Thalassemia
Conditions
Keywords
(β)-Thalassemia, Beta-Thalassemia, Phase 2, Luspatercept, ACE-536, Safety, Efficacy, Placebo, Red Blood Cell Transfusions, Erythrocyte transfusion, Hb increase, NTDT
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)
Interventions
DRUGLuspatercept
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.
OTHERPlacebo
Placebo, Subcutaneous, every 21 days
OTHERBest Supportive Care (BSC)
Best Supportive Care (BSC)
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24) | 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
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24) | Baseline and over a continuous 12 week period (from week 13 through week 24) | 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) | Assessed over a continuous 12 week period (from week 37 through 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) | Baseline and over a continuous 12 week period (from week 13 through 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). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13. |
| Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24) | Baseline and over a continuous 12 week period (from week 13 through week 24) | 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. |
| Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48) | Baseline and over a continuous 12 week period (from week 37 through 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. |
| Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion | 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. |
| Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) | Baseline and over a continuous 12 week period (from week 37 through 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). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. |
| 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) | Baseline and over a continuous 12 week period (from week 37 through week 48) | NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It's a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. |
| 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) | Baseline and over a continuous 12 week period (from week 37 through week 48) | NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It is a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. |
| 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) | Baseline and over a continuous 12 week period (from week 13 through 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered. |
| 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) | Baseline and over a continuous 12 week period (from week 37 through week 48) | 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered. |
| 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) | 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 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. Baseline is defined as the last value taken on or before the first dose of study drug administered. |
| Percentage of Participants With Improvement of Iron Overload | 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) |
| Mean Change From Baseline in Serum Ferritin | Week 24 and 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 |
| Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24) | Baseline and over a continuous 12 week period (from week 13 through week 24) | The NTDT-PRO assesses the severity of anemia-related symptoms with a daily recall of symptoms composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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 is 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 are 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13. |
| Percentage of Participants Who Are Transfusion-Free Over 24 Weeks | From first dose to Week 24 | 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 | From first dose to Week 48 | 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 | From baseline up to approximately 56 months | This outcome measure is the cumulative mean of the duration of hemoglobin response for the ≥ 1.0 g/dL during any 12-week rolling period. Any hemoglobin values within 21 days after a transfusion were excluded from the analysis. |
| Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance | 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. Particiapnts 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 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 | From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment | The responder definition (RD) threshold is the individual participant score change over a predetermined time period that will be interpreted as a treatment benefit. 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. Participants 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 | From first dose to 63 days after last dose (up to approximately 56 months) | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. |
| Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept | From first dose and up to 2 years following last dose, up to approximately 56 months | 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. |
| Apparent Clearance (CL/F) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Apparent Clearance (CL/F) of Luspatercept |
| Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept |
| Time to Reach Maximum Concentration (Tmax) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Time to Reach Maximum Concentration (Tmax) of Luspatercept |
| Maximum Concentration (Cmax) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Maximum Concentration (Cmax) of Luspatercept |
| Maximum Concentration From Steady State (Cmax,ss) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Maximum Concentration From Steady State (Cmax,ss) of Luspatercept |
| Area Under the Curve From Steady State (AUCss) of Luspatercept | Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months | Area Under the Curve From Steady State (AUCss) of Luspatercept |
| Mean Change From Baseline in Liver Iron Concentration (LIC) | Week 24 and 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. |
Countries
Greece, Italy, Lebanon, Thailand, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Luspatercept Luspatercept was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle). The starting dose level was 1.00 mg/kg and could be escalated to 1.25 mg/kg and/or reduced to 0.80, 0.60, and 0.45 mg/kg. Participants were treated for a minimum of 48 weeks. | 96 |
| Placebo Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months. | 49 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Treatment Phase | Adverse Event | 5 | 4 |
| Blinded Treatment Phase | Death | 1 | 0 |
| Blinded Treatment Phase | Lack of Efficacy | 2 | 17 |
| Blinded Treatment Phase | Noncompliance with study drug | 1 | 0 |
| Blinded Treatment Phase | Other reasons | 1 | 0 |
| Blinded Treatment Phase | Physician Decision | 1 | 0 |
| Blinded Treatment Phase | Withdrawal by Subject | 17 | 10 |
| Open-Label Phase | Adverse Event | 0 | 3 |
| Open-Label Phase | Lost to Follow-up | 0 | 1 |
| Open-Label Phase | Other reasons | 0 | 1 |
| Open-Label Phase | Withdrawal by Subject | 0 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Luspatercept |
|---|---|---|---|
| Age, Continuous | 41.1 Years STANDARD_DEVIATION 11.9 | 39.9 Years STANDARD_DEVIATION 12.79 | 39.3 Years STANDARD_DEVIATION 13.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 142 Participants | 94 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 13 Participants | 44 Participants | 31 Participants |
| Race/Ethnicity, Customized Race Other | 8 Participants | 14 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 28 Participants | 87 Participants | 59 Participants |
| Sex: Female, Male Female | 26 Participants | 82 Participants | 56 Participants |
| Sex: Female, Male Male | 23 Participants | 63 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 96 | 0 / 49 | 0 / 38 |
| other Total, other adverse events | 96 / 96 | 48 / 49 | 38 / 38 |
| serious Total, serious adverse events | 23 / 96 | 13 / 49 | 3 / 38 |
Outcome results
Primary
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.
Time frame: From Week 13 to Week 24 of study treatment
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24) | 77.1 Percent of Participants |
| Placebo | Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24) | 0.0 Percent of Participants |
95% CI: [63.4, 87]
95% CI: [68.7, 85.5]
Secondary
Apparent Clearance (CL/F) of Luspatercept
Apparent Clearance (CL/F) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Apparent Clearance (CL/F) of Luspatercept | 0.458 L/day | Geometric Coefficient of Variation 33.8 |
Secondary
Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept
Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept | 7.79 Liters | Geometric Coefficient of Variation 19.6 |
Secondary
Area Under the Curve From Steady State (AUCss) of Luspatercept
Area Under the Curve From Steady State (AUCss) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Area Under the Curve From Steady State (AUCss) of Luspatercept | 130 day*μg/mL | Geometric Coefficient of Variation 34.4 |
Secondary
Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL
This outcome measure is the cumulative mean of the duration of hemoglobin response for the ≥ 1.0 g/dL during any 12-week rolling period. Any hemoglobin values within 21 days after a transfusion were excluded from the analysis.
Time frame: From baseline up to approximately 56 months
Population: All participants with a mean hemoglobin increase ≥1.0 g/dL. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL | 1136.0 Days | Standard Deviation 491.86 |
| Placebo | Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL | 203.3 Days | Standard Deviation 170.82 |
Secondary
Maximum Concentration (Cmax) of Luspatercept
Maximum Concentration (Cmax) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Maximum Concentration (Cmax) of Luspatercept | 5.55 μg/mL | Geometric Coefficient of Variation 16.9 |
Secondary
Maximum Concentration From Steady State (Cmax,ss) of Luspatercept
Maximum Concentration From Steady State (Cmax,ss) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Maximum Concentration From Steady State (Cmax,ss) of Luspatercept | 8.36 μg/mL | Geometric Coefficient of Variation 27.7 |
Secondary
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.
Time frame: Baseline and over a continuous 12 week period (from week 13 through week 24)
Population: All treated participants with available measurements at Baseline and From Week 13 to Week 24. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24) | 1.48 g/dL | Standard Error 0.078 |
| Placebo | Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24) | 0.07 g/dL | Standard Error 0.108 |
p-value: <0.000195% CI: [1.16, 1.67]ANCOVA
Secondary
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.
Time frame: Baseline and over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants with available measurements at Baseline and From Week 37 to Week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48) | 1.50 g/dL | Standard Error 0.083 |
| Placebo | Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48) | 0.01 g/dL | Standard Error 0.13 |
p-value: <0.000195% CI: [1.2, 1.79]ANCOVA
Secondary
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.
Time frame: Week 24 and Week 48 of study treatment
Population: All treated participants with available measurements at Baseline and at week 24 or week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Liver Iron Concentration (LIC) | Week 24 | -0.30 mg/g dry weight | Standard Error 0.125 |
| Luspatercept | Mean Change From Baseline in Liver Iron Concentration (LIC) | Week 48 | -0.34 mg/g dry weight | Standard Error 0.233 |
| Placebo | Mean Change From Baseline in Liver Iron Concentration (LIC) | Week 24 | -0.21 mg/g dry weight | Standard Error 0.169 |
| Placebo | Mean Change From Baseline in Liver Iron Concentration (LIC) | Week 48 | -1.00 mg/g dry weight | Standard Error 0.329 |
Comparison: Mean change from baseline in LIC at Week 24p-value: 0.662895% CI: [-0.47, 0.3]ANCOVA
Comparison: Mean change from baseline in LIC at Week 48p-value: 0.085995% CI: [-0.09, 1.42]ANCOVA
Secondary
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). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13.
Time frame: Baseline and over a continuous 12 week period (from week 13 through week 24)
Population: All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) | 1.64 Score on a scale | Standard Error 0.774 |
| Placebo | Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24) | 0.26 Score on a scale | Standard Error 1.066 |
p-value: 0.264195% CI: [-1.06, 3.83]ANCOVA
Secondary
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). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
Time frame: Baseline and over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) | 2.43 Score on a scale | Standard Error 0.763 |
| Placebo | Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48) | 0.24 Score on a scale | Standard Error 1.15 |
p-value: 0.095995% CI: [-0.39, 4.78]ANCOVA
Secondary
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: 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.
Time frame: Baseline and over a continuous 12 week period (from week 13 through week 24)
Population: All treated participants with available measurements at Baseline and From Week 13 to Week 24. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | 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) | -0.46 Score on a scale | Standard Error 0.168 |
| Placebo | 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) | 0.02 Score on a scale | Standard Error 0.228 |
p-value: 0.072195% CI: [-1.02, 0.04]ANCOVA
Secondary
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)
NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It is a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
Time frame: Baseline and over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants with available measurements at Baseline and From Week 37 to Week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | 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) | -0.59 Score on a scale | Standard Error 0.212 |
| Placebo | 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) | 0.47 Score on a scale | Standard Error 0.32 |
p-value: 0.004795% CI: [-1.8, -0.33]ANCOVA
Secondary
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 assesses the severity of anemia-related symptoms with a daily recall of symptoms composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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 is 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 are 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13.
Time frame: Baseline and over a continuous 12 week period (from week 13 through week 24)
Population: All treated participants with available measurements at Baseline and from Week 13 to Week 24. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | 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) | -0.68 Score on a scale | Standard Error 0.176 |
| Placebo | 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) | -0.20 Score on a scale | Standard Error 0.24 |
p-value: 0.092495% CI: [-1.03, 0.08]ANCOVA
Secondary
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)
NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It's a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness 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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
Time frame: Baseline and over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants with available measurements at Baseline and at Week 37 to Week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept | 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) | -0.78 Score on a scale | Standard Error 0.229 |
| Placebo | 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) | 0.01 Score on a scale | Standard Error 0.347 |
p-value: 0.05195% CI: [-1.58, 0]ANCOVA
Secondary
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
Time frame: Week 24 and Week 48 of study treatment
Population: All treated participants with available measurements at Baseline and at week 24 or week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept | Mean Change From Baseline in Serum Ferritin | Week 24 | 29.32 ug/L | Standard Error 22.949 |
| Luspatercept | Mean Change From Baseline in Serum Ferritin | Week 48 | 84.94 ug/L | Standard Error 23.12 |
| Placebo | Mean Change From Baseline in Serum Ferritin | Week 24 | 2.18 ug/L | Standard Error 32.217 |
| Placebo | Mean Change From Baseline in Serum Ferritin | Week 48 | 71.48 ug/L | Standard Error 32.457 |
Comparison: Mean change from baseline in serum ferritin at Week 24p-value: 0.594995% CI: [-46.77, 101.06]ANCOVA
Comparison: Mean change from baseline in serum ferritin at Week 48p-value: 0.345495% CI: [-61.01, 87.93]ANCOVA
Secondary
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. Particiapnts 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.
Time frame: From baseline to Week 24 and from baseline to Week 48 of study treatment
Population: All treated participants with available measurements at Baseline and at Week 24 or Week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept | Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance | 24 Weeks | 7.20 Meters | Standard Error 7.017 |
| Luspatercept | Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance | 48 Weeks | 8.82 Meters | Standard Error 5.907 |
| Placebo | Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance | 24 Weeks | -8.96 Meters | Standard Error 9.297 |
| Placebo | Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance | 48 Weeks | -3.62 Meters | Standard Error 8.141 |
Comparison: Mean change from baseline in 6MWT distance at Week 24p-value: 0.146695% CI: [-5.73, 38.04]ANCOVA
Comparison: Mean change from baseline in 6MWT distance at Week 48p-value: 0.201195% CI: [-6.72, 31.59]ANCOVA
Secondary
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 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. Baseline is defined as the last value taken on or before the first dose of study drug administered.
Time frame: From baseline to Week 24 and from baseline to Week 48 of study treatment
Population: All treated participants with available measurements at Baseline, at Week 24 and at Week 48. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept | 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) | Physical Component Summary (PCS) up to Week 24 | 1.00 Score on a scale | Standard Error 0.499 |
| Luspatercept | 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) | Physical Component Summary (PCS) up to Week 48 | 1.23 Score on a scale | Standard Error 0.571 |
| Luspatercept | 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) | Mental Component Summary (MCS) up to Week 24 | 0.83 Score on a scale | Standard Error 0.674 |
| Luspatercept | 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) | Mental Component Summary (MCS) up to Week 48 | 0.81 Score on a scale | Standard Error 0.784 |
| Placebo | 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) | Mental Component Summary (MCS) up to Week 48 | -1.89 Score on a scale | Standard Error 1.152 |
| Placebo | 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) | Physical Component Summary (PCS) up to Week 24 | -0.38 Score on a scale | Standard Error 0.684 |
| Placebo | 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) | Mental Component Summary (MCS) up to Week 24 | -0.71 Score on a scale | Standard Error 0.947 |
| Placebo | 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) | Physical Component Summary (PCS) up to Week 48 | -0.52 Score on a scale | Standard Error 0.822 |
Comparison: Mean change from baseline in SF-36 PCS to Week 24p-value: 0.084795% CI: [-0.19, 2.96]Mixed Models Analysis
Comparison: Mean change from baseline in SF-36 PCS to Week 48p-value: 0.071295% CI: [-0.15, 3.65]Mixed Models Analysis
Comparison: Mean change from baseline in SF-36 MCS to Week 24p-value: 0.163395% CI: [-0.63, 3.72]Mixed Models Analysis
Comparison: Mean change from baseline in SF-36 MCS to Week 48p-value: 0.046995% CI: [0.04, 5.36]Mixed Models Analysis
Secondary
Number of Participants Experiencing Adverse Events
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
Time frame: From first dose to 63 days after last dose (up to approximately 56 months)
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-emergent adverse-event (TEAE) | 96 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Serious TEAE | 23 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related TEAE | 79 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related Serious TEAE | 4 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | TEAE Leading to Death | 1 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | TEAE Leading to Dose Reduction | 11 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | TEAE Leading to Dose Delay | 47 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | TEAE Leading to Study Drug Discontinuation | 5 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Death | 0 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Dose Reduction | 11 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Dose Delay | 10 Participants |
| Luspatercept | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Study Drug Discontinuation | 4 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Dose Delay | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-emergent adverse-event (TEAE) | 48 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | TEAE Leading to Dose Delay | 11 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Serious TEAE | 13 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Dose Reduction | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related TEAE | 18 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | TEAE Leading to Study Drug Discontinuation | 4 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related Serious TEAE | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Study Drug Discontinuation | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | TEAE Leading to Death | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | Treatment-related TEAE Leading to Death | 0 Participants |
| Placebo | Number of Participants Experiencing Adverse Events | TEAE Leading to Dose Reduction | 0 Participants |
Secondary
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.
Time frame: From first dose and up to 2 years following last dose, up to approximately 56 months
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo who crossed over to luspatercept.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Luspatercept | Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept | 5 Participants |
| Placebo | Number of Participants With Anti-drug Antibody (ADA) Positive Test for Luspatercept | 3 Participants |
Secondary
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.
Time frame: Assessed over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48) | 70.8 Percentage of Participants |
| Placebo | Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48) | 2.0 Percentage of Participants |
p-value: <0.000195% CI: [54.3, 80.4]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From first dose to Week 24
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | Percentage of Participants Who Are Transfusion-Free Over 24 Weeks | 89.6 Percent of Participants |
| Placebo | Percentage of Participants Who Are Transfusion-Free Over 24 Weeks | 67.3 Percent of Participants |
Comparison: Percentage of participants who were transfusion free over 24 weeksp-value: 0.001395% CI: [5, 38.6]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From first dose to Week 48
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | Percentage of Participants Who Are Transfusion-Free Over 48 Weeks | 82.3 Percent of Participants |
| Placebo | Percentage of Participants Who Are Transfusion-Free Over 48 Weeks | 44.9 Percent of Participants |
Comparison: Percentage of Participants Who are Transfusion-Free Over 48 Weeksp-value: <0.000195% CI: [20.9, 53]Cochran-Mantel-Haenszel
Secondary
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 responder definition (RD) threshold is the individual participant score change over a predetermined time period that will be interpreted as a treatment benefit. 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. Participants with missing NTDT-PRO T/W scores at the indicated 12-week period are classified as non-responders in the analysis.
Time frame: From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment
Population: All treated participants with available measurements at Baseline and at the indicated 12-week periods. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Luspatercept | 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 | Week 13 to week 24 | 37.5 Percent of participants |
| Luspatercept | 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 | Week 37 to week 48 | 31.3 Percent of participants |
| Placebo | 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 | Week 13 to week 24 | 28.6 Percent of participants |
| Placebo | 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 | Week 37 to week 48 | 18.4 Percent of participants |
Comparison: 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 Week 13 to Week 24p-value: 0.198995% CI: [0.8, 3.7]Cochran-Mantel-Haenszel
Comparison: 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 Week 37 to Week 48p-value: 0.073395% CI: [0.9, 5]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From Week 13 to Week 24 of study treatment
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion | 52.1 Percentage of Participants |
| Placebo | Percentage of Participants With an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion | 0.0 Percentage of Participants |
Comparison: Percentage of Participants with an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusionp-value: <0.000195% CI: [36.2, 66.2]Cochran-Mantel-Haenszel
Secondary
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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered.
Time frame: Baseline and over a continuous 12 week period (from week 13 through week 24)
Population: All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | 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) | 40.4 Percent of Participants |
| Placebo | 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) | 27.7 Percent of Participants |
p-value: 0.135995% CI: [0.8, 4]Cochran-Mantel-Haenszel
Secondary
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)
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. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered.
Time frame: Baseline and over a continuous 12 week period (from week 37 through week 48)
Population: All treated participants with available measurements at Baseline and at least one post-baseline FACIT-F questionnaire completed. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept | 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) | 36.2 Percent of Participants |
| Placebo | 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) | 21.3 Percent of Participants |
p-value: 0.065795% CI: [0.9, 5.4]Cochran-Mantel-Haenszel
Secondary
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)
Time frame: Week 24 and Week 48 of study treatment
Population: All treated participants. Placebo participants are assessed up to crossing over to luspatercept. The luspatercept group does not include placebo participants who crossed over to luspatercept.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Luspatercept | Percentage of Participants With Improvement of Iron Overload | Week 24 | 44.8 Percent of participants |
| Luspatercept | Percentage of Participants With Improvement of Iron Overload | Week 48 | 34.4 Percent of participants |
| Placebo | Percentage of Participants With Improvement of Iron Overload | Week 48 | 49.0 Percent of participants |
| Placebo | Percentage of Participants With Improvement of Iron Overload | Week 24 | 49.0 Percent of participants |
Comparison: Percentage of participants with improvement of iron overload (LIC/ICT responders) at Week 24p-value: 0.478795% CI: [-21.4, 13]Cochran-Mantel-Haenszel
Comparison: Percentage of participants with improvement of iron overload (LIC/ICT responders) at Week 48p-value: 0.082795% CI: [-31.5, 2.4]Cochran-Mantel-Haenszel
Secondary
Time to Reach Maximum Concentration (Tmax) of Luspatercept
Time to Reach Maximum Concentration (Tmax) of Luspatercept
Time frame: Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
Population: All treated participants who received the study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Luspatercept | Time to Reach Maximum Concentration (Tmax) of Luspatercept | 5.50 Days |