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

NCT02604433 | Completed Phase 3 Results DMC

• 1 other identifier: ACE-536-B-THAL-001
• Study Type: interventional
• Target: 336
• Locations: 14 countries
• Sites: 72

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

Conditions

Erythrocyte Transfusion; Beta-Thalassemia

Keywords

ACE-536; Safety; Efficacy; Placebo; Red Blood Cell Transfusions; Beta -Thalassemia

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24

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

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

Secondary Outcomes (27)

• 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 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 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

• Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24

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

• Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48

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

Study Arms (2)

Luspatercept (ACE-536) plus Best Supportive Care (BSC)

EXPERIMENTAL

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

Drug: Luspatercept

Placebo plus Best Supportive Care (BSC)

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

Luspatercept DRUG

Subjects will start with luspatercept at 1 mg/kg dose level.

Also known as: ACE-536

Luspatercept (ACE-536) plus Best Supportive Care (BSC)

Placebo OTHER

Placebo, Subcutaneous, every 21 days.

Placebo plus Best Supportive Care (BSC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must satisfy the following criteria to be enrolled in the study:
• Male or female, ≥18 years of age at the time of signing the informed consent document (ICF).
• Subject must understand and voluntarily sign an Inform Consent Form prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia. (β-thalassemia with mutation and/or multiplication of alpha globin is allowed).
• Regularly transfused, defined as: 6-20 Red Blood Cell (RBC) units\* in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.
• \* Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL. (i) sites who use transfusion bags within this range, or ≥ 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, (ii) sites who use transfusion bags \< 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.
• Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
• A female of childbearing potential (FCBP) for this study is defined as a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). FCBP participating in the study must:
• 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.
• Either commit to true abstinence\*\* from heterosexual contact (which must be reviewed on a monthly basis and source documented) If a FCBP engages in sexual activity that may result in a pregnancy, she must agree to use, and be able to comply with, effective\*\*\* contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose Pharmacokinetic PK) data) after discontinuation of study therapy.
• True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. \[Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.\] \*\*\* Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study.
• Such methods include: Combined (estrogen and progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.
• Male subjects must:
• Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy.

You may not qualify if:

• The presence of any of the following will exclude a subject from enrollment:
• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.
• A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H);
• Evidence of active hepatitis C (HCV) infection as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B as demonstrated by the presence of HBsAg and/or HBVDNA-positive,, or known positive human immunodeficiency virus (HIV).
• Note: Subjects receiving antiviral therapies should have 2 negative HCVRNA tests 3 months apart.(ie, one test at the end of the antiviral therapy and a second test 3 months following the first test).
• Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
• Use of chronic anticoagulant therapy is excluded, unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
• Platelet count \> 1000 x 109/L
• Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (eg, stroke or myocardial infarction).
• Treatment with another investigational drug or device ≤ 28 days prior to randomization.
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
• Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization.
• Iron chelation therapy, if initiated ≤ 24 weeks prior to randomization (allowed if initiated \> 24 weeks before or during treatment).

Sponsors & Collaborators

• Celgene: lead
• Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA: collaborator

Study Sites (76)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital and Research Center at Oakland

Oakland, California, 94609, United States

Location

Ann and Robert H Lurie Childrens Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

Location

Mater Hospital Brisbane

South Brisbane, Queensland, 4101, Australia

Location

Royal Adelaide Hospital Institute of Medical and Veterinary Science

Adelaide, South Australia, 5000, Australia

Location

Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

Royal Prince Alfred Hospital

Camperdown, 2050, Australia

Location

University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD

Plovdiv, 4002, Bulgaria

Location

Specialized Hospital for Active Treatment of Haematological Diseases - Sofia

Sofia, 1756, Bulgaria

Location

Multiprofile Hospital for Active Treatment Sveta Marina EAD

Varna, 9010, Bulgaria

Location

University Health Network

Toronto, Ontario, M5G 2C4, Canada

Location

Hopital Henri Mondor

Créteil, 94010, France

Location

GH de Institut Catholique St. VincentHématologie

Lille, 59000, France

Location

Hopitaux de La Timone

Marseille, 13385, France

Location

Hospital of Necker

Paris, 75015, France

Location

Laiko General Hospital of Athens

Ampelokipi - Athens, 115 26, Greece

Location

Local Institution - 405

Ampelokipi - Athens, 115 26, Greece

Location

General Children's Hospital "Agia Sophia"

Athens, 115 27, Greece

Location

General Hospital Georgios Gennimatas of Athens

Athens, 11527, Greece

Location

University General Hospital of Patras

Rio Patras, 26500, Greece

Location

Hippokration Hospital

Thessaloniki, 54642, Greece

Location

Local Institution - 404

Thessaloniki, 54642, Greece

Location

Soroka University Medical Centre

Beersheba, 84101, Israel

Location

Rambam Health Corporation

Haifa, 3109601, Israel

Location

HaEmek Medical Center

Haïfa (Afula), 18101, Israel

Location

Shaare Zedek Medical Center

Jerusalem, 91031, Israel

Location

Hadassah Medical Center

Jerusalem, 91120, Israel

Location

Galilee Medical Center

Nahariya, 22100, Israel

Location

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Presidio Ospedaliero Antonio Perrino

Brindisi, 72100, Italy

Location

Universita degli Studi di Cagliari - ASL8

Cagliari, 09121, Italy

Location

Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna

Ferrara, 44124, Italy

Location

Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite

Genoa, 16128, Italy

Location

Fondazione Ca Granda IRCCS Ospedale Maggiore

Milan, 20122, Italy

Location

Seconda Universita Degli Studi Di Napoli

Naples, 80131, Italy

Location

AORN A Cardarelli

Napoli, 80131, Italy

Location

Azienda Ospedaliero Universitaria S. Luigi Gonzaga

Orbassano, 10043, Italy

Location

Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello

Palermo, 90146, Italy

Location

Azienda Ospedaliera Universitaria Integrata Di Verona

Verona, 37134, Italy

Location

Chronic Care Center

Beirut, Lebanon

Location

Hospital Sultanah Aminah

Johor Bahru, Johor, 80100, Malaysia

Location

Hospital Sultanah Bahiyah

Alor Star, Kedah, 05460, Malaysia

Location

University Malaya Medical Centre

Kuala Lumpur, Kuala Lumpur, 59100, Malaysia

Location

Hospital Raja Permaisuri Bainun

Ipoh, Perak, 30990, Malaysia

Location

Queen Elizabeth Hospital

Kota Kinabalu, Sabah, 88586, Malaysia

Location

Hospital Umum Sarawak

Kuching, Sarawak, 93586, Malaysia

Location

Hospital Pulau Pinang c/o Penang Medical College

George Town, 10990, Malaysia

Location

Changhua Christian Hospital

Changhua, 500, Taiwan

Location

Kaohsiung Medical University Hospital

Kaohsiung City, 807, Taiwan

Location

China Medical University Hospital

Taichung, 40447, Taiwan

Location

National Taiwan University Hospital

Taipei, Zhongzheng Dist., 10002, Taiwan

Location

Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital

Bangkok, 10330, Thailand

Location

Siriraj Hospital Mahidol University

Bangkok, 10700, Thailand

Location

Chiang Mai University - Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, 50200, Thailand

Location

University Hospital Farhat Hached

Sousse, 4031, Tunisia

Location

Bone Marrow Transplant Center

Tunis, 1006, Tunisia

Location

Aziza Othmana Hospital

Tunis, 1008, Tunisia

Location

Military Hospital of Tunis

Tunis, 1089, Tunisia

Location

Acibadem Adana Hospital

Adana, 01130, Turkey (Türkiye)

Location

Cukurova University Medical Faculty Balcali Hospital

Adana, 01330, Turkey (Türkiye)

Location

Local Institution - 524

Adana, 01330, Turkey (Türkiye)

Location

Hacettepe Universitesi

Ankara, 01660, Turkey (Türkiye)

Location

Antalya Egitim Arastirma

Antalya, 07100, Turkey (Türkiye)

Location

Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi

Istanbul, 34093, Turkey (Türkiye)

Location

Ege Universitesi Tip Fakultesi Hastanesi

Izmir, 35100, Turkey (Türkiye)

Location

Mersin University Medical Faculty

Mersin, 33343, Turkey (Türkiye)

Location

St James University Hospital

Leeds, LS9 7TF, United Kingdom

Location

Barts Health NHS Trust - The Royal London Hospital

London, E1 1BB, United Kingdom

Location

Whittington Hospital

London, N19 5NF, United Kingdom

Location

University College Hospital Trust

London Bloomsbury, WC1E 6AU, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Related Publications (7)

• Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361-370. doi: 10.1182/asheducation-2018.1.361.

  PMID: 30504333 RESULT

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

  PMID: 30617198 RESULT

• Cappellini MD, Viprakasit V, Georgiev P, Coates TD, Origa R, Khelif A, Liew HK, Tantiworawit A, Chew LP, Khalil A, Ho PJ, Kuo KHM, Holot N, Perin M, Giuseppi AC, Kuo WL, Lai Y, Medlin LF, Bueno LM, Kattamis A, Taher AT. Long-term efficacy and safety of luspatercept for the treatment of anaemia in patients with transfusion-dependent beta-thalassaemia (BELIEVE): final results from a phase 3 randomised trial. Lancet Haematol. 2025 Mar;12(3):e180-e189. doi: 10.1016/S2352-3026(24)00376-4. Epub 2025 Feb 10.

  PMID: 39947215 DERIVED

• Garbowski MW, Ugidos M, Risueno A, Shetty JK, Schwickart M, Hermine O, Porter JB, Thakurta A, Vodala S. Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia. Am J Hematol. 2024 Feb;99(2):182-192. doi: 10.1002/ajh.27102. Epub 2023 Oct 2.

  PMID: 37782758 DERIVED

• Denton CC, Vodala S, Veluswamy S, Hofstra TC, Coates TD, Wood JC. Splenic iron decreases without change in volume or liver parameters during luspatercept therapy. Blood. 2023 Nov 30;142(22):1932-1934. doi: 10.1182/blood.2023021839.

  PMID: 37704579 DERIVED

• Cappellini MD, Taher AT. The use of luspatercept for thalassemia in adults. Blood Adv. 2021 Jan 12;5(1):326-333. doi: 10.1182/bloodadvances.2020002725.

  PMID: 33570654 DERIVED

• Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, Voskaridou E, Liew HK, Pazgal-Kobrowski I, Forni GL, Perrotta S, Khelif A, Lal A, Kattamis A, Vlachaki E, Origa R, Aydinok Y, Bejaoui M, Ho PJ, Chew LP, Bee PC, Lim SM, Lu MY, Tantiworawit A, Ganeva P, Gercheva L, Shah F, Neufeld EJ, Thompson A, Laadem A, Shetty JK, Zou J, Zhang J, Miteva D, Zinger T, Linde PG, Sherman ML, Hermine O, Porter J, Piga A; BELIEVE Investigators. A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2020 Mar 26;382(13):1219-1231. doi: 10.1056/NEJMoa1910182.

  PMID: 32212518 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

MeSH Terms

Conditions

beta-Thalassemia

Interventions

luspatercept

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2015
• First Posted: November 13, 2015
• Study Start: May 2, 2016
• Primary Completion: January 5, 2021
• Study Completion: January 5, 2021
• Last Updated: April 18, 2023
• Results First Posted: January 27, 2020

Record last verified: 2023-03

Locations

TU (8); LE (1); TW (4); IT (10); TH (3); GR (7); FR (4); MY (7); GB (5); AU (6); IL (7); BU (3); CA (1); US (6)