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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03342404
Recruitment Status : Active, not recruiting
First Posted : November 17, 2017
Last Update Posted : April 20, 2020
Sponsor:
Collaborator:
Acceleron Pharma, Inc.
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE October 30, 2017
First Posted Date  ICMJE November 17, 2017
Last Update Posted Date April 20, 2020
Actual Study Start Date  ICMJE February 1, 2018
Estimated Primary Completion Date September 14, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 9, 2017)
Proportion of subjects who have an increase from baseline ≥1.0 g/dl in mean of hemoglobin values over a continuous 12-week interval Week 13 to Week 24 in the absence of transfusions [ Time Frame: Up to approximately week 24 ]
Number of subjects with increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions in Luspatercept group will be compared with placebo group. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to randomization.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 9, 2017)
  • Mean change from baseline in non-transfusion dependent β- thalassemia-patient reported outcome (NTDT-PRO) Tiredness and Weakness (TW) domain score over a continuous 12-week interval from Week 13 to Week 24 [ Time Frame: Up to approximately week 24 ]
    The non-transfusion dependent β- thalassemia-patient reported outcome (NTDT-PRO) is administered as a daily diary for 24 weeks and after that over the 7 days prior to receiving IP dose. Mean change from baseline in NTDT-PRO total score over a continuous 12-week interval from Week 13 to Week 24 in Luspatercept group will be compared with placebo group. The NTDT-PRO is a six-item PRO instrument delivered on hand-held devices to assess presence and severity of tiredness, weakness, and shortness of breath with and without physical activity using a scale ranging from 0 to 10 with "0" being no tiredness, no weakness, and no shortness of breath.
  • Mean change from baseline in hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 [ Time Frame: Up to approximately week 24 ]
    Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to randomization. Mean change from baseline in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in Luspatercept group will be compared with placebo group
  • Proportion of subjects who have an increase from baseline ≥1.0 [ Time Frame: Up to approximately week 48 ]
    Number of subjects with increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions in Luspatercept group will be compared with placebo group. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to randomization.
  • Mean change from baseline in mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score over a continuous 12-week interval from Week 13 to Week 24 [ Time Frame: Up to approximately week 24 ]
    FACIT-F is administered to subjects every other dose prior to receiving IP dose. Mean change from baseline in mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score over a continuous 12-week interval from Week 13 to Week 24 in Luspatercept group will be compared with placebo group. The total score ranges from 0 to 52. High scores represent less fatigue.
  • Mean change from baseline in mean NTDT-PRO total score over a continuous 12-week interval from Week 13 to Week 24 [ Time Frame: Up to approximately week 24 ]
    The non-transfusion dependent β- thalassemia-patient reported outcome (NTDT-PRO) is administered as a daily diary for 24 weeks and after that over the 7 days prior to receiving IP dose. Mean change from baseline in NTDT-PRO total score over a continuous 12-week interval from Week 13 to Week 24 in Luspatercept group will be compared with placebo group. The NTDT-PRO is a six-item PRO instrument delivered on hand-held devices to assess presence and severity of tiredness, weakness, and shortness of breath with and without physical activity using a scale ranging from 0 to 10 with "0" being no tiredness, no weakness, and no shortness of breath.
  • Mean change from baseline in hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions [ Time Frame: Up to approximately week 48 ]
    Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to randomization. Mean change from baseline in mean hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions in Luspatercept group will be compared with placebo group
  • Mean change from baseline in mean FACIT-F total score over a continuous 12-week interval from Week 37 to Week 48 [ Time Frame: Up to approximately week 48 ]
    FACIT-F is administered to subjects every other dose prior to receiving IP dose. Mean change from baseline in mean FACIT-F total score over a continuous 12-week interval from Week 37 to Week 48 in Luspatercept group will be compared with placebo group. The total score ranges from 0 to 52. High scores represent less fatigue.
  • Mean change from baseline in mean NTDT-PRO TW domain total score over a continuous 12-week interval from Week 37 to Week 48 [ Time Frame: Up to approximately week 48 ]
    The non-transfusion dependent β- thalassemia-patient reported outcome (NTDT-PRO) is administered as a daily diary for 24 weeks and after that over the 7 days prior to receiving IP dose. Mean change from baseline in NTDT-PRO total score over a continuous 12-week interval from Week 37 to Week 48 in Luspatercept group will be compared with placebo group. The NTDT-PRO is a six-item PRO instrument delivered on hand-held devices to assess presence and severity of tiredness, weakness, and shortness of breath with and without physical activity using a scale ranging from 0 to 10 with "0" being no tiredness, no weakness, and no shortness of breath.
  • Mean change from baseline in mean NTDT-PRO total score over a continuous 12-week interval from Week 37 to Week 48 [ Time Frame: Up to approximately week 48 ]
    The The non-transfusion dependent β- thalassemia-patient reported outcome (NTDT-PRO) is administered as a daily diary for 24 weeks and after that over the 7 days prior to receiving IP dose. Mean change from baseline in NTDT-PRO total score over a continuous 12-week interval from Week 37 to Week 48 in Luspatercept group will be compared with placebo group. The NTDT-PRO is a six-item PRO instrument delivered on hand-held devices to assess presence and severity of tiredness, weakness, and shortness of breath with and without physical activity using a scale ranging from 0 to 10 with "0" being no tiredness, no weakness, and no shortness of breath.
  • Proportion of subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 13 to Week 24 [ Time Frame: Up to approximately week 24 ]
    FACIT-F is administered to subjects every other dose prior to receiving IP dose. Number of Subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 13 to Week 24 in Luspatercept group will be compared with placebo group. The total score ranges from 0 to 52. High scores represent less fatigue.
  • Proportion of subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 37 to Week 48 [ Time Frame: Up to approximately week 48 ]
    FACIT-F is administered to subjects every other dose prior to receiving IP dose. Number of Subjects with an increase from baseline ≥ 3 in mean FACIT-F score over a continuous 12-week interval from Week 37 to Week 48 in Luspatercept group will be compared with placebo group. The total score ranges from 0 to 52. High scores represent less fatigue.
  • Mean change from baseline in Medical Outcomes Study 36-Item Short Form (SF-36) at Week 24 and Week 48 [ Time Frame: Up to approximately week 48 ]
    SF-36 is administered to subjects every other dose prior to receiving IP dose. Mean change from baseline in Medical Outcomes Study 36-Item Short Form (SF-36) at Week 24 and Week 48 in Luspatercept group will be compared with placebo group
  • Proportion of subjects with improvement of iron overload at Week 24 and Week 48, as measured by Iron Chelator Treatments use [ Time Frame: Up to approximately week 48 ]
    Changes in Iron Chelators use and regimen will be measured and compared between treatment and placebo groups.
  • Mean change from baseline in serum ferritin at Week 24 and Week 48 [ Time Frame: Up to approximately week 48 ]
    Mean change from baseline in serum ferritin at Week 24 and Week 48 in Luspatercept group will be compared with placebo group
  • Mean change from baseline in LIC at Week 24 and Week 48 [ Time Frame: Up to approximately week 48 ]
    Mean change from baseline in LIC at Week 24 and Week 48 in Luspatercept group will be compared with placebo group
  • Proportion of subjects who are transfusion-free over 48 weeks [ Time Frame: Up to approximately week 48 ]
    Number of subjects who are transfusion-free over 48 weeks in Luspatercept group will be compared with placebo group
  • Duration of the mean hemoglobin increase from baseline ≥1.0 g/dL [ Time Frame: Up to approximately week 48 ]
    Time from first to last Hb measurement with increase from baseline ≥1.0 g/dL in Luspatercept group will be compared with placebo group
  • Mean change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48 [ Time Frame: Up to approximately week 48 ]
    6MWT is performed every 4 doses, eg, Dose 1, 5, 9, etc. and at Week 24 & Week 48 regardless of dose delay and even if the IP is discontinued. Mean change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48 in Luspatercept group will be compared with placebo group.
  • Proportion of subjects who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions [ Time Frame: Up to approximately week 24 ]
    Number of subjects with increase from baseline ≥1.5 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions in Luspatercept group will be compared with placebo group.
  • Adverse Events (AEs) [ Time Frame: Up to approximately 48 weeks ]
    Type, frequency, severity and relationship to investigational product (IP) of adverse events; frequency of anti-drug antibodies and their effect on efficacy and safety. Number of participants with adverse events in Luspatercept group will be compared with placebo group.
  • Pharmacokinetic - AUC [ Time Frame: Up to approximately 2 years ]
    Area under the plasma concentration-time curve
  • Pharmacokinetic - Cmax [ Time Frame: Up to approximately 2 years ]
    Maximum observed concentration in plasma
  • Proportion of subjects with improvement of iron overload at Week 24 and Week 48, as measured via Leaver Iron Concentration (LIC) by MRI [ Time Frame: Up to approximately week 48 ]
    Changes in Leaver Iron Concentration (LIC) by MRI will be measured and compared between treatment and placebo groups.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia
Official Title  ICMJE A Phase 2, Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Adults With Non-Transfusion Dependent Beta (B)-Thalassemia
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) and Post-Treatment Follow-up Period (PTFP).

It is planned to randomize approximately 150 subjects at a 2:1 ratio of luspatercept versus placebo.

Detailed Description

The primary objective is:

- To evaluate the effect of luspatercept in non-transfusion dependent β-thalassemia-patient versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval, from Week 13 to Week 24, compared to baseline.

The secondary objectives are:

  • To evaluate the effect of luspatercept versus placebo on β-thalassemia related symptoms, as measured by non transfusion dependent β-thalassemia-patient reported outcome (NTDT-PRO) over a continuous 12-week intervals (from Weeks 13 to 24 and from Weeks 37 to 48) compared to baseline.
  • To evaluate the effect of luspatercept versus placebo on functional and health-related quality of life (QoL) as measured by Medical Outcomes Study 36-Item Short Form (SF-36) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaires
  • To evaluate the long-term effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval from Week 37 to Week 48, compared to baseline
  • To evaluate the effect of luspatercept versus placebo on iron overload, as measured by liver iron concentration (LIC) and iron chelation therapy (ICT) daily dose
  • To evaluate the effect of luspatercept versus placebo on iron overload, as measured by serum ferritin
  • To evaluate the duration of erythroid response
  • To evaluate the effect of luspatercept versus placebo on physical activity measured by 6-minute walk test (6MWT)

Safety and Pharmacokinetics (PK) Objectives

  • To evaluate safety and tolerability of luspatercept, including immunogenicity
  • To evaluate population pharmacokinetics (PK) of luspatercept in subjects with β- thalassemia

The exploratory objectives are:

  • To evaluate the effect of luspatercept versus placebo on measures of extra-medullary hematopoietic (EMH) masses, bone mineral density, splenomegaly, pulmonary hypertension, and leg ulcers, when present
  • To evaluate the effect of luspatercept versus placebo on the β-thalassemia severity as measured by the NTDT severity score system
  • To examine the relationship of baseline and change in serum Growth Differentiation Factor 11 (GDF11) and other related biomarkers with response to treatment with luspatercept
  • To examine the effect of luspatercept on fetal hemoglobin (HbF)
  • To examine the effect of luspatercept on Health Resource Utilization (HRU)
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Thalassemia
Intervention  ICMJE
  • Drug: Luspatercept
    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.
    Other Name: ACE-536
  • Other: Placebo
    Placebo, Subcutaneous, every 21 days
    Other Name: normal saline
  • Other: Best Supportive Care (BSC)
    Best Supportive Care (BSC)
Study Arms  ICMJE
  • Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC)
    Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days
    Interventions:
    • Drug: Luspatercept
    • Other: Best Supportive Care (BSC)
  • Placebo Comparator: Placebo plus Best Supportive Care (BSC)
    normal saline solution subcutaneous(ly) (SC) once every 21 days
    Interventions:
    • Other: Placebo
    • Other: Best Supportive Care (BSC)
Publications * 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 β-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 8, 2019)
145
Original Estimated Enrollment  ICMJE
 (submitted: November 9, 2017)
150
Estimated Study Completion Date  ICMJE March 14, 2022
Estimated Primary Completion Date September 14, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

  1. Subjects must be ≥ 18 years of age at the time of signing the informed consent document (ICF).
  2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
  3. 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.
  4. Subject must have documented diagnosis of β-thalassemia or hemoglobin E/ β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.
  5. 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.
  6. Subject must not be on a regular transfusion program and must be RBC transfusion-free for at least ≥ 8 weeks prior to randomization
  7. 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.
  8. Subject must have performance status: Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
  9. 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). A FCBP participating in the study must:

  1. 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.
  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 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.

    10. 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

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. Diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg,Hemoglobin H).
  5. Active hepatitis C (HCV) infection
  6. Deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
  7. 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.
  8. Treatment with another investigational drug or device ≤ 28 days prior to randomization.
  9. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
  10. Platelet count > 1000 x 109/L.
  11. 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.
  12. Subject had Hydroxyurea and ESA treatment ≤ 24 weeks prior to randomization, and no prior gene therapy.
  13. Subject is pregnant or a lactating female.
  14. 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).
  15. Subject has major organ damage, including:

    1. Liver disease with alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) or history/evidence of cirrhosis, as well as presence of masses/tumor detected by ultrasound at screening.
    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 (MI) within 6 months of randomization.
    3. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie, ≥G3 NCI CTCAE version 4.0 (current active minor version).
    4. Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 (per Modification of Diet in Renal Disease [MDRD] formula).
  16. Subject has received chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed).
  17. Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
  18. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
  19. Subject has received immunosuppressants ≤ 28 days prior to randomization.
  20. History or current malignancies (solid tumors and hematological malignancies) unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:

    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece,   Italy,   Lebanon,   Thailand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03342404
Other Study ID Numbers  ICMJE ACE-536-B-THAL-002
U1111-1202-7068 ( Registry Identifier: WHO )
2015-003225-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Acceleron Pharma, Inc.
Investigators  ICMJE
Study Director: Jeevan Shetty, MD Celgene Corporation
PRS Account Celgene
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP