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

Myelodysplastic Syndromes Clinical Trial

— MEDALIST  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02631070
• Other study ID #: ACE-536-MDS-001
• Secondary ID: 2015-003454-41
• Status: Completed
• Phase: Phase 3
• Start date: February 9, 2016
• Est. completion date: November 26, 2020

Study information

• Verified date: November 2021
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 229
• Est. completion date: November 26, 2020
• Est. primary completion date: June 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

6. Prior allogeneic or autologous stem cell transplant

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

8. 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.

9. 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)

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

Related Conditions & MeSH terms

• Anemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Luspatercept

Other:
• Placebo

Locations

Country	Name	City	State
Belgium	Algemeen Ziekenhuis Klina	Brasschaat
Belgium	AZ Sint-Jan AV Brugge	Brugge
Belgium	UZ Brussels	Brussel
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	Cliniques Universitaires UCL de Mont-Godine	Yvoir
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
France	CHU d'Angers	Angers
France	CHU Hotel	Grenoble Cedex 09
France	CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang	Lille
France	Institut Paoli Calmettes	Marseille cedex
France	CHU de Nice Archet I	Nice
France	Hopital Saint Louis	Paris
France	Hopital Haut Leveque	Pessac Cedex
France	Centre hospitalier Lyon Sud Hematologie	Pierre-Bénite cedex
France	Hopital civil	Strasbourg
France	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse Cedex 9
France	Hopital Bretonneau	Tours
Germany	Universitatsklinikum Bonn	Bonn
Germany	Universitatsklinikum Carl Gustav Carus an der TU Dresden	Dresden
Germany	Marien Hospital	Dusseldorf
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Klinikum rechts der Isar der Technischen Universität München	München
Italy	Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo	Allessandria
Italy	Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola Malpighi	Bologna
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Azienda Sanitaria Locale Lecce	Lecce
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliera Bianchi Melacrino Morelli	Reggio, Calabria
Italy	Fondazione Policlinico Universitario A Gemelli	Roma
Italy	Fondazione PTV Policlinico Tor Vergata	Roma
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Spaarne Ziekenhuis	Hoofddorp
Spain	Hospital Universitario Cruces	Barakaldo
Spain	Hospital Universitario Vall D hebron	Barcelona
Spain	Instituto Catalan de Oncologia-Hospital Duran i Reynals	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocio	Seville
Spain	Hospital Universitario La Fe	Valencia
Sweden	Sahlgrenska Universitetssjukhus	Göteborg
Sweden	Skanes Universitetssjukhus Lund	Lund
Sweden	Karolinska University Hospital	Stockholm
Sweden	Akademiska Sjukhuset	Uppsala
Turkey	Cukurova University Medical Faculty Balcali Hospital	Adana
Turkey	Ankara University Medical Faculty Cebeci Hospital	Ankara
Turkey	Istanbul University Cerrahpasa Medical Faculty Hospital	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Hastanesi	Izmir
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	John Radcliffe Hospital	Headington
United Kingdom	St James University Hospital	Leeds
United Kingdom	Guys Hospital	London
United Kingdom	Kings College Hospital	London
United Kingdom	Kings Mill Hospital	Sutton in Ashfield
United States	Emory University Hospital	Atlanta	Georgia
United States	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Montefiore Medical Center Albert Einstein Cancer Center	Bronx	New York
United States	Gabrail Cancer Center	Canton	Ohio
United States	Cleveland Clinic Taussig Cancer Institute	Cleveland	Ohio
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	MD Anderson Cancer Center	Houston	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Ochsner Medical Institutions	New Orleans	Louisiana
United States	Columbia-Presbyterian Medical Center	New York	New York
United States	Stanford Cancer Center	Stanford	California
United States	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Celgene	Acceleron Pharma Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Spain,  Sweden,  Turkey,  United Kingdom, 

References & Publications (5)

Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019 Feb 21;133(8):790-794. doi: 10.1182/blood-2018-11-876888. Epub 2019 Jan 2. Review. — View Citation

Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Götze KS, Q — View Citation

Komrokji RS. Luspatercept in Myelodysplastic Syndromes: Who and When? Hematol Oncol Clin North Am. 2020 Apr;34(2):393-400. doi: 10.1016/j.hoc.2019.10.004. Epub 2020 Jan 21. Review. — View Citation

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 ß-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) = 8 Weeks From Week 1 to Week 24	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.	From Week 1 through Week 24 of study treatment
Secondary	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) = 12 Weeks From Week 1 to Week 24	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.	From Week 1 through Week 24 of study treatment
Secondary	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) = 12 Weeks From Week 1 to Week 48	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.	From Week 1 through Week 48 of study treatment
Secondary	Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) = 8 Weeks From Week 1 Through Week 48	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.	From Week 1 through Week 48 of study treatment
Secondary	Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period	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.	At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48
Secondary	Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period	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.	Week 1 through 24 or Week 1 Through Week 48
Secondary	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	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).	Week 1 though Week 24 and Week 1 through 48
Secondary	Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24	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.	From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
Secondary	Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48	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.	From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks
Secondary	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	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.	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.
Secondary	Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period	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.	Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
Secondary	Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period	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%	Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
Secondary	Change From Baseline in Mean Serum Ferritin	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.	Baseline and Week 9 through Week 24 and Week 33 through Week 48
Secondary	Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)	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.	Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment
Secondary	Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24	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	From first dose to Week 24 of study treatment
Secondary	Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48	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	From first dose to Week 48 of study treatment
Secondary	Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)	Percentage of participants progressing to AML throughout the course of the study	From randomization to study completion (up to approximately 57 months)
Secondary	Time to Acute Myeloid Leukemia (AML) Progression	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.	From randomization to study completion (up to approximately 57 months)
Secondary	Overall Survival	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.	From randomization to study completion (up to approximately 57 months)
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	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.	From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)	Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (?).	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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)	Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/?.	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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)	Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/?z.	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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)	Tmax was defined as the observed time to maximum plasma concentration of luspatercept.	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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)	Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.	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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State	Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a 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.
Secondary	Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)	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.	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.
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."	From randomization to 1 year post first dose