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

Sponsor
Celgene (Industry)
Overall Status
Completed
CT.gov ID
NCT02604433
Collaborator
Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) (Industry)
336
73
2
56.1
4.6
0.1

Study Details

Study Description

Brief Summary

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

The study is divided into the following periods:
  • Historical Period,

  • Screening/Run-in Period,

  • Double-blind Treatment Period (48 weeks),

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

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

  • Post-treatment Follow-up Period

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
336 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 3, Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Adults With Transfusion Dependent Beta (B)-Thalassemia
Actual Study Start Date :
May 2, 2016
Actual Primary Completion Date :
Nov 24, 2017
Actual Study Completion Date :
Jan 5, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC)

Luspatercept, subcutaneous(ly) (SC) once every 21 days

Drug: Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.
Other Names:
  • ACE-536
  • Placebo Comparator: Placebo plus Best Supportive Care (BSC)

    normal saline solution subcutaneous(ly) (SC) once every 21 days

    Other: Placebo
    Placebo, Subcutaneous, every 21 days.

    Outcome Measures

    Primary Outcome Measures

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

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

    Secondary Outcome Measures

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

      Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Weeks 37 - 48 compared to the 12-week interval on or prior to Dose 1 Day 1.

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

      Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Weeks 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.

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

      Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Week 37 to Week 48 compared to the 12-week interval on or prior to Dose 1 Day 1.

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

      Baseline was defined as the total number of Red Blood Cells (RBC) units transfused during the 12-week interval on or prior to Dose 1 Day 1. This is compared to the total number of RBC units transfused during the 12-week interval from treatment weeks 13-24.

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

      Baseline was defined as the last value on or before the first dose of study drug was administered; if multiple values were present for the same date, the average of these values was used. If a participant had 1 postbaseline assessment, it was used as the Week 48 value. If a participant had multiple postbaseline assessments, the last one was used as the Week 48 value. The value of LIC was collected by magnetic resonance imaging. Participants with a LIC value > 43 mg/g were not included in the analysis.

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

      Three different types of Iron Chelation Therapy (ICT) were analyzed: Deferasirox Deferiprone Deferoxamine Mesilate/Deferoxamine The baseline mean daily dose was calculated using the ICT dosage during the 12 weeks prior to first study drug administration and the postbaseline mean daily dose was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or the last 12 weeks of the study treatment for early discontinued participants.

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

      For each participant, the baseline mean serum ferritin level was calculated during the 12 weeks prior to first study drug administration. The postbaseline mean serum ferritin level was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or last 12 weeks of study treatment, if discontinued early. The change was calculated as the difference of post baseline mean serum ferritin level and baseline mean serum ferritin level.

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

      For BMD, the lumbar spine and total hip were measured at baseline and 48 weeks by dual energy x-ray absorptiometry (DXA). Baseline was defined as the last value on or before the first dose of study drug is administered; if multiple values are present for the same date, the average of these values was used. If during the 48 week double-blinded treatment period, a participant has only one assessment, it is counted as 'Week 48' visit; if a participant has multiple assessments, the last one is used as 'Week 48' visit. The analysis was done on the population that had at least 2 measurements.

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

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

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

      The TranQol is a self-administered quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 36 questions assessed on a 5-point response, that are grouped into 5 domains (Physical Health, Emotional Health, Sexual Health, Family Functioning, School/Career Functioning). Scores are calculated according to specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.

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

      The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0-100 scale score for each health domain is further converted to normbased scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL. The domains/summaries reported are: Physical Functioning (Range of possible T-scores is 19.26 - 57.54) General Health (Range of possible T-scores is 18.95 - 66.50) Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.

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

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

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

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

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

      Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, i.e, Days 1 to 56, Days 2 to 57 and so on.

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

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

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

      Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, ie, Days 1 to 56, Days 2 to 57 and so on. Longest duration of transfusion independence was estimated based on Kaplan-Meier model.

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

      Time to erythroid response was defined as the time from first dose of the study drug to first erythroid response. This is reported for participants with a ≥ 33% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval., as well as participants with a ≥ 50% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval.

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

      The number of transfusion events after start of study treatment were evaluated. For the definition of transfusion events, if multiple transfusions happen on the same date, they are counted as one event; if multiple transfusions happen on two consecutive dates, they are counted as one event; if multiple transfusions happen on three consecutive dates, they are counted as two events. Results are presented in 24-week intervals, up to 96 weeks after start of study treatment

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

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

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

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

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

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

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

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

      An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A serious AE is any AE occurring at any dose that - Results in death - Is life-threatening - Requires or prolongs existing inpatient hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death

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

      Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as "treatment-emergent" if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as "preexisting" if the baseline sample was ADA positive and the participant was not qualified for "treatment-emergent."

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    Subjects must satisfy the following criteria to be enrolled in the study:
    1. Male or female, ≥18 years of age at the time of signing the informed consent document (ICF).

    2. Subject must understand and voluntarily sign an Inform Consent Form prior to any study-related assessments/procedures being conducted.

    3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

    4. Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia. (β-thalassemia with mutation and/or multiplication of alpha globin is allowed).

    5. Regularly transfused, defined as: 6-20 Red Blood Cell (RBC) units* in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.

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

    2. A female of childbearing potential (FCBP) for this study is defined as a female who:

    1. has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:
    1. Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence ** from heterosexual contact.

    2. Either commit to true abstinence** from heterosexual contact (which must be reviewed on a monthly basis and source documented) If a FCBP engages in sexual activity that may result in a pregnancy, she must agree to use, and be able to comply with, effective*** contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose Pharmacokinetic PK) data) after discontinuation of study therapy.

    • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.] *** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study.

    Such methods include: Combined (estrogen and progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

    1. Male subjects must:
    • Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy.
    Exclusion Criteria:
    The presence of any of the following will exclude a subject from enrollment:
    1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

    2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

    3. Any condition that confounds the ability to interpret data from the study.

    4. A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H);

    5. Evidence of active hepatitis C (HCV) infection as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B as demonstrated by the presence of HBsAg and/or HBVDNA-positive,, or known positive human immunodeficiency virus (HIV).

    Note: Subjects receiving antiviral therapies should have 2 negative HCVRNA tests 3 months apart.(ie, one test at the end of the antiviral therapy and a second test 3 months following the first test).

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

    2. Use of chronic anticoagulant therapy is excluded, unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.

    3. Platelet count > 1000 x 109/L

    4. Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (eg, stroke or myocardial infarction).

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

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

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

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

    9. Hydroxyurea treatment ≤ 24 weeks prior to randomization.

    10. Pregnant or lactating females.

    11. Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (current active minor version).

    12. Major organ damage, including:

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

    14. Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization.

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

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

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

    18. Chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed). Single day glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions, is allowed).

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

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

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

    22. History of malignancy with the exception of:

    23. Curatively resected nonmelanoma skin cancer.

    24. Curatively treated cervical carcinoma in situ.

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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Los Angeles Los Angeles California United States 90027
    2 Children's Hospital and Research Center at Oakland Oakland California United States 94609
    3 Ann and Robert H Lurie Childrens Hospital of Chicago Chicago Illinois United States 60611
    4 Boston Children's Hospital Boston Massachusetts United States 02115
    5 Weill Cornell Medical College New York New York United States 10065
    6 Hospital of the University of Pennsylvania Philadelphia Pennsylvania United States 19104
    7 Prince of Wales Hospital Randwick New South Wales Australia 2031
    8 Mater Hospital Brisbane South Brisbane Queensland Australia 4101
    9 Royal Adelaide Hospital Institute of Medical and Veterinary Science Adelaide South Australia Australia 5000
    10 Monash Medical Centre Clayton Victoria Australia 3168
    11 Sir Charles Gairdner Hospital Nedlands Western Australia Australia 6009
    12 Royal Prince Alfred Hospital Camperdown Australia 2050
    13 University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD Plovdiv Bulgaria 4002
    14 Specialized Hospital for Active Treatment of Haematological Diseases - Sofia Sofia Bulgaria 1756
    15 Multiprofile Hospital for Active Treatment Sveta Marina EAD Varna Bulgaria 9010
    16 University Health Network Toronto Ontario Canada M5G 2C4
    17 Hopital Henri Mondor Creteil France 94010
    18 GH de Institut Catholique St. VincentHématologie Lille France 59000
    19 Hopitaux de La Timone Marseille Cedex 9 France 13385
    20 Hospital of Necker Paris France 75015
    21 Laiko General Hospital of Athens Ampelokipi - Athens Greece 115 26
    22 General Children's Hospital "Agia Sophia" Athens Greece 115 27
    23 General Hospital Georgios Gennimatas of Athens Athens Greece 11527
    24 University General Hospital of Patras Rio Patras Greece 26500
    25 Hippokration Hospital Thessaloniki Greece 54642
    26 Soroka University Medical Centre Beer Sheva Israel 84101
    27 Rambam Health Corporation Haifa Israel 3109601
    28 HaEmek Medical Center Haïfa (Afula) Israel 18101
    29 Shaare Zedek Medical Center Jerusalem Israel 91031
    30 Hadassah Medical Center Jerusalem Israel 91120
    31 Galilee Medical Center Nahariya Israel 22100
    32 Rabin Medical Center Petah Tikva Israel 49100
    33 Presidio Ospedaliero Antonio Perrino Brindisi Italy 72100
    34 Universita degli Studi di Cagliari - ASL8 Cagliari Italy 09121
    35 Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna Ferrara Italy 44124
    36 Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite Genoa Italy 16128
    37 Fondazione Ca Granda IRCCS Ospedale Maggiore Milan Italy 20122
    38 Seconda Universita Degli Studi Di Napoli Naples Italy 80131
    39 AORN A Cardarelli Napoli Italy 80131
    40 Azienda Ospedaliero Universitaria S. Luigi Gonzaga Orbassano Italy 10043
    41 Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello Palermo Italy 90146
    42 Azienda Ospedaliera Universitaria Integrata Di Verona Verona Italy 37134
    43 Chronic Care Center Beirut Lebanon
    44 Hospital Sultanah Aminah Johor Bahru Johor Malaysia 80100
    45 Hospital Sultanah Bahiyah Alor Setar Kedah Malaysia 05460
    46 Hospital Raja Permaisuri Bainun Ipoh Perak Malaysia 30990
    47 Queen Elizabeth Hospital Kota Kinabalu Sabah Malaysia 88586
    48 Hospital Umum Sarawak Kuching Sarawak Malaysia 93586
    49 University Malaya Medical Centre Kuala Lumpur Wilayah Persekutuan Kuala Lumpur Malaysia 59100
    50 Hospital Pulau Pinang c/o Penang Medical College Georgetown Malaysia 10990
    51 Changhua Christian Hospital Changhua City Taiwan 500
    52 Kaohsiung Medical University Hospital Kaohsiung Taiwan 807
    53 China Medical University Hospital Taichung Taiwan 40447
    54 National Taiwan University Hospital Taipei, Zhongzheng Dist. Taiwan 10002
    55 Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital Bangkok Thailand 10330
    56 Siriraj Hospital Mahidol University Bangkok Thailand 10700
    57 Chiang Mai University - Maharaj Nakorn Chiang Mai Hospital Chiang Mai Thailand 50200
    58 University Hospital Farhat Hached Sousse Tunisia 4031
    59 Bone Marrow Transplant Center Tunis Tunisia 1006
    60 Aziza Othmana Hospital Tunis Tunisia 1008
    61 Military Hospital of Tunis Tunis Tunisia 1089
    62 Acibadem Adana Hospital Adana Turkey 01130
    63 Cukurova University Medical Faculty Balcali Hospital Adana Turkey 01330
    64 Hacettepe Universitesi Ankara Turkey 01660
    65 Antalya Egitim Arastirma Antalya Turkey 07100
    66 Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi Istanbul Turkey 34093
    67 Ege Universitesi Tip Fakultesi Hastanesi Izmir Turkey 35100
    68 Mersin University Medical Faculty Mersin Turkey 33343
    69 St James University Hospital Leeds United Kingdom LS9 7TF
    70 University College Hospital Trust London Bloomsbury United Kingdom WC1E 6AU
    71 Barts Health NHS Trust - The Royal London Hospital London United Kingdom E1 1BB
    72 Whittington Hospital London United Kingdom N19 5NF
    73 Manchester Royal Infirmary Manchester United Kingdom M13 9WL

    Sponsors and Collaborators

    • Celgene
    • Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT02604433
    Other Study ID Numbers:
    • ACE-536-B-THAL-001
    First Posted:
    Nov 13, 2015
    Last Update Posted:
    Jan 25, 2022
    Last Verified:
    Jan 1, 2022

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 336 participants were randomized, 332 participants were treated.
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Period Title: Overall Study
    STARTED 224 112
    Participants Treated 223 109
    Completed 24 Weeks of Treatment 211 102
    Completed 48 Weeks of Treatment 202 96
    Completed 96 Weeks of Treatment 155 3
    Completed 144 Weeks of Treatment 125 0
    Completed 192 Weeks of Treatment 6 0
    COMPLETED 6 6
    NOT COMPLETED 218 106

    Baseline Characteristics

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

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
    Description Erythroid Response was defined as red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Week 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Number [Percentage of participants]
    21.4
    9.6%
    4.5
    4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Significance level of 0.050 for 2-sided tests.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 5.79
    Confidence Interval (2-Sided) 95%
    2.24 to 14.97
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Difference in Percentages
    Estimated Value 17.0
    Confidence Interval (2-Sided) 95%
    10.4 to 23.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Luspatercept - Placebo
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Common Risk Difference
    Estimated Value 17.0
    Confidence Interval () 95%
    10.4 to 23.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments Luspatercept - Placebo
    2. Secondary Outcome
    Title Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
    Description Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Weeks 37 - 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Number [Percentage of participants]
    19.6
    8.8%
    3.6
    3.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Odds ratio 95% CIs, and p-value were estimated from the CMH test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate for outcomes 2-4, the testing procedure was implemented strictly in order: the test for this outcome was only conducted when there was evidence showing that erythroid response was achieved in the luspatercept group from Week 13 to Week 24 (primary endpoint).
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Significance level of 0.050 for 2-sided tests.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 6.44
    Confidence Interval (2-Sided) 95%
    2.27 to 18.26
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24
    Description Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Weeks 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Number [Percentage of participants]
    7.6
    3.4%
    1.8
    1.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and 33% hematological improvement was achieved in the luspatercept group in outcome 2.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0303
    Comments Significance level of 0.050 for 2-sided tests.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 4.55
    Confidence Interval (2-Sided) 95%
    1.03 to 20.11
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
    Description Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Week 37 to Week 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Number [Percentage of participants]
    10.3
    4.6%
    0.9
    0.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and achievement of objective in the luspatercept group in outcomes 2+3.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments Significance level of 0.050 for 2-sided tests.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 11.92
    Confidence Interval (2-Sided) 95%
    1.65 to 86.29
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24
    Description Baseline was defined as the total number of Red Blood Cells (RBC) units transfused during the 12-week interval on or prior to Dose 1 Day 1. This is compared to the total number of RBC units transfused during the 12-week interval from treatment weeks 13-24.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 210 102
    Mean (Standard Deviation) [RBC units]
    -0.67
    (1.795)
    0.66
    (1.774)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Change from baseline at Week 48 LSM = least squares mean
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Significance level of 0.050 for 2-sided tests.
    Method ANCOVA
    Comments Estimates were based on an ANCOVA model with geographical regions defined at randomization and baseline transfusion burden as covariates.
    Method of Estimation Estimation Parameter LSM Difference
    Estimated Value -1.35
    Confidence Interval (2-Sided) 95%
    -1.77 to -0.93
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    6. Secondary Outcome
    Title Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
    Description Baseline was defined as the last value on or before the first dose of study drug was administered; if multiple values were present for the same date, the average of these values was used. If a participant had 1 postbaseline assessment, it was used as the Week 48 value. If a participant had multiple postbaseline assessments, the last one was used as the Week 48 value. The value of LIC was collected by magnetic resonance imaging. Participants with a LIC value > 43 mg/g were not included in the analysis.
    Time Frame Baseline: Week -12 to Day -1; Treatment: Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 185 99
    Mean (Standard Deviation) [mg/g dry weight]
    0.05
    (5.770)
    -0.00
    (5.329)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Change from baseline at Week 48 P-value ANCOVA model with geographical regions defined at randomization and baseline LIC as covariates. LS = least square
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7598
    Comments Significance level of 0.050 for 2-sided tests.
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value 0.20
    Confidence Interval (2-Sided) 95%
    -1.10 to 1.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    7. Secondary Outcome
    Title Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
    Description Three different types of Iron Chelation Therapy (ICT) were analyzed: Deferasirox Deferiprone Deferoxamine Mesilate/Deferoxamine The baseline mean daily dose was calculated using the ICT dosage during the 12 weeks prior to first study drug administration and the postbaseline mean daily dose was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or the last 12 weeks of the study treatment for early discontinued participants.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 129 66
    Deferasirox
    -105.0
    (378.67)
    -60.4
    (297.11)
    Deferiprone
    -229.1
    (893.62)
    -73.4
    (614.80)
    Deferoxamine Mesilate/Deferoxamine
    84.9
    (523.45)
    274.2
    (613.05)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Deferasirox: Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2552
    Comments Significance level of 0.050 for 2-sided tests
    Method ANCOVA
    Comments Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -68.0
    Confidence Interval (2-Sided) 95%
    -185.8 to 49.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Deferiprone: Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7746
    Comments Significance level of 0.050 for 2-sided tests
    Method ANCOVA
    Comments Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -76.4
    Confidence Interval (2-Sided) 95%
    -612.9 to 460.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Deferoxamine Mesilate / Deferoxamine: Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5186
    Comments Significance level of 0.050 for 2-sided tests
    Method ANCOVA
    Comments Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline ICT as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -147.3
    Confidence Interval (2-Sided) 95%
    -673.1 to 378.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    8. Secondary Outcome
    Title Mean Change From Baseline In Mean Serum Ferritin At Week 48
    Description For each participant, the baseline mean serum ferritin level was calculated during the 12 weeks prior to first study drug administration. The postbaseline mean serum ferritin level was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or last 12 weeks of study treatment, if discontinued early. The change was calculated as the difference of post baseline mean serum ferritin level and baseline mean serum ferritin level.
    Time Frame Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 207 101
    Mean (Standard Deviation) [μg/L]
    -247.19
    (713.767)
    100.38
    (522.047)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Significance level of 0.050 for 2-sided tests
    Method ANCOVA
    Comments Estimates based on an ANCOVA model with geographical regions defined at randomization and baseline serum ferritin as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -342.59
    Confidence Interval (2-Sided) 95%
    -498.30 to -186.87
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    9. Secondary Outcome
    Title Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
    Description For BMD, the lumbar spine and total hip were measured at baseline and 48 weeks by dual energy x-ray absorptiometry (DXA). Baseline was defined as the last value on or before the first dose of study drug is administered; if multiple values are present for the same date, the average of these values was used. If during the 48 week double-blinded treatment period, a participant has only one assessment, it is counted as 'Week 48' visit; if a participant has multiple assessments, the last one is used as 'Week 48' visit. The analysis was done on the population that had at least 2 measurements.
    Time Frame Baseline: Day 1; Treatment: Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 190 97
    Total Hip
    0.01
    (0.050)
    0.01
    (0.057)
    Lumbar Spine
    -0.00
    (0.063)
    0.00
    (0.078)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Total Hip Bone Mineral Density: Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9201
    Comments Significance level of 0.050 for 2-sided tests.
    Method ANCOVA
    Comments Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline BMD measurement as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.01 to 0.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Lumbar Spine Bone Mineral Density: Change from baseline at Week 48 LS = least squares
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4620
    Comments Significance level of 0.050 for 2-sided tests.
    Method ANCOVA
    Comments Estimates are based on an ANCOVA model with geographical regions defined at randomization and baseline BMD measurement as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.02 to 0.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    10. Secondary Outcome
    Title Mean Change From Baseline In Myocardial Iron At Week 48
    Description Myocardial Iron levels were measured by Magnetic Resonance Imaging (MRI), using MRI parameter T2* (Unit: ms). T2* values correlates with heart failure (HF) risk (e.g. T2*<6ms: high HF risk).
    Time Frame Baseline: Day 1; Treatment: Week 48

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available measurements at the specified timepoints
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 201 102
    Mean (Standard Deviation) [ms]
    -1.83
    (15.084)
    -0.01
    (6.780)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Change from baseline at Week 48 LS = least square
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0543
    Comments Significance level of 0.050 for 2-sided tests.
    Method ANCOVA
    Comments Estimates were based on an ANCOVA model with geographical regions defined at randomization and baseline myocardial T2* as covariates.
    Method of Estimation Estimation Parameter LS Mean of Difference
    Estimated Value -2.22
    Confidence Interval (2-Sided) 95%
    -4.48 to 0.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    11. Secondary Outcome
    Title Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
    Description The TranQol is a self-administered quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 36 questions assessed on a 5-point response, that are grouped into 5 domains (Physical Health, Emotional Health, Sexual Health, Family Functioning, School/Career Functioning). Scores are calculated according to specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.
    Time Frame Baseline: 4 weeks prior to Day 1; Treatment: Week 24

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with an evaluable TranQoL questionnaire at screening visit and at least one post-screening visit
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 200 94
    Physical Health Domain Score - Change from Baseline
    -1.5
    (14.26)
    -0.7
    (14.24)
    Total Score - Change from Baseline
    0.8
    (11.56)
    -0.4
    (11.62)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Physical Health Domain Score - Change from Baseline at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.148
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Total Score - Change from Baseline at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.318
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    12. Secondary Outcome
    Title Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
    Description The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0-100 scale score for each health domain is further converted to normbased scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL. The domains/summaries reported are: Physical Functioning (Range of possible T-scores is 19.26 - 57.54) General Health (Range of possible T-scores is 18.95 - 66.50) Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.
    Time Frame Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with an evaluable SF-36 questionnaire at screening visit and at least one post-screening visit
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 210 103
    Physical Functioning Domain Score - Change from Baseline
    -0.3
    (6.93)
    -0.2
    (7.86)
    General Health Domain Score - Change from Baseline
    0.4
    (7.18)
    0.3
    (7.03)
    PCS - Change from Baseline
    -0.4
    (7.01)
    -0.3
    (7.97)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Physical Functioning Domain - Change from Baseline at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.596
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments General Health Domain - Change from Baseline at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.395
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments PCS - Change from Baseline at Week 24
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.373
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    13. Secondary Outcome
    Title Number of Participants Who Utilized Healthcare Resources During Study
    Description Number of participants who had any of the following types of Healthcare Resource Utilization (HRU): a doctor office visit (non-study scheduled) an emergency department visit a hospitalization
    Time Frame From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Doctor Office Visit
    186
    83%
    69
    61.6%
    Emergency Department Visit
    71
    31.7%
    22
    19.6%
    Hospital Admission
    61
    27.2%
    5
    4.5%
    14. Secondary Outcome
    Title Number of Days Spent in Higher Care Hospital Units
    Description Types of hospitals units considered to be 'higher care' are: Intensive Care Unit Coronary Care Unit
    Time Frame From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who spent time in higher care hospital units
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 43 5
    Mean (Standard Deviation) [Days]
    8.0
    (23.70)
    0.6
    (0.55)
    15. Secondary Outcome
    Title Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment
    Description Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, i.e, Days 1 to 56, Days 2 to 57 and so on.
    Time Frame From first dose through 3 weeks post last dose (up to approximately 218 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 224 112
    Number [Percentage of participants]
    12.1
    5.4%
    1.8
    1.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0015
    Comments Significance level of 0.050 for 2-sided tests.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 7.6
    Confidence Interval (2-Sided) 95%
    1.8 to 32.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Duration of Reduction in Transfusion Burden
    Description Responders were defined as subjects who achieved ≥ 33% reduction or ≥ 50% reduction in Red Blood Cells Transfusion (RBC-T) burden from baseline with a reduction of at least 2 RBC units during any rolling 12-week interval. The duration of reduction is calculated as Last Day of Response - First day of response +1
    Time Frame From first dose to end of study treatment (up to approximately 215 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with ≥ 33% reduction or ≥ 50% reduction in RBC-T burden
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 173 39
    ≥ 33% Transfusion Burden Reduction
    627.3
    (390.54)
    224.0
    (155.15)
    ≥ 50% Transfusion Burden Reduction
    491.1
    (386.37)
    193.0
    (142.51)
    17. Secondary Outcome
    Title Longest Duration of Transfusion Independence
    Description Transfusion independence was defined as the absence of any transfusion during any consecutive "rolling" 8-week time interval within the treatment period, ie, Days 1 to 56, Days 2 to 57 and so on. Longest duration of transfusion independence was estimated based on Kaplan-Meier model.
    Time Frame From first dose through 3 weeks post last dose (up to approximately 218 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who were transfusion independent for ≥ 8 weeks
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 27 2
    Median (95% Confidence Interval) [Days]
    72.0
    71.5
    18. Secondary Outcome
    Title Time to Erythroid Response
    Description Time to erythroid response was defined as the time from first dose of the study drug to first erythroid response. This is reported for participants with a ≥ 33% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval., as well as participants with a ≥ 50% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval.
    Time Frame From first dose to 48 weeks following first dose

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who achieved erythroid response
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 173 39
    ≥ 33% Transfusion Burden Reduction
    96.3
    (163.92)
    163.5
    (148.78)
    ≥ 50% Transfusion Burden Reduction
    189.1
    (257.69)
    160.9
    (160.17)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments ≥ 33% Transfusion Burden Reduction
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0195
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value -67.27
    Confidence Interval (2-Sided) 95%
    -123.63 to -10.91
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Luspatercept + BSC, Placebo + BSC
    Comments ≥ 50% Transfusion Burden Reduction
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7473
    Comments Significance level of 0.050 for 2-sided tests.
    Method t-test, 2 sided
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 28.24
    Confidence Interval (2-Sided) 95%
    -144.87 to 201.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments luspatercept - placebo
    19. Secondary Outcome
    Title Post-Baseline Transfusion Event Frequency
    Description The number of transfusion events after start of study treatment were evaluated. For the definition of transfusion events, if multiple transfusions happen on the same date, they are counted as one event; if multiple transfusions happen on two consecutive dates, they are counted as one event; if multiple transfusions happen on three consecutive dates, they are counted as two events. Results are presented in 24-week intervals, up to 96 weeks after start of study treatment
    Time Frame From first dose through 3 weeks post last dose (up to approximately 218 weeks)

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received transfusions
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 210 102
    Week 1 - 24
    7.1
    (2.03)
    7.9
    (1.65)
    Week 25 - 48
    7.0
    (2.02)
    7.6
    (1.61)
    Week 49 - 72
    7.0
    (2.04)
    7.5
    (1.28)
    Week 73 - 96
    7.0
    (2.13)
    7.0
    (1.00)
    20. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [L/day]
    0.437
    (38.5)
    21. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [Liters]
    7.08
    (26.7)
    22. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [days]
    11.2
    (25.7)
    23. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Median (Full Range) [Days]
    5.48
    24. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [μg/mL]
    5.64
    (25.1)
    25. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [μg/mL]
    8.31
    (30.1)
    26. Secondary Outcome
    Title Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)
    Description
    Time Frame Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337

    Outcome Measure Data

    Analysis Population Description
    All randomized participants with available PK measurements for Luspatercept
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 221 0
    Geometric Mean (Geometric Coefficient of Variation) [day*μg/mL]
    129
    (36.0)
    27. Secondary Outcome
    Title Participants With Treatment-Emergent Adverse Events (TEAE)
    Description An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A serious AE is any AE occurring at any dose that - Results in death - Is life-threatening - Requires or prolongs existing inpatient hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death
    Time Frame From first dose to 90 days following last dose (up to approximately 52 months)

    Outcome Measure Data

    Analysis Population Description
    All treated participants
    Arm/Group Title Luspatercept + BSC Placebo + BSC
    Arm/Group Description Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, total dose per administration during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Measure Participants 223 109
    ≥ 1 Treatment-emergent adverse event (TEAE)
    219
    97.8%
    102
    91.1%
    Serious TEAE
    53
    23.7%
    8
    7.1%
    Grade ≥ 3 TEAE
    84
    37.5%
    19
    17%
    Treatment-related TEAE
    135
    60.3%
    31
    27.7%
    Treatment-related Serious TEAE
    13
    5.8%
    0
    0%
    Treatment-related TEAE ≥ Grade 3
    27
    12.1%
    1
    0.9%
    TEAE leading to death
    2
    0.9%
    1
    0.9%
    Trt-related TEAE leading to death
    0
    0%
    0
    0%
    TEAE leading to dose reduction
    10
    4.5%
    3
    2.7%
    TEAE leading to dose delay
    46
    20.5%
    11
    9.8%
    TEAE leading to drug discontinuation
    25
    11.2%
    2
    1.8%
    Trt-related TEAE leading to dose reduction
    9
    4%
    2
    1.8%
    Trt-related TEAE leading to dose delay
    15
    6.7%
    3
    2.7%
    Trt-related TEAE leading to drug discontinuation
    20
    8.9%
    1
    0.9%
    28. Secondary Outcome
    Title Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
    Description Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as "treatment-emergent" if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as "preexisting" if the baseline sample was ADA positive and the participant was not qualified for "treatment-emergent."
    Time Frame Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316

    Outcome Measure Data

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

    Adverse Events

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

    Limitations/Caveats

    [Not Specified]

    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/Title Bristol-Myers Squibb Study Director
    Organization Bristol-Myers Squibb
    Phone Please email
    Email Clinical.Trials@bms.com
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT02604433
    Other Study ID Numbers:
    • ACE-536-B-THAL-001
    First Posted:
    Nov 13, 2015
    Last Update Posted:
    Jan 25, 2022
    Last Verified:
    Jan 1, 2022