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

Primary Purpose

Thalassemia

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Luspatercept

Placebo

Best Supportive Care (BSC)

About this trial

This is an interventional treatment trial for Thalassemia focused on measuring (β)-Thalassemia, Beta-Thalassemia, Phase 2, Luspatercept, ACE-536, Safety, Efficacy, Placebo, Red Blood Cell Transfusions, Erythrocyte transfusion, Hb increase, NTDT

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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:

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:

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.
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:

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).
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).
Subject has received chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed).
Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
Subject has received immunosuppressants ≤ 28 days prior to randomization.
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)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

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

Placebo plus Best Supportive Care (BSC)

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

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

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.

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

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.

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

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).

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)

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48)

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.

Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)

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).

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)

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

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)

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

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)

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.

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)

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)

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.

Percentage of Participants With Improvement of Iron Overload

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)

Mean Change From Baseline in Serum Ferritin

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

Mean Change From Baseline in Liver Iron Concentration (LIC)

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.

Percentage of Participants Who Are Transfusion-Free Over 24 Weeks

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.

Percentage of Participants Who Are Transfusion-Free Over 48 Weeks

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.

Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL

The duration of increase is defined as Last Day of mean hemoglobin increase by >=1.0g/dL - First Day of increase +1.

Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance

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.

Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion

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.

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

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.

Number of Participants Experiencing Adverse Events

Number of participants experiencing different types (any grade) of adverse events

Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept

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.

Apparent Clearance (CL/F) of Luspatercept

Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept

Time to Reach Maximum Concentration (Tmax) of Luspatercept

Maximum Concentration (Cmax) of Luspatercept

Maximum Concentration From Steady State (Cmax,ss) of Luspatercept

Area Under the Curve From Steady State (AUCss) of Luspatercept

Full Information

NCT ID

NCT03342404

First Posted

October 30, 2017

Last Updated

December 15, 2022

Sponsor

Celgene

Collaborators

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

1. Study Identification

Unique Protocol Identification Number

NCT03342404

Brief Title

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

Acronym

BEYOND

Official Title

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 BEYOND™ Study)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2022

Overall Recruitment Status

Completed

Study Start Date

February 1, 2018 (Actual)

Primary Completion Date

September 14, 2020 (Actual)

Study Completion Date

November 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Celgene

Collaborators

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

The primary objective is: - To evaluate the effect of luspatercept (BMS-986346) 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 in anemia-related symptoms in participants with β-thalassemia, as measured by non-transfusion dependent β-thalassemia-patient reported outcome (NTDT-PRO) over 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 evaluate the effect of luspatercept versus placebo on the β-thalassemia severity as measured by the Morbidity-free Survival parameters 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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Thalassemia

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

145 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo plus Best Supportive Care (BSC)

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Luspatercept

Other Intervention Name(s)

ACE-536

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

normal saline

Intervention Description

Placebo, Subcutaneous, every 21 days

Intervention Type

Other

Intervention Name(s)

Best Supportive Care (BSC)

Intervention Description

Best Supportive Care (BSC)

Primary Outcome Measure Information:

Title

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

Description

Time Frame

From Week 13 to Week 24 of study treatment

Secondary Outcome Measure Information:

Title

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)

Description

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Title

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

Description

Time Frame

From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)

Title

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

Description

Time Frame

From Week 37 to Week 48 of study treatment

Title

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

Description

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Title

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)

Description

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 13 to Week 24 of study treatment

Title

Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48)

Description

Time Frame

From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)

Title

Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)

Description

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).

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Title

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)

Description

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Title

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)

Description

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: Tiredness (lack of energy) when not doing physical activity Tiredness (lack of energy) when doing physical activity Weakness (lack of strength) when not doing physical activity Weakness (lack of strength) when doing physical activity Shortness of breath when not doing physical activity 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.

Time Frame

Baseline (up to 7 days prior to start of study treatment) and from Week 37 to Week 48 of study treatment

Title

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)

Description

Time Frame

From Week 13 to Week 24 of study treatment (over a continuous 12-week interval)

Title

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)

Description

Time Frame

From Week 37 to Week 48 of study treatment (over a continuous 12-week interval)

Title

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)

Description

Time Frame

From baseline to Week 24 and from baseline to Week 48 of study treatment

Title

Percentage of Participants With Improvement of Iron Overload

Description

Time Frame

Week 24 and Week 48 of study treatment

Title

Mean Change From Baseline in Serum Ferritin

Description

Time Frame

From baseline to Week 24 and from baseline to Week 48 of study treatment

Title

Mean Change From Baseline in Liver Iron Concentration (LIC)

Description

Time Frame

From baseline to Week 24 and from baseline to Week 48 of study treatment

Title

Percentage of Participants Who Are Transfusion-Free Over 24 Weeks

Description

Time Frame

From start of treatment to 24 weeks following start of treatment

Title

Percentage of Participants Who Are Transfusion-Free Over 48 Weeks

Description

Time Frame

From start of treatment to 48 weeks following start of treatment

Title

Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL

Description

The duration of increase is defined as Last Day of mean hemoglobin increase by >=1.0g/dL - First Day of increase +1.

Time Frame

From first to last Hemoglobin measurement with increase from baseline ≥1.0 g/dL (up to approximately 20 months)

Title

Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance

Description

Time Frame

From baseline to Week 24 and from baseline to Week 48 of study treatment

Title

Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion

Description

Time Frame

From Week 13 to Week 24 of study treatment

Title

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

Description

Time Frame

From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment

Title

Number of Participants Experiencing Adverse Events

Description

Number of participants experiencing different types (any grade) of adverse events

Time Frame

From first dose to 63 days after last dose (up to approximately 50 months)

Title

Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept

Description

Time Frame

From first dose and up to 2 years following last dose

Title

Apparent Clearance (CL/F) of Luspatercept

Description

Apparent Clearance (CL/F) of Luspatercept

Time Frame