The PRONTO Study, a Global Phase 2b Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis

Study Overview
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Brief Summary
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This is a global, 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 had a hematologic response to previous treatment for their amyloidosis (e.g., chemotherapy, autologous stem cell transplant [ASCT]) and have persistent cardiac dysfunction.

Official Title
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A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of NEOD001 in Previously Treated Subjects With Light Chain (AL) Amyloidosis Who Have Persistent Cardiac Dysfunction

Conditions
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AL 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: Age ≥18 years Confirmed diagnosis of systemic AL amyloidosis ≥1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response Cardiac involvement NT-proBNP ≥650 Exclusion Criteria: Non-AL amyloidosis Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma NT-proBNP >5000 Received Plasma cell directed chemotherapy within 6 months Received autologous stem cell transplant (ASCT) within 12 months

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 |
| --- | --- | --- |
| Number of Participants With Cardiac Response and Non-Response | N-terminal pro-brain natriuretic peptide (NT-proBNP ) best response (Response or Non-Response [Stable, Progression]) from baseline through 12 months of treatment. Cardiac best response, as assessed by NT-proBNP alone, is defined as the most favorable category among response (ie, decrease in NT-proBNP from baseline of >30% and >300 ng/L), stable (ie, neither response nor progression), and progression (ie, increase in NT-proBNP from baseline of >30% and >300 ng/L) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Non-response is defined as either stable or progression. | Baseline through 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SF-36v2 PCS Score | Change in Short Form-36 (SF-36 version 2) questionnaire Physical Component Summary [PCS] Score. PCS scores are calculated based on responses to specific Short Form-36 (version 2) questions using a weight scoring method. The lower the PCS score the more disability, the higher the score the less disability. A score of 50 is the mean in the US General Population and the standard deviation is 10. Minimum is 0 and maximum value is 100. | Baseline to 12 months of treatment | 
| 6MWT Distance | Change in 6 Minute Walk Test (6MWT) Distance (meters) | Baseline to 12 months of treatment | 
| Number of Participants With Renal Best Response and Non-Response | Proteinuria and estimated Glomerular Filtration Rate (eGFR) response (Response or Non-Response [Stable, Progression]) from baseline through 12 months of treatment in subjects with renal involvement. Renal best response, as assessed by proteinuria, is defined as the most favorable category among response (ie, ≥30% decrease from baseline or <0.5 g/24 hours postbaseline result if subject does not meet criteria for progression), stable (ie, neither response nor progression), and progression (ie, ≥25% decrease in eGFR from baseline) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Assessments that qualify as both a response and progression are counted as progression. Non-response is defined as either stable or progression. | Baseline through 12 months of treatment | 
| NIS-LL Total Score | Change in Neuropathy Impairment Score-Lower Limb (NIS-LL) Total Score in subjects with peripheral nerve involvement. NIS-LL is a scoring system graduated from 0 points to a maximum of 88 points (the absence of all motor, sensory, and reflex activity in the lower extremities). The scale is an additive of all deficits (64 potential points for muscle strength, 8 points for reflexes, and 16 points for sensory function) in the lower extremities. A score of 0 is normal and score of 88 is total impairment. | Baseline to 12 months of treatment | 
| NT-proBNP Slope | Rate of change in NT-proBNP (ng/L per infusion). Estimates of the intercept, slope, SE, and associated 95% CI for each treatment group, and the NEOD001 and placebo group difference comparisons are estimated using a general linear mixed effects model. The model fits a random intercept and slope for each subject and includes fixed effects for treatment group, time, treatment group by time interaction, IWRS stratification factors (hematologic response to first-line therapy: CR/VGPR, PR and NT-proBNP <1800 ng/L, ≥1800 ng/L), and an unstructured covariance structure to model the within-subject errors. Time is represented in months as a continuous variable and includes all scheduled time points, including baseline. The p-value is associated with the visit by treatment group interaction term. | Baseline through 12 months of treatment | 
| Hepatic Best Response | Alkaline Phosphatase response (Response or Non-Response [Stable, Progression]) from baseline through 12 months of treatment in subjects with hepatic involvement | Baseline through 12 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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plasma cell dyscrasia, amyloidosis, ntprobnp, NEOD001, Prothena, PRONTO, amyloid, immunotherapy