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

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

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.

Study Overview

• Status: Completed
• Conditions: AL Amyloidosis
• Intervention / Treatment: Drug: NEOD001; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • The University of Queensland - Princess Alexandra Hospital (PAH)
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Eastern Health (Box Hill Hospital)
• Austria
  • Vienna, Austria
    • Medizinische Universität Wien, Allgemeines Krankenhaus der Stadt Wien
• France
  • Limoges, France, 87042
    • Hôpital Dupuytren - CHU Limoges
  • Paris, France, 75013
    • Hôpital Pitié-Salpétrière
  • Pierre-Benite Cedex, France, 69495
    • Hopitaux Lyon Sud
  • Rennes Cedex 2, France
    • CHU Rennes, Service de Medecine Interne
• Germany
  • Berlin, Germany, 12203
    • Charité-Universitätsmedizin
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf (UKE
  • Heidelberg, Germany, 69120
    • Universitatsklinikum Heidelberg
• Greece
  • Athens, Greece, 11528
    • Alexandra General Hospital of Athens
  • Patras, Greece
    • University Hospital of Patras
• Israel
  • Jerusalem, Israel, 91120
    • Hadassah University Medical Center
• Italy
  • Pavia, Italy, 27100
    • Policlinica San Matteo
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro - Majadahonda
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Centre for Clinical Haematology
  • London, United Kingdom, NW3 2PF
    • The Royal Free London NHS Foundation Trust - The Royal Free Hospital
  • Southampton, United Kingdom
    • Southampton General Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute (SCI)
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Minnesota
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas; MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington/Seattle Cancer Care Alliance
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin, Cancer Center - Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years
2. Confirmed diagnosis of systemic AL amyloidosis
3. ≥1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response
4. Cardiac involvement
5. NT-proBNP ≥650

Exclusion Criteria:

1. Non-AL amyloidosis
2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma
3. NT-proBNP >5000
4. Received Plasma cell directed chemotherapy within 6 months
5. Received autologous stem cell transplant (ASCT) within 12 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Saline Bag
Experimental: NEOD001; Study Drug given IV every 28 days at 24mg/kg	Drug: NEOD001; NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Prothena Biosciences Ltd.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: December 9, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimate): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 2, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; amyloid; amyloidosis; NEOD001; plasma cell dyscrasia; ntprobnp; Prothena; PRONTO
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Paraproteinemias; Proteostasis Deficiencies; Neoplasms, Plasma Cell; Immunoglobulin Light-chain Amyloidosis; Amyloidosis
• Other Study ID Numbers: NEOD001-201