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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
Results First Posted : November 18, 2021
Last Update Posted : November 18, 2021
Sponsor:
Collaborator:
Acceleron Pharma Inc.
Information provided by (Responsible Party):
Celgene

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.


Condition or disease Intervention/treatment Phase
Thalassemia Drug: Luspatercept Other: Placebo Other: Best Supportive Care (BSC) Phase 2

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)

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 145 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 1, 2018
Actual Primary Completion Date : September 14, 2020
Estimated Study Completion Date : March 14, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Thalassemia

Arm Intervention/treatment
Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC)
Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days
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: Best Supportive Care (BSC)
Best Supportive Care (BSC)

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
Other Name: normal saline

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




Primary Outcome Measures :
  1. Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24) [ Time Frame: From Week 13 to Week 24 of study treatment ]

    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.



Secondary Outcome Measures :
  1. 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) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment ]

    The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items:

    1. Tiredness (lack of energy) when not doing physical activity
    2. Tiredness (lack of energy) when doing physical activity
    3. Weakness (lack of strength) when not doing physical activity
    4. Weakness (lack of strength) when doing physical activity
    5. Shortness of breath when not doing physical activity
    6. Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the T/W Domain Score at baseline.

  2. Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24) [ Time Frame: From Week 13 to Week 24 of study treatment (over a continuous 12-week interval) ]

    Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions.

    Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.


  3. Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48) [ Time Frame: From Week 37 to Week 48 of study treatment ]

    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 37 to 48 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.


  4. Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment ]

    The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study.

    For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much").

    The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome).

    The questionnaire is completed every other dose, and the mean of FS scores from Week 13 to Week 24 is compared to the FS score at baseline (last score available before start of study treatment).


  5. 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) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment ]

    The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items:

    1. Tiredness (lack of energy) when not doing physical activity
    2. Tiredness (lack of energy) when doing physical activity
    3. Weakness (lack of strength) when not doing physical activity
    4. Weakness (lack of strength) when doing physical activity
    5. Shortness of breath when not doing physical activity
    6. Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the SoB Domain Score at baseline.

  6. Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48) [ Time Frame: From Week 37 to Week 48 of study treatment (over a continuous 12-week interval) ]

    Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions.

    Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.


  7. Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment ]

    The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study.

    For the Fatigue subscale, each of the 13 items is scored from 0 ("not at all") to 4 ("very much").

    The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome).

    The questionnaire is completed every other dose, and the mean of FS scores from Week 37 to Week 48 is compared to the FS score at baseline (last score available before start of study treatment).


  8. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 37 to Week 48) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment ]

    The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items:

    1. Tiredness (lack of energy) when not doing physical activity
    2. Tiredness (lack of energy) when doing physical activity
    3. Weakness (lack of strength) when not doing physical activity
    4. Weakness (lack of strength) when doing physical activity
    5. Shortness of breath when not doing physical activity
    6. Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the T/W Domain Score at baseline.

  9. Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 37 to Week 48) [ Time Frame: Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment ]

    The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items:

    1. Tiredness (lack of energy) when not doing physical activity
    2. Tiredness (lack of energy) when doing physical activity
    3. Weakness (lack of strength) when not doing physical activity
    4. Weakness (lack of strength) when doing physical activity
    5. Shortness of breath when not doing physical activity
    6. Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 37 to Week 48) are compared to the SoB Domain Score at baseline.

  10. Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) [ Time Frame: From Week 13 to Week 24 of study treatment (over a continuous 12-week interval) ]

    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much).

    Participants completed the questionnaire at screening and every other dose.


  11. Percentage of Participants With an Increase From Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) [ Time Frame: From Week 37 to Week 48 of study treatment (over a continuous 12-week interval) ]

    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much).

    Participants completed the questionnaire at screening and every other dose.


  12. Mean Change From Baseline in the Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of the Medical Outcomes Study 36-Item Short Form (SF-36) [ Time Frame: From baseline to Week 24 and from baseline to Week 48 of study treatment ]

    The SF-36v2 is a 36-item generic PRO questionnaire used to assess patient-reported outcomes. The SF-36 yields scores for 8 domains of health: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH) as well as physical component summary (PCS) and mental component summary (MCS) scores.

    Scores from each of the 8 domains of health are first normalized based on US general population means, then aggregated and transformed (according to specific standardization formulas detailed in the Statistical Protocol Analysis), so that the scores from each of the 8 domains of health will contribute differently to the determination of PCS and MCS summary scores.

    PCS and MCS scores range from 0 to 100, with higher scores indicating a better quality of life.


  13. Percentage of Participants With Improvement of Iron Overload [ Time Frame: Week 24 and Week 48 of study treatment ]

    Iron overload was measured by Liver Iron Concentration (LIC) and Iron Chelation Therapy (ICT) daily dose.

    Improvement is defined as:

    • For participants with baseline LIC ≥3 mg/g: ≥20% reduction in LIC or ≥ 33% decrease in ICT daily dose
    • For participants with baseline LIC <3 mg/g: no increase in LIC >1 mg/g and not starting treatment with ICT, or no increase in ICT daily dose ≥ 33% (if on ICT at baseline)

  14. Mean Change From Baseline in Serum Ferritin [ Time Frame: From baseline to Week 24 and from baseline to Week 48 of study treatment ]
    Baseline mean serum ferritin is calculated during the 24 weeks on or prior to dose 1 day 1. Post-baseline mean serum ferritin is calculated as mean of ferritin values during the last 24 weeks on or prior to the end date of the first 24 week or 48 week treatment

  15. Mean Change From Baseline in Liver Iron Concentration (LIC) [ Time Frame: From baseline to Week 24 and from baseline to Week 48 of study treatment ]

    LIC was measured by Magnetic Resonance Imaging (MRI). Baseline is defined as the last value on or before the first dose of study drug is administered; Postbaseline is defined as the closest visit at Week 24 or Week 48.

    Participants with LIC value >43 are not included in the analysis.


  16. Percentage of Participants Who Are Transfusion-Free Over 24 Weeks [ Time Frame: From start of treatment to 24 weeks following start of treatment ]

    Transfusion free is defined as the absence of any transfusion during Week 1-24 of study treatment.

    Participants who discontinued treatment prior to Week 24 were not considered as transfusion free during Week 1-24.


  17. Percentage of Participants Who Are Transfusion-Free Over 48 Weeks [ Time Frame: From start of treatment to 48 weeks following start of treatment ]

    Transfusion free is defined as the absence of any transfusion during Week 1-48 of study treatment.

    Participants who discontinued treatment prior to Week 48 were not considered as transfusion free during Week 1-48.


  18. Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL [ Time Frame: From first to last Hemoglobin measurement with increase from baseline ≥1.0 g/dL (up to approximately 20 months) ]
    The duration of increase is defined as Last Day of mean hemoglobin increase by >=1.0g/dL - First Day of increase +1.

  19. Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance [ Time Frame: From baseline to Week 24 and from baseline to Week 48 of study treatment ]

    The 6MWT is typically used to objectively assess functional exercise capacity and response to medical interventions in patients with various moderate to severe diseases. Subjects are asked to walk as quickly as possible without running along a 30-meter corridor for six minutes, and the total distance covered during that time is measured.

    Baseline is defined as the last value on or before the first dose of study drug is administered. Postbaseline is defined as the closest visit at Week 24 or Week 48.


  20. Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion [ Time Frame: From Week 13 to Week 24 of study treatment ]

    Percentage of participants who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions.

    Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.


  21. Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score [ Time Frame: From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment ]

    The RD for the NTDT-PRO T/W domain score was defined as ≥ 1-point decrease (ie, RD = -1) from baseline over the time from Week 13 to Week 24 or from Week 37 to Week 48.

    Subjects with missing NTDT-PRO T/W scores at the indicated 12-week period are classified as non-responders in the analysis.


  22. Number of Participants Experiencing Adverse Events [ Time Frame: From first dose to 63 days after last dose (up to approximately 50 months) ]
    Number of participants experiencing different types (any grade) of adverse events

  23. Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept [ Time Frame: From first dose and up to 2 years following last dose ]

    Presence of anti-drug (ACE-536/Luspatercept) antibodies was assessed every 24 weeks from serum samples.

    A participant is counted as 'positive' if there is any positive result captured during the study. A participant is counted as 'negative' if there is no positive result captured during the study.


  24. Apparent Clearance (CL/F) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Apparent Clearance (CL/F) of Luspatercept

  25. Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept

  26. Time to Reach Maximum Concentration (Tmax) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Time to Reach Maximum Concentration (Tmax) of Luspatercept

  27. Maximum Concentration (Cmax) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Maximum Concentration (Cmax) of Luspatercept

  28. Maximum Concentration From Steady State (Cmax,ss) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Maximum Concentration From Steady State (Cmax,ss) of Luspatercept

  29. Area Under the Curve From Steady State (AUCss) of Luspatercept [ Time Frame: At predose (Dose 1 Day 1, before the first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 6 Day 8, Dose 6 Day 15, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1 (up to approximately 48 months) ]
    Area Under the Curve From Steady State (AUCss) of Luspatercept



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03342404


Locations
Layout table for location information
United States, California
Children's Hospital of Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital and Research Center at Oakland
Oakland, California, United States, 94609
United States, Illinois
Ann & Robert H Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
Greece
Laiko General Hospital of Athens
Athens, Greece, 115 27
Aghia Sofia Children's Hospital
Athens, Greece, 11527
Italy
Universita degli Studi di Cagliari - ASL8
Cagliari, Italy, 09121
Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite
Genoa, Italy, 16128
Fondazione Ca Granda IRCCS Ospedale Maggiore
Milan, Italy, 20122
Seconda Universita Degli Studi Di Napoli
Naples, Italy, 80131
AORN A Cardarelli
Napoli, Italy, 80131
Azienda Ospedaliero Universitaria S. Luigi Gonzaga
Orbassano, Italy, 10043
Lebanon
Chronic Care Center
Hazmieh, Lebanon, 1003
Thailand
Siriraj Hospital Mahidol University
Bangkok, Thailand, 10700
United Kingdom
University College London Hospitals NHS Foundation Trust - University College Hospital
London Bloomsbury, United Kingdom, WC1E 6AU
Sponsors and Collaborators
Celgene
Acceleron Pharma Inc.
Investigators
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Study Director: Jeevan Shetty, MD Celgene Corporation
  Study Documents (Full-Text)

Documents provided by Celgene:
Study Protocol  [PDF] June 12, 2020
Statistical Analysis Plan  [PDF] November 5, 2020

Publications:
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03342404    
Other Study ID Numbers: ACE-536-B-THAL-002
U1111-1202-7068 ( Registry Identifier: WHO )
2015-003225-33 ( EudraCT Number )
First Posted: November 17, 2017    Key Record Dates
Results First Posted: November 18, 2021
Last Update Posted: November 18, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene:
(β)-Thalassemia
Beta-Thalassemia
Phase 2
Luspatercept
ACE-536
Safety
Efficacy
Placebo
Red Blood Cell Transfusions
Erythrocyte transfusion
Hb increase
NTDT
Additional relevant MeSH terms:
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Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Luspatercept
Hematinics