NCT03342404已完成2 期
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)
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Celgene
- 入组人数
- 145
- 试验地点
- 16
- 主要终点
- Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •A female of childbearing potential (FCBP) for this study is defined as a female who:
- •has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must:
- •Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.
- •Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented). If a FCBP engages in sexual activity that may result in a pregnancy, she must agree to use, and be able to comply during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple dose pharmacokinetics [PK] data) after discontinuation of study therapy.
- •Male subjects must:
- •a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy
排除标准
- •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:
- •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.
- •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.
- •Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie, ≥G3 NCI CTCAE version 4.0 (current active minor version).
- •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)
研究组 & 干预措施
Luspatercept (ACE-536) plus Best Supportive Care (BSC)
Experimental
Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days
干预措施: Luspatercept (Drug)
Luspatercept (ACE-536) plus Best Supportive Care (BSC)
Experimental
Arm Description: Luspatercept, subcutaneous(ly) (SC) once every 21 days
干预措施: Best Supportive Care (BSC) (Other)
Placebo plus Best Supportive Care (BSC)
Placebo Comparator
normal saline solution subcutaneous(ly) (SC) once every 21 days
干预措施: Placebo (Other)
Placebo plus Best Supportive Care (BSC)
Placebo Comparator
normal saline solution subcutaneous(ly) (SC) once every 21 days
干预措施: Best Supportive Care (BSC) (Other)
结局指标
主要结局
Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)
时间窗: 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.
次要结局
- Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24)(Baseline and over a continuous 12 week period (from week 13 through week 24))
- Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24)(Baseline and over a continuous 12 week period (from week 13 through week 24))
- 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))
- 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)
- 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 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)
- 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)
- Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48)(Assessed over a continuous 12 week period (from week 37 through week 48))
- Mean Change From Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)(Baseline and over a continuous 12 week period (from week 13 through week 24))
- Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24)(Baseline and over a continuous 12 week period (from week 13 through week 24))
- 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))
- Percentage of Participants With Improvement of Iron Overload(Week 24 and Week 48 of study treatment)
- Mean Change From Baseline in Serum Ferritin(Week 24 and Week 48 of study treatment)
- 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))
- 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))
- 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))
- 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)
- Percentage of Participants Who Are Transfusion-Free Over 24 Weeks(From first dose to Week 24)
- 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))
- Mean Change From Baseline in Liver Iron Concentration (LIC)(Week 24 and Week 48 of study treatment)
- Number of Participants Experiencing Adverse Events(From first dose to 63 days after last dose (up to approximately 56 months))
- 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)
- 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 Are Transfusion-Free Over 48 Weeks(From first dose to Week 48)
- Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL(From baseline up to approximately 56 months)
- 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)
- 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)
- 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 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)
研究者
研究点 (16)
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