A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia

NCT03342404 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: ACE-536-B-THAL-002U1111-1202-70682015-003225-33
• Study Type: interventional
• Target: 145
• Locations: 6 countries
• Sites: 16

Brief Summary

This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in adults with non-transfusion dependent beta (β)-thalassemia. The study is divided into the Screening Period, Double-blind Treatment Period (DBTP), Open-label Phase (OLP), and Post-Treatment Follow-up Period (PTFP). It is planned to randomize approximately 150 subjects at a 2:1 ratio of luspatercept versus placebo.

Conditions

Thalassemia

Keywords

(β)-Thalassemia; Beta-Thalassemia; Phase 2; Luspatercept; ACE-536; Safety; Efficacy; Placebo; Red Blood Cell Transfusions; Erythrocyte transfusion; Hb increase; NTDT

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)

  Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 13 to 24 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.

  From Week 13 to Week 24 of study treatment

Secondary Outcomes (29)

• Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24)

  Baseline and over a continuous 12 week period (from week 13 through week 24)

• Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24)

  Baseline and over a continuous 12 week period (from week 13 through week 24)

• Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48)

  Assessed over a continuous 12 week period (from week 37 through week 48)

• Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)

  Baseline and over a continuous 12 week period (from week 13 through week 24)

• Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24)

  Baseline and over a continuous 12 week period (from week 13 through week 24)

Study Arms (2)

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

EXPERIMENTAL

Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days

Drug: Luspatercept; Other: Best Supportive Care (BSC)

Placebo plus Best Supportive Care (BSC)

PLACEBO COMPARATOR

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

Other: Placebo; Other: Best Supportive Care (BSC)

Interventions

Luspatercept DRUG

Subjects will start with luspatercept at 1 mg/kg dose level every 3 weeks and can be dose escalated up to 1.25 mg/kg.

Also known as: ACE-536

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

Placebo OTHER

Placebo, Subcutaneous, every 21 days

Also known as: normal saline

Placebo plus Best Supportive Care (BSC)

Best Supportive Care (BSC) OTHER

Best Supportive Care (BSC)

Luspatercept (ACE-536) plus Best Supportive Care (BSC); 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:
• Subjects must be ≥ 18 years of age at the time of signing the informed consent document (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule (eg, not scheduled to receive hematopoietic stem cell transplantation) and other protocol requirements.
• Subject must have documented diagnosis of β-thalassemia or hemoglobin E/ β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.
• Subject must be non-transfusion dependent, defined as 0 to 5 units of RBCs received during the 24-week period prior to randomization. Note: 1 unit defined for this entry criterion as approximately 200 to 350 mL of transfused packed RBCs.
• Subject must not be on a regular transfusion program and must be RBC transfusion-free for at least ≥ 8 weeks prior to randomization
• Subject must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.
• Subject must have performance status: Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
• A female of childbearing potential (FCBP) for this study is defined as a female who:
• \) 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). A FCBP participating in the study must:
• Have 2 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 during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple dose pharmacokinetics \[PK\] data) after discontinuation of study therapy.
• \. Male subjects must:
• a. Practice true abstinence (which must be reviewed on a monthly basis) 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 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following IP 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.
• Diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg,Hemoglobin H).
• Active hepatitis C (HCV) infection
• Deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
• Subjects on chronic anticoagulant therapy are excluded, unless they stopped the treatment at least 28 days prior to randomization. Anticoagulant therapies for prophylaxis and for surgery or high-risk procedures as well as low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) and chronic aspirin are allowed before and during the study.
• Treatment with another investigational drug or device ≤ 28 days prior to randomization.
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
• Platelet count \> 1000 x 109/L.
• Subjects on iron chelation therapy (ICT) at the time of ICF signature must have initiated the treatment with ICT at least 24 weeks before the predicted randomization date. ICT can be initiated at any time during treatment and should be used according to the label.
• Subject had Hydroxyurea and ESA treatment ≤ 24 weeks prior to randomization, and no prior gene therapy.
• Subject is pregnant or a lactating female.
• Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) version 4.0 (current active minor version).

Sponsors & Collaborators

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

Study Sites (16)

Children's Hospital of Los Angeles

Los Angeles, California, 90027, United States

Location

Local Institution - 501

Los Angeles, California, 90027, United States

Location

Children's Hospital and Research Center at Oakland

Oakland, California, 94609, United States

Location

Local Institution - 503

Chicago, Illinois, 60611, United States

Location

Local Institution - 102

Athens, 115 27, Greece

Location

Local Institution - 101

Athens, 11527, Greece

Location

Local Institution - 205

Cagliari, 09121, Italy

Location

Universita degli Studi di Cagliari - ASL8

Cagliari, 09121, Italy

Location

Local Institution - 202

Genoa, 16128, Italy

Location

Local Institution - 201

Milan, 20122, Italy

Location

Local Institution - 203

Naples, 80131, Italy

Location

Local Institution - 206

Napoli, 80131, Italy

Location

Local Institution - 204

Orbassano, 10043, Italy

Location

Local Institution - 301

Hazmiyeh, 00961, Lebanon

Location

Local Institution - 401

Bangkok, 10700, Thailand

Location

Local Institution - 601

London Bloomsbury, WC1E 6AU, United Kingdom

Location

Related Publications (5)

• 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 BACKGROUND

• Taher AT, Viprakasit V, Kattamis A, Perrotta S, Ricchi P, Porter JB, Coates TD, Forni GL, Musallam KM, Esposito O, Pilot R, Kuo WL, Lai Y, Reverte M, Wei R, Bueno LM, Cappellini MD. Efficacy and safety of luspatercept in non-transfusion-dependent beta-thalassemia: long-term results from the BEYOND study. Blood Adv. 2025 Dec 9;9(23):6108-6119. doi: 10.1182/bloodadvances.2025016554.

  PMID: 40875596 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

• Taher AT, Musallam KM, Viprakasit V, Kattamis A, Lord-Bessen J, Yucel A, Guo S, Pelligra C, Shields AL, Shetty JK, Miteva D, Bueno LM, Cappellini MD. Psychometric evaluation of the NTDT-PRO questionnaire for assessing symptoms in patients with non-transfusion-dependent beta-thalassaemia. BMJ Open. 2023 Mar 22;13(3):e066683. doi: 10.1136/bmjopen-2022-066683.

  PMID: 36948565 DERIVED

• Taher AT, Cappellini MD, Kattamis A, Voskaridou E, Perrotta S, Piga AG, Filosa A, Porter JB, Coates TD, Forni GL, Thompson AA, Tartaglione I, Musallam KM, Backstrom JT, Esposito O, Giuseppi AC, Kuo WL, Miteva D, Lord-Bessen J, Yucel A, Zinger T, Shetty JK, Viprakasit V; BEYOND Investigators. Luspatercept for the treatment of anaemia in non-transfusion-dependent beta-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial. Lancet Haematol. 2022 Oct;9(10):e733-e744. doi: 10.1016/S2352-3026(22)00208-3. Epub 2022 Aug 22.

  PMID: 36007538 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Thalassemia; beta-Thalassemia

Interventions

luspatercept; Saline Solution

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

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

Clinical.Trials@bms.com

Please email

Study Officials

• Jeevan Shetty, MD

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• 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 30, 2017
• First Posted: November 17, 2017
• Study Start: February 5, 2018
• Primary Completion: November 28, 2022
• Study Completion: November 28, 2022
• Last Updated: December 20, 2023
• Results First Posted: November 18, 2021

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); IT (7); GR (2); TH (1); GB (1); LE (1)