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
NCT ID: NCT02604433
Last Updated: 2023-04-18
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
336 participants
INTERVENTIONAL
2016-05-02
2021-01-05
Brief Summary
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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
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Luspatercept (ACE-536) plus Best Supportive Care (BSC)
Luspatercept, subcutaneous(ly) (SC) once every 21 days
Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.
Placebo plus Best Supportive Care (BSC)
normal saline solution subcutaneous(ly) (SC) once every 21 days
Placebo
Placebo, Subcutaneous, every 21 days.
Interventions
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Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.
Placebo
Placebo, Subcutaneous, every 21 days.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
6. Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
7. 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.
8. 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
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).
6. Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
7. 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.
8. Platelet count \> 1000 x 109/L
9. 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).
10. Treatment with another investigational drug or device ≤ 28 days prior to randomization.
11. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
12. Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization.
13. Iron chelation therapy, if initiated ≤ 24 weeks prior to randomization (allowed if initiated \> 24 weeks before or during treatment).
14. Hydroxyurea treatment ≤ 24 weeks prior to randomization.
15. Pregnant or lactating females.
16. 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).
17. Major organ damage, including:
1. Liver disease with alanine aminotransferase (ALT) \> 3 x the upper limit of normal (ULN) or history of evidence of cirrhosis;
2. 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.
3. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant ie, ≥ Grade 3 NCI CTCAE version 4.0 (current active minor version).
4. Creatinine clearance \< 60 mL/min (per Cockroft-Gault formula).
18. Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).
19. 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).
20. Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
22. Cytotoxic agents, immunosuppressants ≤ 28 days prior to randomization (ie, antithymocite globulin (ATG) or cyclosporine)
23. History of malignancy with the exception of:
1. Curatively resected nonmelanoma skin cancer.
2. Curatively treated cervical carcinoma in situ.
3. Other solid tumor with no known active disease in the opinion of the investigator.
18 Years
ALL
No
Sponsors
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Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
INDUSTRY
Celgene
INDUSTRY
Responsible Party
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Principal Investigators
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Bristol-Myers Squibb
Role: STUDY_DIRECTOR
Bristol-Myers Squibb
Locations
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Children's Hospital of Los Angeles
Los Angeles, California, United States
Children's Hospital and Research Center at Oakland
Oakland, California, United States
Ann and Robert H Lurie Childrens Hospital of Chicago
Chicago, Illinois, United States
Boston Children's Hospital
Boston, Massachusetts, United States
Weill Cornell Medical College
New York, New York, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Prince of Wales Hospital
Randwick, New South Wales, Australia
Mater Hospital Brisbane
South Brisbane, Queensland, Australia
Royal Adelaide Hospital Institute of Medical and Veterinary Science
Adelaide, South Australia, Australia
Monash Medical Centre
Clayton, Victoria, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
Royal Prince Alfred Hospital
Camperdown, , Australia
University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
Plovdiv, , Bulgaria
Specialized Hospital for Active Treatment of Haematological Diseases - Sofia
Sofia, , Bulgaria
Multiprofile Hospital for Active Treatment Sveta Marina EAD
Varna, , Bulgaria
University Health Network
Toronto, Ontario, Canada
Hopital Henri Mondor
Créteil, , France
GH de Institut Catholique St. VincentHématologie
Lille, , France
Hopitaux de La Timone
Marseille, , France
Hospital of Necker
Paris, , France
Laiko General Hospital of Athens
Ampelokipi - Athens, , Greece
Local Institution - 405
Ampelokipi - Athens, , Greece
General Children's Hospital "Agia Sophia"
Athens, , Greece
General Hospital Georgios Gennimatas of Athens
Athens, , Greece
University General Hospital of Patras
Rio Patras, , Greece
Hippokration Hospital
Thessaloniki, , Greece
Local Institution - 404
Thessaloniki, , Greece
Soroka University Medical Centre
Beersheba, , Israel
Rambam Health Corporation
Haifa, , Israel
HaEmek Medical Center
Haïfa (Afula), , Israel
Shaare Zedek Medical Center
Jerusalem, , Israel
Hadassah Medical Center
Jerusalem, , Israel
Galilee Medical Center
Nahariya, , Israel
Rabin Medical Center
Petah Tikva, , Israel
Presidio Ospedaliero Antonio Perrino
Brindisi, , Italy
Universita degli Studi di Cagliari - ASL8
Cagliari, , Italy
Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna
Ferrara, , Italy
Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite
Genoa, , Italy
Fondazione Ca Granda IRCCS Ospedale Maggiore
Milan, , Italy
Seconda Universita Degli Studi Di Napoli
Naples, , Italy
AORN A Cardarelli
Napoli, , Italy
Azienda Ospedaliero Universitaria S. Luigi Gonzaga
Orbassano, , Italy
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
Palermo, , Italy
Azienda Ospedaliera Universitaria Integrata Di Verona
Verona, , Italy
Chronic Care Center
Beirut, , Lebanon
Hospital Sultanah Aminah
Johor Bahru, Johor, Malaysia
Hospital Sultanah Bahiyah
Alor Star, Kedah, Malaysia
University Malaya Medical Centre
Kuala Lumpur, Kuala Lumpur, Malaysia
Hospital Raja Permaisuri Bainun
Ipoh, Perak, Malaysia
Queen Elizabeth Hospital
Kota Kinabalu, Sabah, Malaysia
Hospital Umum Sarawak
Kuching, Sarawak, Malaysia
Hospital Pulau Pinang c/o Penang Medical College
George Town, , Malaysia
Changhua Christian Hospital
Changhua, , Taiwan
Kaohsiung Medical University Hospital
Kaohsiung City, , Taiwan
China Medical University Hospital
Taichung, , Taiwan
National Taiwan University Hospital
Taipei, Zhongzheng Dist., , Taiwan
Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital
Bangkok, , Thailand
Siriraj Hospital Mahidol University
Bangkok, , Thailand
Chiang Mai University - Maharaj Nakorn Chiang Mai Hospital
Chiang Mai, , Thailand
University Hospital Farhat Hached
Sousse, , Tunisia
Bone Marrow Transplant Center
Tunis, , Tunisia
Aziza Othmana Hospital
Tunis, , Tunisia
Military Hospital of Tunis
Tunis, , Tunisia
Acibadem Adana Hospital
Adana, , Turkey (Türkiye)
Cukurova University Medical Faculty Balcali Hospital
Adana, , Turkey (Türkiye)
Local Institution - 524
Adana, , Turkey (Türkiye)
Hacettepe Universitesi
Ankara, , Turkey (Türkiye)
Antalya Egitim Arastirma
Antalya, , Turkey (Türkiye)
Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi
Istanbul, , Turkey (Türkiye)
Ege Universitesi Tip Fakultesi Hastanesi
Izmir, , Turkey (Türkiye)
Mersin University Medical Faculty
Mersin, , Turkey (Türkiye)
St James University Hospital
Leeds, , United Kingdom
Barts Health NHS Trust - The Royal London Hospital
London, , United Kingdom
Whittington Hospital
London, , United Kingdom
University College Hospital Trust
London Bloomsbury, , United Kingdom
Manchester Royal Infirmary
Manchester, , United Kingdom
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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BMS Clinical Trial Information
BMS Clinical Trial Patient Recruiting
FDA Safety Alerts and Recalls
Other Identifiers
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ACE-536-B-THAL-001
Identifier Type: -
Identifier Source: org_study_id
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