Renal AL Amyloid Involvement and NEOD001

Study Overview
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Brief Summary
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This is a multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant [ASCT]) and have persistent renal dysfunction.

Detailed Description
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This is a multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant [SCT]) and have persistent renal dysfunction. Subject screening will occur during the 28 days prior to the first administration of study drug (i.e. month 1 day 1). If screening assessments are completed and all eligibility requirements are met, the subject will be enrolled. Study visits will occur every 28 days based on scheduling from month 1 day 1. A ±5-day window is allowed for visits starting after month 1. Subjects may receive up to 12 infusions of study drug. Subjects who discontinue study drug before the initial End of Study (EOS) visit should have an Early Treatment Discontinuation (ETD) Visit 30 (±5) days after their final administration of study drug. After completing 12 months of treatment and the confirmatory EOS visit, a subject may enter an open-label extension (OLE) study, during which subjects will receive active treatment with NEOD001 for 12 months and may receive concurrent chemotherapy.

Official Title
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The RAIN Study, a Multicenter Randomized Double-blind Phase 2b Study of NEOD001 in Previously Treated Subjects With Systemic Light-chain (AL) Amyloidosis and Persistent Renal Involvement

Conditions
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Amyloidosis

Intervention / Treatment
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* Drug: NEOD001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Biopsy-proven diagnosis of AL amyloidosis by immunohistochemistry or mass spectroscopy of a tissue biopsy excluding bone marrow Screening renal biopsy for RAIN confirming AL amyloidosis as exclusive or dominant cause of renal damage Persistent renal involvement from diagnosis with proteinuria (predominantly albumin) > 500mg/day in a 24-hour urine collection CKD 1 to 3 (eGFR > 30) ≥1 prior systemic hematologic therapy for a free light chain (FLC) producing hematologic malignancy underlying the initial diagnosis of AL amyloidosis with at least a partial FLC response (PR, VGPR, CR) to treatment deemed stable and not requiring further treatment ECOG Performance Status ≤ 2 Clinical laboratory values: Absolute neutrophil count > 1000/μL Platelet count > 75,000/μL Total bilirubin ≤ 1.5X ULN Alkaline phosphatase ≤ 5X ULN NT-proBNP < 1800 pg/mL Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care Exclusion Criteria: Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis Female patients who are lactating, breastfeeding, or pregnant Patients who have not been treated or who have received chemotherapy within 6 months, or SCT within 12 months, for the light-chain producing hematologic disease causing AL amyloidosis, at the time of the first dose of NEOD001 (month 1 day 1) Patients who at initial diagnosis or later met the International Myeloma Working Group (IMWG) definition of active multiple myeloma requiring therapy (Appendix 3) Patients whose screening renal biopsies for RAIN show dominant causes of renal damage not related to AL amyloidosis Medically documented cardiac syncope, uncompensated congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive atrial or ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically significant uncompensated autonomic insufficiency Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Ongoing or active infection, known HIV positive, known to be hepatitis B surface antigen-positive or has known or suspected active hepatitis C infection. Psychiatric illness/social situations that would limit compliance with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEOD001<br>Study Drug given IV every 28 days at 24mg/kg | Drug: NEOD001<br>* NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Saline bag<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Renal Response After Treatment With NEOD001 | A renal response is a ≥ 30% reduction in proteinuria in the absence of a ≥ 25% decrease in eGFR. A confirmed renal response is one that has been documented as present one month after 12 monthly treatments. | Baseline to 13 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measured GFR at Study Entry | The aim of this study is to assess the performance of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine in comparison to iothalamate clearance measured in AL amyloidosis patients. Iothalamate will be given subcutaneously. Urine and plasma samples will then be obtained. All laboratory tests for samples obtained for GFR measurement will be performed at Mayo Clinic Rochester. Quantification of iothalamate in urine and plasma will be performed using a tandem mass spectrometric method. | Baseline | 
| Time to CKD 4 or 5 | Months to Chronic Kidney Disease level 4 or 5 | Baseline to 13 Months | 
| Time to eGFR ≤ 15 or Dialysis | Months to estimated Glomerular Filtration Rate ≤ 15 or dialysis | Baseline to 13 Months | 
| Time to Doubling of Creatinine | Months to doubling of serum creatinine | Baseline to 13 Months | 
| Time to ≥ 40% Reduction in eGFR | Months to ≥ 40% reduction in estimated glomerular filtration rate | Baseline to 13 Months | 
| Renal Response in Patients With Maintained Hematologic Responses After 24 Monthly Treatments. | A renal response is a ≥ 30% decrease in proteinuria or drop of proteinuria below 0.5 g/24h in the absence of renal progression. | Baseline to 26 months | 
| All Cause of Mortality at 26 Months | Death at 26 months from Baseline due to any cause | Baseline to 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyloidosis, NEOD001, RAIN