AL amyloidosis AL amyloidosis amyloidosis
Conditions
Sponsors
Alexion Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Patient Inclusion Criteria Each patient must meet the following criteria to be enrolled in this study. 1. Be able to and provide written informed consent and be willing and able to comply with all study procedures 2. Adult, 18 years and older 3. AL amyloidosis stage IIIa based on the European Modification of the 2004 Standard Mayo Clinic Staging (see Table 2) who also have NT-proBNP >= 650 ng/L (See Inclusion Criterion #7) (Wechalekar 2013, Palladini 2016, Dispenzieri 2004) at the time of Screening 4. Measurable hematologic disease at Screening as defined by at least one of the following: a. dFLC > 4 mg/dL or b. iFLC > 4 mg/dL with abnormal Kappa/Lambda ratio or c. SPEP m-spike > 0.5 g/dL 5. 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/Immunofluorescence b. Mass spectrometry or c. Characteristic electron microscopy appearance/Immunoelectron microscopy 6. 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 MRI with gadolinium contrast agent diagnostic of cardiac amyloidosis 7. NT-proBNP >= 650 and = 1.0 x 109/L b. Platelet count >= 75 x 109/L c. Hemoglobin >= 9 g/dL d. Total bilirubin
Exclusion criteria
Exclusion criteria: Patients who meet any of the following criteria will not be permitted entry to the study. 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 syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed 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 177 mol/L (> 2 mg/dL) OR iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion 5. Taking prednisone or its equivalent > 10 mg/day 6. Taking doxycycline 7. Receiving dialysis 8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted. 9. Have had acute coronary syndrome, uncontrolled ventricular arrhythmias within 3 months prior to screening or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting within 2 months prior to screening. Exacerbation of chronic condition or new acute condition will require discussion and approval by the Medical Monitor. 10. LVEF is 500 msec on Screening ECG. Patients with a QTcF of > 500 msec who have a QRS of > 120 msec and confirmed right bundle branch block, left bundle bran
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 10.7.1. Primary Efficacy Endpoint The primary efficacy endpoint is the time to all-cause mortality and will be assessed from the date of randomization to the date of death (for patients who died) or EOS. Patients living at the end of the study will be censored at their last known date recorded. Patients who prematurely discontinue study treatment or withdraw early from the study will be included in the analysis (even after discontinuation of study treatment or the study) using the date of death or censoring time point (ie, last known date recorded), as appropriate. The primary efficacy endpoint will be estimated using a Cox proportional hazard model adjusted by the randomization factor (geographic region). A stratified log-rank test by geographic region will be used to test the treatment effect between the 2 study intervention groups. Kaplan-Meier curves as well as KM estimates of median survival time will also be provided. Primary Estimand The primary estimand attributes are as follows: • Study intervention: o CAEL-101 plus SoC PCD o Placebo plus SoC PCD • Population: adults (>= 18 years of age) with Mayo Stage IIIa AL amyloidosis • Variable: time to all-cause mortality from randomization up to the date of death (for patients who died) or the End of Study. • Summary measure: hazard ratio of CAEL-101 vs placebo for all-cause mortality • Intercurrent events: treatment policy strategy (ICH E9 [R1] Addendum) will be applied to the following intercurrent events: 1. Study intervention discontinuation 2. Selected major protocol deviations as described in the SAP | — |
Secondary
| Measure | Time frame |
|---|---|
| 10.7.2. Key Secondary Efficacy Endpoints The key secondary efficacy endpoints are as follows: • Changes from baseline to Week 50 in the KCCQ-OS • Changes from baseline to Week 50 in GLS% • Changes from baseline to Week 50 in the 6MWT distance • Changes from baseline to Week 50 in the SF-36 v2 PCS The time slope of each key secondary endpoint will be analyzed using a linear mixed effects model with each parameter (ie, KCCQ-OS, or GLS%, or 6MWT, or SF-36 v2 PCS) as dependent variable and treatment, baseline value for each parameter, time (as a continuous variable), geographic region, and treatment by time interaction as fixed effect and intercept and time as random effects. The parameter of interest is the coefficient for study intervention group and time interaction term, which measures the slope difference between CAEL-101 and placebo over time. Estimated LS means (+/-SE) for the slope by each study intervention group as well as the difference in LS mean slopes between the 2 study intervention groups along with the p-value of the interaction test between study intervention group and time will be provided. | — |
Countries
Netherlands
Outcome results
None listed