21.8%	11.84 15.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Common Risk Difference on Response Rate
	Estimated Value	21.37
	Confidence Interval	(2-Sided) 95%; 11.23 to 31.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.045
	Confidence Interval	(2-Sided) 95%; 1.827 to 8.956
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
Description	RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.
Time Frame	From Week 1 through Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Number (95% Confidence Interval) [Percentage of Participants]	45.10 29.5%	15.79 20.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Common Risk Difference on Response Rate
	Estimated Value	29.55
	Confidence Interval	(2-Sided) 95%; 18.73 to 40.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.306
	Confidence Interval	(2-Sided) 95%; 2.526 to 11.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period
Description	Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.
Time Frame	At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements at the indicated timepoints

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	128	68
Weeks 9 to 24	-3.0 (5.17)	0.4 (4.25)
Weeks 33 to 48	-4.9 (4.22)	-3.9 (7.14)

6. Secondary Outcome

Title	Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period
Description	A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of <4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
Time Frame	Week 1 through 24 or Week 1 Through Week 48

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Week 1 Through Week 24	52.9 34.6%	11.8 15.5%
Week 1 Through Week 48	58.8 38.4%	17.1 22.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 -24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 - 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions
Description	A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).
Time Frame	Week 1 though Week 24 and Week 1 through 48

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Week 1 Through Week 24	35.3 23.1%	7.9 10.4%
Week 1 Through Week 48	41.2 26.9%	10.5 13.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 Through Week 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 Through Week 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
Description	Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
Time Frame	From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Outcome Measure Data

Analysis Population Description

All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24 of study treatment

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	58	10
Median (95% Confidence Interval) [Weeks]	30.6	13.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0445
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.446
	Confidence Interval	(2-Sided) 95%; 0.196 to 1.013
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is from the Cox proportional hazards model

9. Secondary Outcome

Title	Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
Description	Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
Time Frame	From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Outcome Measure Data

Analysis Population Description

All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48 of study treatment

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	69	12
Median (95% Confidence Interval) [Weeks]	30.6	18.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5121
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.784
	Confidence Interval	(2-Sided) 95%; 0.362 to 1.699
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is from the Cox proportional hazards model

10. Secondary Outcome

Title	Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score
Description	The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.
Time Frame	Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.

Outcome Measure Data

Analysis Population Description

All treated participants who completed the EORTC QLQ-C30 assessment at baseline and at least one post-baseline assessment visit.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	149	76
Cycle 3 Day 1 (C3 D1)	-4.1 (21.01)	0.1 (15.95)
C5 D1	-2.4 (20.73)	2.2 (17.13)
C7 D1	-2.1 (23.04)	-0.6 (18.63)
Week 25	-1.8 (21.75)	0.2 (18.88)
Extension Phase C1 D1	0.0 (25.32)	6.3 (14.60)
Extension Phase C3 D1	2.0 (19.68)	-3.9 (26.86)
Extension Phase C5 D1	0.8 (18.40)	0.6 (20.04)
Extension Phase C7 D1	-0.5 (20.03)	3.8 (20.87)
Extension Phase C9 D1	-2.4 (18.42)	11.9 (19.75)
Extension Phase C11 D1	-1.8 (19.53)	4.8 (24.47)
Extension Phase C13 D1	-2.6 (20.84)	8.3 (24.15)
Extension Phase C15 D1	3.1 (18.27)	4.2 (27.26)
Extension Phase C17 D1	-0.6 (19.03)	13.9 (26.79)
Extension Phase C19 D1	-1.6 (18.78)	-16.7 (14.43)
Extension Phase C21 D1	3.1 (18.32)	4.2 (17.68)
Extension Phase C23 D1	0.9 (17.84)	16.7 (NA)
Extension Phase C25 D1	-2.0 (18.15)	16.7 (NA)
Extension Phase C27 D1	2.5 (20.40)
Extension Phase C29 D1	2.1 (21.12)
Extension Phase C31 D1	-0.3 (15.93)
Extension Phase C33 D1	-1.5 (19.41)
Extension Phase C35 D1	3.6 (23.33)
Extension Phase C37 D1	0.5 (22.04)
Extension Phase C39 D1	0.3 (23.63)
Extension Phase C41 D1	6.6 (20.11)
Extension Phase C43 D1	4.8 (15.29)
Extension Phase C45 D1	-2.2 (21.24)
Extension Phase C47 D1	1.4 (19.08)
Extension Phase C49 D1	-3.8 (16.40)
Extension Phase C51 D1	8.3 (8.33)
Extension Phase C53 D1	12.5 (10.76)
Extension Phase C55 D1	2.8 (17.35)
Extension Phase C57 D1	12.5 (5.89)
Extension Phase C59 D1	16.7 (NA)
End of Treatment	-9.2 (23.97)	-0.8 (23.07)

11. Secondary Outcome

Title	Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period
Description	Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase > 0.5 X 10^9/L.
Time Frame	Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	15	10
Week 1 Through Week 24	13.3 8.7%	0 0%
Week 1 Through Week 48	20.0 13.1%	10.0 13.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 -24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2382
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 - 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5127
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

12. Secondary Outcome

Title	Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period
Description	Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI - P reponse was defined as: Absolute increase of ≥ 30 X 10^9/L in platelets for participants starting with > 20 X 10^9/L platelets Increase in platelets from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%
Time Frame	Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	8	6
Week 1 Through Week 24	50.0 32.7%	33.3 43.8%
Week 1 Through Week 48	62.5 40.8%	33.3 43.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 -24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5479
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 1 - 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2980
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

13. Secondary Outcome

Title	Change From Baseline in Mean Serum Ferritin
Description	Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.
Time Frame	Baseline and Week 9 through Week 24 and Week 33 through Week 48

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	148	74
Weeks 9-24	-2.7 (54.05)	226.5 (68.02)
Weeks 33-48	-72.0 (74.76)	247.4 (140.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 9 Through 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-229.1
	Confidence Interval	(2-Sided) 95%; -375.8 to -82.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 74.43
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Week 33 Through 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0294
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-319.5
	Confidence Interval	(2-Sided) 95%; -606.3 to -32.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 144.57
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)
Description	Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.
Time Frame	Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All treated participants with available measurements

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	128	68
Weeks 9-24	10.0 (29.25)	51.0 (35.92)
Weeks 33-48	-148.8 (46.13)	-123.8 (92.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Weeks 9 Through 24
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3087
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-41.0
	Confidence Interval	(2-Sided) 95%; -120.3 to 38.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 40.18
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments	Weeks 33 Through 48
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7903
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-24.9
	Confidence Interval	(2-Sided) 95%; -210.7 to 160.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 93.42
	Estimation Comments

15. Secondary Outcome

Title	Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
Description	Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24
Time Frame	From first dose to Week 24 of study treatment

Outcome Measure Data

Analysis Population Description

All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	58	10
Mean (Standard Deviation) [Days]	17.2 (29.40)	26.0 (31.83)

16. Secondary Outcome

Title	Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
Description	Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48
Time Frame	From first dose to Week 48 of study treatment

Outcome Measure Data

Analysis Population Description

All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	69	12
Mean (Standard Deviation) [Days]	40.3 (61.03)	57.2 (79.18)

17. Secondary Outcome

Title	Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)
Description	Percentage of participants progressing to AML throughout the course of the study
Time Frame	From randomization to study completion (up to approximately 57 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Number [Percentage of Participants]	2.6 1.7%	3.9 5.1%

18. Secondary Outcome

Title	Time to Acute Myeloid Leukemia (AML) Progression
Description	Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML.
Time Frame	From randomization to study completion (up to approximately 57 months)

Outcome Measure Data

Analysis Population Description

All treated participants who progressed to AML

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	4	3
Median (95% Confidence Interval) [Months]	NA	NA

19. Secondary Outcome

Title	Overall Survival
Description	Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.
Time Frame	From randomization to study completion (up to approximately 57 months)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Median (95% Confidence Interval) [Months]	46.0	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Luspatercept, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9580
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.986
	Confidence Interval	(2-Sided) 95%; 0.595 to 1.636
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is from the Cox proportional hazards model

20. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs). TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP. The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
Time Frame	From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
≥ 1 TEAE	151 98.7%	70 92.1%
≥ 1 Suspected Related TEAE	71 46.4%	26 34.2%
≥ 1 Serious TEAE	66 43.1%	23 30.3%
≥ 1 Suspected Related Serious TEAE	6 3.9%	0 0%
≥ 1 TEAE CTCAE Toxicity Grade (GR) 5	8 5.2%	4 5.3%
≥ 1 Suspected Related TEAE With CTCAE GR 5	0 0%	0 0%
≥ 1 TEAE with CTCAE GR 3 or 4	86 56.2%	34 44.7%
≥ 1 Suspected Related TEAE With CTCAE GR 3 or 4	13 8.5%	3 3.9%
≥ 1 TEAE Leading to Dose Interruption	42 27.5%	4 5.3%
≥ 1 TEAE Leading to Dose Reduction	9 5.9%	0 0%
≥ 1 TEAE Leading to Study Drug Discontinuation	22 14.4%	6 7.9%

21. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
Description	Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [L/day]	0.516 (41.2)

22. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
Description	Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [L]	9.68 (26.5)

23. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
Description	Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [Day]	13.0 (31.6)

24. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
Description	Tmax was defined as the observed time to maximum plasma concentration of luspatercept.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Median (Full Range) [Day]	5.40

25. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)
Description	Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	5.77 (20.5)

26. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State
Description	Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [μg/mL]	9.17 (29.9)

27. Secondary Outcome

Title	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)
Description	Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.
Time Frame	Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	0
Geometric Mean (Geometric Coefficient of Variation) [day/μg/mL]	145 (38.3)

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	From randomization to 1 year post first dose

Outcome Measure Data

Analysis Population Description

Safety population of participants with ADA samples collected.

Arm/Group Title	Luspatercept	Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Measure Participants	153	76
Pre-Existing ADA	7 4.6%	2 2.6%
Treatment Emergent ADA	11 7.2%	3 3.9%
Treatment Emergent Neutralizing ADA	5 3.3%	2 2.6%

Adverse Events

Time Frame	All-cause mortality was assessed from first dose to study completion (up to approximately 57 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 91 weeks)
Arm/Group Title	Luspatercept		Placebo
Arm/Group Description	Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle		Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
All Cause Mortality
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/153 (29.4%)		24/76 (31.6%)
Serious Adverse Events
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/153 (43.1%)		23/76 (30.3%)
Blood and lymphatic system disorders
Anaemia	3/153 (2%)		0/76 (0%)
Disseminated intravascular coagulation	1/153 (0.7%)		0/76 (0%)
Febrile neutropenia	1/153 (0.7%)		0/76 (0%)
Cardiac disorders
Acute myocardial infarction	1/153 (0.7%)		0/76 (0%)
Angina pectoris	3/153 (2%)		0/76 (0%)
Aortic valve stenosis	1/153 (0.7%)		0/76 (0%)
Arteriosclerosis coronary artery	1/153 (0.7%)		0/76 (0%)
Atrial fibrillation	2/153 (1.3%)		0/76 (0%)
Atrioventricular block	2/153 (1.3%)		0/76 (0%)
Atrioventricular block second degree	1/153 (0.7%)		0/76 (0%)
Bradycardia	1/153 (0.7%)		0/76 (0%)
Cardiac failure	2/153 (1.3%)		0/76 (0%)
Cardiac failure acute	1/153 (0.7%)		0/76 (0%)
Coronary artery disease	1/153 (0.7%)		0/76 (0%)
Myocardial infarction	0/153 (0%)		1/76 (1.3%)
Supraventricular tachycardia	1/153 (0.7%)		0/76 (0%)
Gastrointestinal disorders
Abdominal pain	1/153 (0.7%)		0/76 (0%)
Abdominal pain upper	1/153 (0.7%)		0/76 (0%)
Ascites	1/153 (0.7%)		0/76 (0%)
Constipation	1/153 (0.7%)		0/76 (0%)
Duodenal ulcer	1/153 (0.7%)		0/76 (0%)
Duodenal ulcer haemorrhage	1/153 (0.7%)		0/76 (0%)
Dysphagia	1/153 (0.7%)		0/76 (0%)
Gastrointestinal haemorrhage	1/153 (0.7%)		0/76 (0%)
Nausea	1/153 (0.7%)		0/76 (0%)
Pancreatitis acute	1/153 (0.7%)		0/76 (0%)
Vomiting	1/153 (0.7%)		0/76 (0%)
General disorders
Asthenia	1/153 (0.7%)		0/76 (0%)
Chest pain	1/153 (0.7%)		0/76 (0%)
Death	0/153 (0%)		1/76 (1.3%)
Gait disturbance	1/153 (0.7%)		0/76 (0%)
General physical health deterioration	0/153 (0%)		1/76 (1.3%)
Generalised oedema	1/153 (0.7%)		0/76 (0%)
Multiple organ dysfunction syndrome	1/153 (0.7%)		0/76 (0%)
Non-cardiac chest pain	1/153 (0.7%)		0/76 (0%)
Pyrexia	3/153 (2%)		2/76 (2.6%)
Hepatobiliary disorders
Cholangitis	0/153 (0%)		1/76 (1.3%)
Cholelithiasis	1/153 (0.7%)		0/76 (0%)
Hyperbilirubinaemia	1/153 (0.7%)		0/76 (0%)
Infections and infestations
Abdominal infection	1/153 (0.7%)		0/76 (0%)
Bacteraemia	0/153 (0%)		1/76 (1.3%)
Bronchitis	2/153 (1.3%)		0/76 (0%)
Cellulitis	1/153 (0.7%)		1/76 (1.3%)
Diverticulitis	0/153 (0%)		1/76 (1.3%)
Endocarditis	1/153 (0.7%)		0/76 (0%)
Enterocolitis infectious	0/153 (0%)		1/76 (1.3%)
Epididymitis	1/153 (0.7%)		0/76 (0%)
Escherichia urinary tract infection	1/153 (0.7%)		0/76 (0%)
Gastroenteritis	1/153 (0.7%)		0/76 (0%)
Localised infection	1/153 (0.7%)		0/76 (0%)
Lower respiratory tract infection	2/153 (1.3%)		0/76 (0%)
Metapneumovirus infection	0/153 (0%)		1/76 (1.3%)
Orchitis	1/153 (0.7%)		0/76 (0%)
Parainfluenzae virus infection	1/153 (0.7%)		0/76 (0%)
Pharyngitis	1/153 (0.7%)		0/76 (0%)
Pneumonia	8/153 (5.2%)		2/76 (2.6%)
Pneumonia moraxella	1/153 (0.7%)		0/76 (0%)
Pneumonia staphylococcal	1/153 (0.7%)		0/76 (0%)
Sepsis	4/153 (2.6%)		1/76 (1.3%)
Septic shock	1/153 (0.7%)		1/76 (1.3%)
Soft tissue infection	1/153 (0.7%)		0/76 (0%)
Staphylococcal infection	1/153 (0.7%)		0/76 (0%)
Streptococcal infection	0/153 (0%)		1/76 (1.3%)
Upper respiratory tract infection	1/153 (0.7%)		0/76 (0%)
Urinary tract infection	4/153 (2.6%)		1/76 (1.3%)
Urinary tract infection bacterial	0/153 (0%)		1/76 (1.3%)
Urosepsis	1/153 (0.7%)		1/76 (1.3%)
Injury, poisoning and procedural complications
Ankle fracture	0/153 (0%)		1/76 (1.3%)
Clavicle fracture	1/153 (0.7%)		0/76 (0%)
Fall	7/153 (4.6%)		3/76 (3.9%)
Femur fracture	6/153 (3.9%)		0/76 (0%)
Head injury	1/153 (0.7%)		0/76 (0%)
Hip fracture	0/153 (0%)		3/76 (3.9%)
Humerus fracture	2/153 (1.3%)		1/76 (1.3%)
Joint dislocation	1/153 (0.7%)		0/76 (0%)
Joint injury	1/153 (0.7%)		0/76 (0%)
Pelvic bone injury	1/153 (0.7%)		0/76 (0%)
Rib fracture	1/153 (0.7%)		0/76 (0%)
Road traffic accident	1/153 (0.7%)		0/76 (0%)
Spinal column injury	1/153 (0.7%)		0/76 (0%)
Spinal fracture	1/153 (0.7%)		0/76 (0%)
Subdural haematoma	1/153 (0.7%)		0/76 (0%)
Thoracic vertebral fracture	0/153 (0%)		1/76 (1.3%)
Investigations
General physical condition abnormal	1/153 (0.7%)		0/76 (0%)
Metabolism and nutrition disorders
Dehydration	1/153 (0.7%)		0/76 (0%)
Hypoglycaemia	1/153 (0.7%)		0/76 (0%)
Lactic acidosis	1/153 (0.7%)		0/76 (0%)
Type 2 diabetes mellitus	1/153 (0.7%)		0/76 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/153 (2%)		0/76 (0%)
Chondritis	1/153 (0.7%)		0/76 (0%)
Flank pain	1/153 (0.7%)		0/76 (0%)
Gouty arthritis	1/153 (0.7%)		0/76 (0%)
Muscle haemorrhage	1/153 (0.7%)		0/76 (0%)
Muscular weakness	1/153 (0.7%)		0/76 (0%)
Myositis	1/153 (0.7%)		0/76 (0%)
Polymyalgia rheumatica	1/153 (0.7%)		0/76 (0%)
Rheumatoid arthritis	1/153 (0.7%)		0/76 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	3/153 (2%)		0/76 (0%)
Colon adenoma	1/153 (0.7%)		0/76 (0%)
Intraductal papillary mucinous neoplasm	1/153 (0.7%)		0/76 (0%)
Myelodysplastic syndrome	2/153 (1.3%)		1/76 (1.3%)
Refractory anaemia with an excess of blasts	4/153 (2.6%)		0/76 (0%)
Squamous cell carcinoma	1/153 (0.7%)		0/76 (0%)
Squamous cell carcinoma of skin	3/153 (2%)		0/76 (0%)
Systemic mastocytosis	1/153 (0.7%)		0/76 (0%)
Transformation to acute myeloid leukaemia	3/153 (2%)		1/76 (1.3%)
Nervous system disorders
Cerebral haemorrhage	2/153 (1.3%)		0/76 (0%)
Cerebral ischaemia	0/153 (0%)		1/76 (1.3%)
Cerebrospinal fluid leakage	0/153 (0%)		1/76 (1.3%)
Haemorrhage intracranial	0/153 (0%)		1/76 (1.3%)
Seizure	1/153 (0.7%)		0/76 (0%)
Syncope	3/153 (2%)		0/76 (0%)
Product Issues
Thrombosis in device	1/153 (0.7%)		0/76 (0%)
Psychiatric disorders
Confusional state	1/153 (0.7%)		0/76 (0%)
Delirium	0/153 (0%)		1/76 (1.3%)
Suicide attempt	0/153 (0%)		1/76 (1.3%)
Renal and urinary disorders
Acute kidney injury	2/153 (1.3%)		0/76 (0%)
Renal colic	1/153 (0.7%)		0/76 (0%)
Renal failure	1/153 (0.7%)		1/76 (1.3%)
Urethral stenosis	1/153 (0.7%)		0/76 (0%)
Urinary retention	1/153 (0.7%)		1/76 (1.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/153 (0.7%)		0/76 (0%)
Dyspnoea	2/153 (1.3%)		0/76 (0%)
Dyspnoea exertional	1/153 (0.7%)		0/76 (0%)
Epistaxis	2/153 (1.3%)		0/76 (0%)
Hypoxia	1/153 (0.7%)		1/76 (1.3%)
Pulmonary fibrosis	1/153 (0.7%)		0/76 (0%)
Respiratory failure	0/153 (0%)		1/76 (1.3%)
Vascular disorders
Aortic stenosis	1/153 (0.7%)		0/76 (0%)
Granulomatosis with polyangiitis	1/153 (0.7%)		0/76 (0%)
Orthostatic hypotension	1/153 (0.7%)		0/76 (0%)
Shock haemorrhagic	1/153 (0.7%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	Luspatercept		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	145/153 (94.8%)		63/76 (82.9%)
Blood and lymphatic system disorders
Anaemia	14/153 (9.2%)		6/76 (7.9%)
Neutropenia	8/153 (5.2%)		7/76 (9.2%)
Cardiac disorders
Palpitations	11/153 (7.2%)		5/76 (6.6%)
Tachycardia	8/153 (5.2%)		0/76 (0%)
Ear and labyrinth disorders
Vertigo	12/153 (7.8%)		0/76 (0%)
Gastrointestinal disorders
Abdominal pain	11/153 (7.2%)		4/76 (5.3%)
Abdominal pain upper	11/153 (7.2%)		2/76 (2.6%)
Constipation	21/153 (13.7%)		7/76 (9.2%)
Diarrhoea	44/153 (28.8%)		8/76 (10.5%)
Nausea	35/153 (22.9%)		6/76 (7.9%)
Vomiting	14/153 (9.2%)		5/76 (6.6%)
General disorders
Asthenia	40/153 (26.1%)		9/76 (11.8%)
Fatigue	46/153 (30.1%)		11/76 (14.5%)
Influenza like illness	9/153 (5.9%)		3/76 (3.9%)
Malaise	8/153 (5.2%)		3/76 (3.9%)
Oedema peripheral	37/153 (24.2%)		13/76 (17.1%)
Pyrexia	19/153 (12.4%)		6/76 (7.9%)
Infections and infestations
Bronchitis	19/153 (12.4%)		1/76 (1.3%)
Influenza	11/153 (7.2%)		0/76 (0%)
Nasopharyngitis	18/153 (11.8%)		4/76 (5.3%)
Upper respiratory tract infection	19/153 (12.4%)		4/76 (5.3%)
Urinary tract infection	21/153 (13.7%)		4/76 (5.3%)
Injury, poisoning and procedural complications
Fall	25/153 (16.3%)		7/76 (9.2%)
Investigations
Alanine aminotransferase increased	9/153 (5.9%)		3/76 (3.9%)
Aspartate aminotransferase increased	10/153 (6.5%)		1/76 (1.3%)
Weight decreased	9/153 (5.9%)		5/76 (6.6%)
Metabolism and nutrition disorders
Decreased appetite	14/153 (9.2%)		3/76 (3.9%)
Hyperglycaemia	12/153 (7.8%)		3/76 (3.9%)
Hyperkalaemia	10/153 (6.5%)		1/76 (1.3%)
Hyperuricaemia	12/153 (7.8%)		2/76 (2.6%)
Iron overload	9/153 (5.9%)		3/76 (3.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/153 (8.5%)		9/76 (11.8%)
Back pain	32/153 (20.9%)		6/76 (7.9%)
Myalgia	13/153 (8.5%)		5/76 (6.6%)
Nervous system disorders
Dizziness	35/153 (22.9%)		4/76 (5.3%)
Headache	27/153 (17.6%)		5/76 (6.6%)
Syncope	10/153 (6.5%)		1/76 (1.3%)
Psychiatric disorders
Anxiety	9/153 (5.9%)		1/76 (1.3%)
Confusional state	9/153 (5.9%)		0/76 (0%)
Depression	9/153 (5.9%)		5/76 (6.6%)
Insomnia	13/153 (8.5%)		4/76 (5.3%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	8/153 (5.2%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	35/153 (22.9%)		10/76 (13.2%)
Dyspnoea	30/153 (19.6%)		5/76 (6.6%)
Epistaxis	12/153 (7.8%)		3/76 (3.9%)
Oropharyngeal pain	6/153 (3.9%)		6/76 (7.9%)
Skin and subcutaneous tissue disorders
Erythema	2/153 (1.3%)		4/76 (5.3%)
Pruritus	11/153 (7.2%)		3/76 (3.9%)
Vascular disorders
Hypertension	16/153 (10.5%)		6/76 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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