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. (Industry)
229
Enrollment
74
Locations
2
Arms
57.6
Actual Duration (Months)
3.1
Patients Per Site
0.1
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

    SiteCityStateCountryPostal Code
    1Stanford Cancer CenterStanfordCaliforniaUnited States94305
    2Yale University School of MedicineNew HavenConnecticutUnited States06510
    3H Lee Moffitt Cancer Center and Research InstituteTampaFloridaUnited States33612
    4Emory University HospitalAtlantaGeorgiaUnited States30322
    5Ochsner Medical InstitutionsNew OrleansLouisianaUnited States70123
    6Johns Hopkins Sidney Kimmel Comprehensive Cancer CenterBaltimoreMarylandUnited States21287
    7Karmanos Cancer InstituteDetroitMichiganUnited States48201
    8Montefiore Medical Center Albert Einstein Cancer CenterBronxNew YorkUnited States10467
    9Columbia-Presbyterian Medical CenterNew YorkNew YorkUnited States10032
    10Gabrail Cancer CenterCantonOhioUnited States44718
    11Cleveland Clinic Taussig Cancer InstituteClevelandOhioUnited States44195-0001
    12Vanderbilt University Medical CenterNashvilleTennesseeUnited States37232
    13MD Anderson Cancer CenterHoustonTexasUnited States77030
    14Algemeen Ziekenhuis KlinaBrasschaatBelgium2930
    15AZ Sint-Jan AV BruggeBruggeBelgium8000
    16UZ BrusselsBrusselBelgium1090
    17Grand Hopital de CharleroiCharleroiBelgium6000
    18UZ GentGentBelgium9000
    19UZ LeuvenLeuvenBelgium3000
    20Cliniques Universitaires UCL de Mont-GodineYvoirBelgium5530
    21Tom Baker Cancer CenterCalgaryAlbertaCanadaT2N 4N2
    22Juravinski Cancer CentreHamiltonOntarioCanadaL8V 1C3
    23Sunnybrook Health Sciences CentreTorontoOntarioCanadaM4N 3M5
    24Princess Margaret HospitalTorontoOntarioCanadaM5G 2M9
    25CHU d'AngersAngersFrance49033
    26CHU HotelGrenoble Cedex 09France38043
    27CHRU de Lille-Hopital Claude Huriez Service des Maladies du SangLilleFrance59037
    28Institut Paoli CalmettesMarseille cedexFrance13273
    29CHU de Nice Archet INiceFrance06202
    30Hopital Saint LouisParisFrance75010
    31Hopital Haut LevequePessac CedexFrance33604
    32Centre hospitalier Lyon Sud HematologiePierre-Bénite cedexFrance69495
    33Hopital civilStrasbourgFrance67091
    34Institut Universitaire du Cancer de Toulouse - OncopoleToulouse Cedex 9France31059
    35Hopital BretonneauToursFrance37044
    36Universitatsklinikum BonnBonnGermany53105
    37Universitatsklinikum Carl Gustav Carus an der TU DresdenDresdenGermany01307
    38Marien HospitalDusseldorfGermany40479
    39Universitätsklinikum DüsseldorfDüsseldorfGermany40225
    40Medizinische Hochschule HannoverHannoverGermany30625
    41Klinikum rechts der Isar der Technischen Universität MünchenMünchenGermany81675
    42Azienda Ospedaliera Santi Antonio Biagio E Cesare ArrigoAllessandriaItaly15100
    43Azienda Ospedaliero Universitaria Di Bologna Policlinico Sorsola MalpighiBolognaItaly40138
    44Azienda Ospedaliera Universitaria CareggiFirenzeItaly50121
    45Azienda Sanitaria Locale LecceLecceItaly73100
    46Fondazione IRCCS Policlinico San MatteoPaviaItaly27100
    47Azienda Ospedaliera Bianchi Melacrino MorelliReggio, CalabriaItaly89100
    48Fondazione Policlinico Universitario A GemelliRomaItaly00168
    49Fondazione PTV Policlinico Tor VergataRomaItaly00168
    50VU Medisch CentrumAmsterdamNetherlands1081 HV
    51Universitair Medisch Centrum GroningenGroningenNetherlands9713 GZ
    52Spaarne ZiekenhuisHoofddorpNetherlands2135
    53Hospital Universitario CrucesBarakaldoSpain48903
    54Hospital Universitario Vall D hebronBarcelonaSpain08035
    55Instituto Catalan de Oncologia-Hospital Duran i ReynalsBarcelonaSpain08908
    56Hospital General Universitario Gregorio MarañonMadridSpain28007
    57Hospital Universitario Central de AsturiasOviedoSpain33011
    58Hospital Universitario de SalamancaSalamancaSpain37007
    59Hospital Universitario Virgen del RocioSevilleSpain41013
    60Hospital Universitario La FeValenciaSpain46026
    61Sahlgrenska UniversitetssjukhusGöteborgSwedenSE-41685
    62Skanes Universitetssjukhus LundLundSweden222 41
    63Karolinska University HospitalStockholmSwedenSE-17176
    64Akademiska SjukhusetUppsalaSweden75185
    65Cukurova University Medical Faculty Balcali HospitalAdanaTurkey01330
    66Ankara University Medical Faculty Cebeci HospitalAnkaraTurkey06590
    67Istanbul University Cerrahpasa Medical Faculty HospitalIstanbulTurkey34098
    68Ege Universitesi Tip Fakultesi HastanesiIzmirTurkey35100
    69Aberdeen Royal InfirmaryAberdeenUnited KingdomAB25 2ZN
    70John Radcliffe HospitalHeadingtonUnited KingdomOX3 9DU
    71St James University HospitalLeedsUnited KingdomLS1 3EX
    72Guys HospitalLondonUnited KingdomSE1 9RT
    73Kings College HospitalLondonUnited KingdomSE5 9RS
    74Kings Mill HospitalSutton in AshfieldUnited KingdomNG17 4SL

    Sponsors and Collaborators

    • Celgene
    • Acceleron Pharma Inc.

    Investigators

    • Study Director: Rodrigo Ito, MD, Celgene

    Study Documents (Full-Text)

    More Information

    Publications

    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

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail229 participants were randomized and treated.
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Period Title: Overall Study
    STARTED15376
    COMPLETED412
    NOT COMPLETED14964

    Baseline Characteristics

    Arm/Group TitleLuspaterceptPlaceboTotal
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycleTotal of all reporting groups
    Overall Participants15376229
    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
    TitlePercentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
    DescriptionRBC-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 FrameFrom Week 1 through Week 24 of study treatment

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterCommon Risk Difference on Response Rate
    Estimated Value24.56
    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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value5.065
    Confidence Interval (2-Sided) 95%
    2.278 to 11.259
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    TitlePercentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
    DescriptionRBC-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 FrameFrom Week 1 through Week 24 of study treatment

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value0.0002
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterCommon Risk Difference on Response Rate
    Estimated Value20.00
    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 Hypothesisp-Value0.0002
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value5.071
    Confidence Interval (2-Sided) 95%
    2.002 to 12.844
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    TitlePercentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
    DescriptionRBC-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 FrameFrom Week 1 through Week 48 of study treatment

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value0.0003
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterCommon Risk Difference on Response Rate
    Estimated Value21.37
    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 Hypothesisp-Value0.0003
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value4.045
    Confidence Interval (2-Sided) 95%
    1.827 to 8.956
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    TitlePercentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
    DescriptionRBC-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 FrameFrom Week 1 through Week 48 of study treatment

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterCommon Risk Difference on Response Rate
    Estimated Value29.55
    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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value5.306
    Confidence Interval (2-Sided) 95%
    2.526 to 11.146
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    TitleChange From Baseline in RBC Units Transfused Over Fixed 16-Week Period
    DescriptionMean 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 FrameAt 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants12868
    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
    TitlePercentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period
    DescriptionA 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 FrameWeek 1 through 24 or Week 1 Through Week 48

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-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 Hypothesisp-Value<0.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    7. Secondary Outcome
    TitlePercentage 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
    DescriptionA 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 FrameWeek 1 though Week 24 and Week 1 through 48

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value<0.0001
    Comments
    MethodFisher 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 Hypothesisp-Value<0.0001
    Comments
    MethodFisher Exact
    Comments
    8. Secondary Outcome
    TitleDuration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
    DescriptionDuration 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 FrameFrom 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants5810
    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 Hypothesisp-Value0.0445
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.446
    Confidence Interval (2-Sided) 95%
    0.196 to 1.013
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHR is from the Cox proportional hazards model
    9. Secondary Outcome
    TitleDuration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
    DescriptionDuration 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 FrameFrom 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants6912
    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 Hypothesisp-Value0.5121
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.784
    Confidence Interval (2-Sided) 95%
    0.362 to 1.699
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHR is from the Cox proportional hazards model
    10. Secondary Outcome
    TitleMean 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
    DescriptionThe 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 FrameBaseline 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants14976
    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
    TitlePercentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period
    DescriptionPercentage 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 FrameWeek 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1510
    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 Hypothesisp-Value0.2382
    Comments
    MethodCochran-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 Hypothesisp-Value0.5127
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    12. Secondary Outcome
    TitlePercentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period
    DescriptionPercentage 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 FrameWeek 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants86
    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 Hypothesisp-Value0.5479
    Comments
    MethodCochran-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 Hypothesisp-Value0.2980
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    13. Secondary Outcome
    TitleChange From Baseline in Mean Serum Ferritin
    DescriptionMean 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 FrameBaseline 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants14874
    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 Hypothesisp-Value0.0024
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterLS 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 Hypothesisp-Value0.0294
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterLS 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
    TitleChange From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)
    DescriptionMean 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 FrameBaseline 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants12868
    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 Hypothesisp-Value0.3087
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterLS 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 Hypothesisp-Value0.7903
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterLS 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
    TitleTime to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
    DescriptionTime 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 FrameFrom 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants5810
    Mean (Standard Deviation) [Days]
    17.2
    (29.40)
    26.0
    (31.83)
    16. Secondary Outcome
    TitleTime to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
    DescriptionTime 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 FrameFrom 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants6912
    Mean (Standard Deviation) [Days]
    40.3
    (61.03)
    57.2
    (79.18)
    17. Secondary Outcome
    TitlePercentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)
    DescriptionPercentage of participants progressing to AML throughout the course of the study
    Time FrameFrom randomization to study completion (up to approximately 57 months)

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    Number [Percentage of Participants]
    2.6
    1.7%
    3.9
    5.1%
    18. Secondary Outcome
    TitleTime to Acute Myeloid Leukemia (AML) Progression
    DescriptionTime 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 FrameFrom randomization to study completion (up to approximately 57 months)

    Outcome Measure Data

    Analysis Population Description
    All treated participants who progressed to AML
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants43
    Median (95% Confidence Interval) [Months]
    NA
    NA
    19. Secondary Outcome
    TitleOverall Survival
    DescriptionOverall 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 FrameFrom randomization to study completion (up to approximately 57 months)

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 Hypothesisp-Value0.9580
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.986
    Confidence Interval (2-Sided) 95%
    0.595 to 1.636
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHR is from the Cox proportional hazards model
    20. Secondary Outcome
    TitleNumber of Participants With Treatment Emergent Adverse Events (TEAEs)
    DescriptionThe 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 FrameFrom 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    ≥ 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
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
    DescriptionApparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [L/day]
    0.516
    (41.2)
    22. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
    DescriptionApparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [L]
    9.68
    (26.5)
    23. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
    DescriptionTerminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [Day]
    13.0
    (31.6)
    24. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
    DescriptionTmax was defined as the observed time to maximum plasma concentration of luspatercept.
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Median (Full Range) [Day]
    5.40
    25. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)
    DescriptionCmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [μg/mL]
    5.77
    (20.5)
    26. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State
    DescriptionCmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.
    Time FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [μg/mL]
    9.17
    (29.9)
    27. Secondary Outcome
    TitlePharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)
    DescriptionArea 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 FrameBlood 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 TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants1530
    Geometric Mean (Geometric Coefficient of Variation) [day/μg/mL]
    145
    (38.3)
    28. Secondary Outcome
    TitleParticipants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
    DescriptionNumber 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 FrameFrom randomization to 1 year post first dose

    Outcome Measure Data

    Analysis Population Description
    Safety population of participants with ADA samples collected.
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Measure Participants15376
    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 FrameAll-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)
    Adverse Event Reporting Description
    Arm/Group TitleLuspaterceptPlacebo
    Arm/Group DescriptionLuspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cyclePlacebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    All Cause Mortality
    LuspaterceptPlacebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total45/153 (29.4%) 24/76 (31.6%)
    Serious Adverse Events
    LuspaterceptPlacebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total66/153 (43.1%) 23/76 (30.3%)
    Blood and lymphatic system disorders
    Anaemia3/153 (2%) 0/76 (0%)
    Disseminated intravascular coagulation1/153 (0.7%) 0/76 (0%)
    Febrile neutropenia1/153 (0.7%) 0/76 (0%)
    Cardiac disorders
    Acute myocardial infarction1/153 (0.7%) 0/76 (0%)
    Angina pectoris3/153 (2%) 0/76 (0%)
    Aortic valve stenosis1/153 (0.7%) 0/76 (0%)
    Arteriosclerosis coronary artery1/153 (0.7%) 0/76 (0%)
    Atrial fibrillation2/153 (1.3%) 0/76 (0%)
    Atrioventricular block2/153 (1.3%) 0/76 (0%)
    Atrioventricular block second degree1/153 (0.7%) 0/76 (0%)
    Bradycardia1/153 (0.7%) 0/76 (0%)
    Cardiac failure2/153 (1.3%) 0/76 (0%)
    Cardiac failure acute1/153 (0.7%) 0/76 (0%)
    Coronary artery disease1/153 (0.7%) 0/76 (0%)
    Myocardial infarction0/153 (0%) 1/76 (1.3%)
    Supraventricular tachycardia1/153 (0.7%) 0/76 (0%)
    Gastrointestinal disorders
    Abdominal pain1/153 (0.7%) 0/76 (0%)
    Abdominal pain upper1/153 (0.7%) 0/76 (0%)
    Ascites1/153 (0.7%) 0/76 (0%)
    Constipation1/153 (0.7%) 0/76 (0%)
    Duodenal ulcer1/153 (0.7%) 0/76 (0%)
    Duodenal ulcer haemorrhage1/153 (0.7%) 0/76 (0%)
    Dysphagia1/153 (0.7%) 0/76 (0%)
    Gastrointestinal haemorrhage1/153 (0.7%) 0/76 (0%)
    Nausea1/153 (0.7%) 0/76 (0%)
    Pancreatitis acute1/153 (0.7%) 0/76 (0%)
    Vomiting1/153 (0.7%) 0/76 (0%)
    General disorders
    Asthenia1/153 (0.7%) 0/76 (0%)
    Chest pain1/153 (0.7%) 0/76 (0%)
    Death0/153 (0%) 1/76 (1.3%)
    Gait disturbance1/153 (0.7%) 0/76 (0%)
    General physical health deterioration0/153 (0%) 1/76 (1.3%)
    Generalised oedema1/153 (0.7%) 0/76 (0%)
    Multiple organ dysfunction syndrome1/153 (0.7%) 0/76 (0%)
    Non-cardiac chest pain1/153 (0.7%) 0/76 (0%)
    Pyrexia3/153 (2%) 2/76 (2.6%)
    Hepatobiliary disorders
    Cholangitis0/153 (0%) 1/76 (1.3%)
    Cholelithiasis1/153 (0.7%) 0/76 (0%)
    Hyperbilirubinaemia1/153 (0.7%) 0/76 (0%)
    Infections and infestations
    Abdominal infection1/153 (0.7%) 0/76 (0%)
    Bacteraemia0/153 (0%) 1/76 (1.3%)
    Bronchitis2/153 (1.3%) 0/76 (0%)
    Cellulitis1/153 (0.7%) 1/76 (1.3%)
    Diverticulitis0/153 (0%) 1/76 (1.3%)
    Endocarditis1/153 (0.7%) 0/76 (0%)
    Enterocolitis infectious0/153 (0%) 1/76 (1.3%)
    Epididymitis1/153 (0.7%) 0/76 (0%)
    Escherichia urinary tract infection1/153 (0.7%) 0/76 (0%)
    Gastroenteritis1/153 (0.7%) 0/76 (0%)
    Localised infection1/153 (0.7%) 0/76 (0%)
    Lower respiratory tract infection2/153 (1.3%) 0/76 (0%)
    Metapneumovirus infection0/153 (0%) 1/76 (1.3%)
    Orchitis1/153 (0.7%) 0/76 (0%)
    Parainfluenzae virus infection1/153 (0.7%) 0/76 (0%)
    Pharyngitis1/153 (0.7%) 0/76 (0%)
    Pneumonia8/153 (5.2%) 2/76 (2.6%)
    Pneumonia moraxella1/153 (0.7%) 0/76 (0%)
    Pneumonia staphylococcal1/153 (0.7%) 0/76 (0%)
    Sepsis4/153 (2.6%) 1/76 (1.3%)
    Septic shock1/153 (0.7%) 1/76 (1.3%)
    Soft tissue infection1/153 (0.7%) 0/76 (0%)
    Staphylococcal infection1/153 (0.7%) 0/76 (0%)
    Streptococcal infection0/153 (0%) 1/76 (1.3%)
    Upper respiratory tract infection1/153 (0.7%) 0/76 (0%)
    Urinary tract infection4/153 (2.6%) 1/76 (1.3%)
    Urinary tract infection bacterial0/153 (0%) 1/76 (1.3%)
    Urosepsis1/153 (0.7%) 1/76 (1.3%)
    Injury, poisoning and procedural complications
    Ankle fracture0/153 (0%) 1/76 (1.3%)
    Clavicle fracture1/153 (0.7%) 0/76 (0%)
    Fall7/153 (4.6%) 3/76 (3.9%)
    Femur fracture6/153 (3.9%) 0/76 (0%)
    Head injury1/153 (0.7%) 0/76 (0%)
    Hip fracture0/153 (0%) 3/76 (3.9%)
    Humerus fracture2/153 (1.3%) 1/76 (1.3%)
    Joint dislocation1/153 (0.7%) 0/76 (0%)
    Joint injury1/153 (0.7%) 0/76 (0%)
    Pelvic bone injury1/153 (0.7%) 0/76 (0%)
    Rib fracture1/153 (0.7%) 0/76 (0%)
    Road traffic accident1/153 (0.7%) 0/76 (0%)
    Spinal column injury1/153 (0.7%) 0/76 (0%)
    Spinal fracture1/153 (0.7%) 0/76 (0%)
    Subdural haematoma1/153 (0.7%) 0/76 (0%)
    Thoracic vertebral fracture0/153 (0%) 1/76 (1.3%)
    Investigations
    General physical condition abnormal1/153 (0.7%) 0/76 (0%)
    Metabolism and nutrition disorders
    Dehydration1/153 (0.7%) 0/76 (0%)
    Hypoglycaemia1/153 (0.7%) 0/76 (0%)
    Lactic acidosis1/153 (0.7%) 0/76 (0%)
    Type 2 diabetes mellitus1/153 (0.7%) 0/76 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain3/153 (2%) 0/76 (0%)
    Chondritis1/153 (0.7%) 0/76 (0%)
    Flank pain1/153 (0.7%) 0/76 (0%)
    Gouty arthritis1/153 (0.7%) 0/76 (0%)
    Muscle haemorrhage1/153 (0.7%) 0/76 (0%)
    Muscular weakness1/153 (0.7%) 0/76 (0%)
    Myositis1/153 (0.7%) 0/76 (0%)
    Polymyalgia rheumatica1/153 (0.7%) 0/76 (0%)
    Rheumatoid arthritis1/153 (0.7%) 0/76 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma3/153 (2%) 0/76 (0%)
    Colon adenoma1/153 (0.7%) 0/76 (0%)
    Intraductal papillary mucinous neoplasm1/153 (0.7%) 0/76 (0%)
    Myelodysplastic syndrome2/153 (1.3%) 1/76 (1.3%)
    Refractory anaemia with an excess of blasts4/153 (2.6%) 0/76 (0%)
    Squamous cell carcinoma1/153 (0.7%) 0/76 (0%)
    Squamous cell carcinoma of skin3/153 (2%) 0/76 (0%)
    Systemic mastocytosis1/153 (0.7%) 0/76 (0%)
    Transformation to acute myeloid leukaemia3/153 (2%) 1/76 (1.3%)
    Nervous system disorders
    Cerebral haemorrhage2/153 (1.3%) 0/76 (0%)
    Cerebral ischaemia0/153 (0%) 1/76 (1.3%)
    Cerebrospinal fluid leakage0/153 (0%) 1/76 (1.3%)
    Haemorrhage intracranial0/153 (0%) 1/76 (1.3%)
    Seizure1/153 (0.7%) 0/76 (0%)
    Syncope3/153 (2%) 0/76 (0%)
    Product Issues
    Thrombosis in device1/153 (0.7%) 0/76 (0%)
    Psychiatric disorders
    Confusional state1/153 (0.7%) 0/76 (0%)
    Delirium0/153 (0%) 1/76 (1.3%)
    Suicide attempt0/153 (0%) 1/76 (1.3%)
    Renal and urinary disorders
    Acute kidney injury2/153 (1.3%) 0/76 (0%)
    Renal colic1/153 (0.7%) 0/76 (0%)
    Renal failure1/153 (0.7%) 1/76 (1.3%)
    Urethral stenosis1/153 (0.7%) 0/76 (0%)
    Urinary retention1/153 (0.7%) 1/76 (1.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome1/153 (0.7%) 0/76 (0%)
    Dyspnoea2/153 (1.3%) 0/76 (0%)
    Dyspnoea exertional1/153 (0.7%) 0/76 (0%)
    Epistaxis2/153 (1.3%) 0/76 (0%)
    Hypoxia1/153 (0.7%) 1/76 (1.3%)
    Pulmonary fibrosis1/153 (0.7%) 0/76 (0%)
    Respiratory failure0/153 (0%) 1/76 (1.3%)
    Vascular disorders
    Aortic stenosis1/153 (0.7%) 0/76 (0%)
    Granulomatosis with polyangiitis1/153 (0.7%) 0/76 (0%)
    Orthostatic hypotension1/153 (0.7%) 0/76 (0%)
    Shock haemorrhagic1/153 (0.7%) 0/76 (0%)
    Other (Not Including Serious) Adverse Events
    LuspaterceptPlacebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total145/153 (94.8%) 63/76 (82.9%)
    Blood and lymphatic system disorders
    Anaemia14/153 (9.2%) 6/76 (7.9%)
    Neutropenia8/153 (5.2%) 7/76 (9.2%)
    Cardiac disorders
    Palpitations11/153 (7.2%) 5/76 (6.6%)
    Tachycardia8/153 (5.2%) 0/76 (0%)
    Ear and labyrinth disorders
    Vertigo12/153 (7.8%) 0/76 (0%)
    Gastrointestinal disorders
    Abdominal pain11/153 (7.2%) 4/76 (5.3%)
    Abdominal pain upper11/153 (7.2%) 2/76 (2.6%)
    Constipation21/153 (13.7%) 7/76 (9.2%)
    Diarrhoea44/153 (28.8%) 8/76 (10.5%)
    Nausea35/153 (22.9%) 6/76 (7.9%)
    Vomiting14/153 (9.2%) 5/76 (6.6%)
    General disorders
    Asthenia40/153 (26.1%) 9/76 (11.8%)
    Fatigue46/153 (30.1%) 11/76 (14.5%)
    Influenza like illness9/153 (5.9%) 3/76 (3.9%)
    Malaise8/153 (5.2%) 3/76 (3.9%)
    Oedema peripheral37/153 (24.2%) 13/76 (17.1%)
    Pyrexia19/153 (12.4%) 6/76 (7.9%)
    Infections and infestations
    Bronchitis19/153 (12.4%) 1/76 (1.3%)
    Influenza11/153 (7.2%) 0/76 (0%)
    Nasopharyngitis18/153 (11.8%) 4/76 (5.3%)
    Upper respiratory tract infection19/153 (12.4%) 4/76 (5.3%)
    Urinary tract infection21/153 (13.7%) 4/76 (5.3%)
    Injury, poisoning and procedural complications
    Fall25/153 (16.3%) 7/76 (9.2%)
    Investigations
    Alanine aminotransferase increased9/153 (5.9%) 3/76 (3.9%)
    Aspartate aminotransferase increased10/153 (6.5%) 1/76 (1.3%)
    Weight decreased9/153 (5.9%) 5/76 (6.6%)
    Metabolism and nutrition disorders
    Decreased appetite14/153 (9.2%) 3/76 (3.9%)
    Hyperglycaemia12/153 (7.8%) 3/76 (3.9%)
    Hyperkalaemia10/153 (6.5%) 1/76 (1.3%)
    Hyperuricaemia12/153 (7.8%) 2/76 (2.6%)
    Iron overload9/153 (5.9%) 3/76 (3.9%)
    Musculoskeletal and connective tissue disorders
    Arthralgia13/153 (8.5%) 9/76 (11.8%)
    Back pain32/153 (20.9%) 6/76 (7.9%)
    Myalgia13/153 (8.5%) 5/76 (6.6%)
    Nervous system disorders
    Dizziness35/153 (22.9%) 4/76 (5.3%)
    Headache27/153 (17.6%) 5/76 (6.6%)
    Syncope10/153 (6.5%) 1/76 (1.3%)
    Psychiatric disorders
    Anxiety9/153 (5.9%) 1/76 (1.3%)
    Confusional state9/153 (5.9%) 0/76 (0%)
    Depression9/153 (5.9%) 5/76 (6.6%)
    Insomnia13/153 (8.5%) 4/76 (5.3%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia8/153 (5.2%) 0/76 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough35/153 (22.9%) 10/76 (13.2%)
    Dyspnoea30/153 (19.6%) 5/76 (6.6%)
    Epistaxis12/153 (7.8%) 3/76 (3.9%)
    Oropharyngeal pain6/153 (3.9%) 6/76 (7.9%)
    Skin and subcutaneous tissue disorders
    Erythema2/153 (1.3%) 4/76 (5.3%)
    Pruritus11/153 (7.2%) 3/76 (3.9%)
    Vascular disorders
    Hypertension16/153 (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.

    Results Point of Contact

    Name/TitleBristol-Myers Squibb Study Director
    OrganizationBristol-Myers Squibb
    PhonePlease email
    EmailClinical.Trials@bms.com
    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