A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment Naïve Patients With Mayo Stage IIIb AL Amyloidosis
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 125
- 试验地点
- 91
- 主要终点
- A hierarchical combination of Time to All-cause Mortality and Frequency of Cardiovascular hospitalizations
研究概览
简要总结
AL (or light chain) amyloidosis begins in the bone marrow where abnormal proteins misfold and create free light chains that cannot be broken down. These free light chains bind together to form amyloid fibrils that build up in the extracellular space of organs, affecting the kidneys, heart, liver, spleen, nervous system and digestive tract.
The primary purpose of this study is to determine whether CAEL-101, a monoclonal antibody that removes AL amyloid deposits from tissues and organs, improves overall survival, reduces cardiovascular related hospitalizations and it is safe and well tolerated in patients with stage IIIb AL amyloidosis.
详细描述
This is a double-blind, randomized, multicenter international Phase 3 study of CAEL-101 combined with standard of care (SoC) plasma cell dyscrasia (PCD) treatment versus placebo combined with SoC PCD treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. The primary evaluation treatment period (PETP) part of the study will stop when the last patient is randomized in the PETP plus 18 months. Approximately 124 patients will be enrolled using a 2:1 randomization ratio. Stratification will be based on geographic region across investigator sites. The primary endpoint is a composite endpoint of all-cause mortality and frequency of cardiovascular hospitalizations. Patients in both study intervention groups will be followed from randomization until death from any cause, heart transplant, left wall assist device (LVAD) implantation or until the end of study.
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)
盲法说明
This is a double-blind, randomized, multicenter international Phase 3 study.
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
- •AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo Clinic Staging (NT-proBNP > 8,500 ng/L) at the time of Screening
- •Measurable hematologic disease at Screening as defined by at least one of the following:
- •Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL or
- •Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio or
- •Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL
- •Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:
- •Immunohistochemistry/Immunofluorescence or
- •Mass spectrometry or
- •Characteristic electron microscopy appearance/Immunoelectron microscopy
- •Cardiac involvement as defined by:
- •Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure AND
- •At least one of the following:
- •i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis
- •Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC
- •Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer
- •Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer
排除标准
- •Have any other form of amyloidosis other than AL amyloidosis
- •Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained and prior to randomization is allowed
- •Has POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed ≤ 3 months prior to signing the ICF) or biopsy-proven (performed ≤ 3 months prior to signing the ICF) bony or extramedullary plasmacytoma AND one or more of the following CRAB features:
- •a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder (e.g., multiple myeloma and POEMS syndrome), specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177 mol/L (> 2 mg/dL) OR iii. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed ≤ 3 months prior to signing the ICF): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination OR ii. More than one focal lesion on MRI that is at least 5mm or greater in size
- •Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion
研究组 & 干预措施
Placebo combined with SoC plasma cell dyscrasia
Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months.
干预措施: Placebo (Other)
CAEL-101 combined with SoC plasma cell dyscrasia
CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months. The study is divided into 2 parts, the Primary Evaluation Treatment period part and the Open-Label Extension period of Study.
干预措施: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen (Drug)
CAEL-101 combined with SoC plasma cell dyscrasia
CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months. The study is divided into 2 parts, the Primary Evaluation Treatment period part and the Open-Label Extension period of Study.
干预措施: CAEL-101 (Drug)
Placebo combined with SoC plasma cell dyscrasia
Patients randomized to receive placebo will receive 0.9% normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250 cc). It is planned that all patients will continue their double-blind treatment until the last patient is randomized in the study plus 18 months.
干预措施: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) regimen (Drug)
结局指标
主要结局
A hierarchical combination of Time to All-cause Mortality and Frequency of Cardiovascular hospitalizations
时间窗: From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months)
Number of Participants with Treatment Emergent Adverse Events (TEAEs)
时间窗: From date of randomization to Primary Evaluation Treatment Period (PETP) (up to 56 months)
A Hierarchical Combination of Time to All-cause Mortality and Frequency of Cardiovascular Hospitalizations (CVHs) Analyzed by Win Ratio
时间窗: Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, the primary analysis for the study was conducted 18-47 months after the study randomization.)
Time to all-cause mortality was defined as the number of weeks from the date of randomization to the date of death if it is on or before the end of PETP. Participants alive at the end of PETP (LPI+18 months) were censored at their last known alive date recorded within the PETP. CVHs were events adjudicated and confirmed as such by the Clinical Event Adjudication Committee (CEAC). Hypothesis testing with the Finkelstein-Schoenfeld test and treatment effect estimation with the win-ratio method based on pairwise comparisons of participant outcomes with comparisons performed in a hierarchical manner. To calculate win ratio, participant outcomes based on time to all-cause mortality were first compared and if there was no 'winner' due to censoring then a comparison based on frequency of cardiovascular hospitalization was made. A win ratio \>1 represents a more favorable outcome for CAEL-101 over placebo.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
时间窗: Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, the primary analysis for the study was conducted 18-47 months after the study randomization.)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, at any dose, that was not necessarily related to the treatment. A TEAE was an AE with an occurrence defined as follows: last study intervention day-first study intervention day + 140 days. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
次要结局
- Time to All-cause Mortality(From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months))
- Frequency of cardiovascular-related hospitalizations (CVH)(From the date of randomization to date of death or Primary Evaluation Treatment Period (PETP) (up to 51 months))
- Change from Baseline to week 50 in the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS)(Baseline, Week 50)
- Change from Baseline to Week 50 in N - Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in blood samples(Baseline, Week 50)
- Change from Baseline to Week 50 in Cardiac Improvement by Global Longitudinal Strain (GLS%)(Baseline, Week 50)
- Change from Baseline to Week 50 in distance walked (in meters) during a six-minute walk test (6MWT)(Baseline, Week 50)
- Change from Baseline to Week 50 the Short Form-36 (SF-36) v2 Physical Component Score (PCS)(Baseline, Week 50)
- Change From Baseline in Global Longitudinal Strain (GLS%)(Baseline, Week 50)
- Change From Baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Score (KCCQ-OS)(Baseline, Week 50)
- Change From Baseline in Distance Walked During a Six-minute Walk Test (6MWT)(Baseline, Week 50)
- All-cause Mortality(Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, analysis for the study was conducted 18-47 months after the study randomization.))
- Frequency of CVHs(Day 1 through end of the participant's PETP (Participants were enrolled on a rolling basis. Therefore, analysis for the study was conducted 18-47 months after the study randomization.))
- Change From Baseline in the Short Form-36 (SF-36) Version 2 (v2) Physical Component Score (PCS)(Baseline, Week 50)
- Change From Baseline in N-Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in Blood Samples(Baseline, Week 50)