E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
stage IIIb cardiac AL amyloidosis |
|
E.1.1.1 | Medical condition in easily understood language |
Cardiac amyloidosis is a disorder caused by deposits of an abnormal protein (amyloid) in the heart tissue. These deposits make it hard for the heart to work properly. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives are: • To determine if CAEL-101 and treatment for plasma cell dyscrasia improves overall survival in Mayo stage IIIb AL amyloidosis patients who are treatment naïve compared to treatment for plasma cell dyscrasia alone • To evaluate the safety and tolerability of CAEL-101 in combination with treatment for plasma cell dyscrasia |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objectives in this study are: • To assess functional improvement as measured by the distance walked in the six-minute walk test (6MWT) • To assess quality of life as measured by the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) • To assess quality of life as measured by the Short Form 36 version 2 Physical Component Score (SF-36 v2® PCS) • To assess cardiac improvement as measured by percent Global Longitudinal Strain (GLS%) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria: 1. AL amyloidosis stage IIIb based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement at the time of Screening 2. Measurable hematologic disease at Screening as defined by at least one of the following: a. Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL or b. Involved free light chain (iFLC)> 4 mg/dL with abnormal ratio or c. Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL 3. 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: a. Immunohistochemistry or b. Mass spectrometry or c. Characteristic electron microscopy appearance 4. Cardiac involvement as defined by: a. 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 b. 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 5. Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomibdexamethasone (CyBorD)-based regimen administered as SoC. 6. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective physician approved contraception (Section 6.9) from Screening to 90 days at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer 7. Men must be surgically sterile or must agree to use effective physician approved contraception (Section 6.9) and refrain from donating sperm from Screening to 90 days at least 5 months following the last study drug administration or 12 months following the last dose of his PCD therapy, whichever is longer |
|
E.4 | Principal exclusion criteria |
Key Exclusion Criteria: 1. Have any other form of amyloidosis other than AL amyloidosis 2. 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. 3. 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% or biopsy-proven bony or extramedullary plasmacytoma and 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, specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the upper limit of normal (ULN) or > 2.75 mmol/L (> 11mg/dL) ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177mol/L (> 2mg/dL) iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100g/L iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)/CT. 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 ii. More than one focal lesion on MRI that is at least 5mm or greater in size 4. 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is overall survival and will be assessed as the date of randomization to the date of death. Patients living at the end of the study will be censored at their last known date alive. Patients who discontinue study treatment or the study prematurely will be included in the analysis (even if after discontinuation of study treatment or the study) using the death date or censoring time point, as appropriate.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of Treatment (EoT) and Follow-up every 12 weeks thereafter. The primary endpoint is also evaluated during the Treatment Period. |
|
E.5.2 | Secondary end point(s) |
The four key secondary efficacy endpoints are: • Changes from baseline to Week 50 in the 6MWT distance • Changes from baseline to Week 50 in the KCCQ-OS • Changes from baseline to Week 50 in the SF-36 v2 PCS • Changes from baseline to Week 50 in GLS% |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
6MWT, KCCQ-QS & SF-36: Weeks 1, 14, 26, 38 & 50. GLS% (echocardiogram): Screening (Week -4 to 0), Weeks 14, 26 & 50. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Israel |
Japan |
Russian Federation |
United States |
Austria |
Belgium |
France |
Germany |
Italy |
Poland |
Spain |
United Kingdom |
Greece |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study will be considered complete at the time when the expected number of deaths have been observed, the last surviving patient to start study drug completes at least 50 weeks of treatment or Sponsor decision to terminate the study, whichever comes first. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |