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

• Sponsor: Prothena Therapeutics Ltd.
• Information provided by (Responsible Party): Prothena Therapeutics Ltd.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
AL Amyloidosis	Drug: NEOD001; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 129 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2016
• Actual Primary Completion Date: March 2018
• Actual Study Completion Date: March 2018

Arms and Interventions

Arm	Intervention/treatment
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
Placebo Comparator: Placebo; Placebo	Drug: Placebo; Saline Bag

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Cardiac Response and Non-Response [ Time Frame: Baseline through 12 months of treatment ]
   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.

Secondary Outcome Measures :

1. SF-36v2 PCS Score [ Time Frame: Baseline to 12 months of treatment ]
   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.
2. 6MWT Distance [ Time Frame: Baseline to 12 months of treatment ]
   Change in 6 Minute Walk Test (6MWT) Distance (meters)
3. Number of Participants With Renal Best Response and Non-Response [ Time Frame: Baseline through 12 months of treatment ]

   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.

4. NIS-LL Total Score [ Time Frame: Baseline to 12 months of treatment ]
   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.
5. NT-proBNP Slope [ Time Frame: Baseline through 12 months of treatment ]
   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.
6. Hepatic Best Response [ Time Frame: Baseline through 12 months of treatment ]
   Alkaline Phosphatase response (Response or Non-Response [Stable, Progression]) from baseline through 12 months of treatment in subjects with hepatic involvement

Eligibility Criteria

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

Criteria

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

Contacts and Locations

  Show 40 Study Locations

Sponsors and Collaborators

Prothena Therapeutics Ltd.

  Study Documents (Full-Text)

Documents provided by Prothena Therapeutics Ltd.:

Study Protocol  [PDF] October 22, 2017

Statistical Analysis Plan  [PDF] February 15, 2018

More Information

• Responsible Party: Prothena Therapeutics Ltd.
• ClinicalTrials.gov Identifier: NCT02632786 History of Changes
• Other Study ID Numbers: NEOD001-201
• First Posted: December 17, 2015
• Results First Posted: April 5, 2019
• Last Update Posted: April 5, 2019
• Last Verified: April 2019

Keywords provided by Prothena Therapeutics Ltd.:

amyloidosis; ntprobnp; NEOD001; Prothena; PRONTO; amyloid; plasma cell dyscrasia; immunotherapy

Additional relevant MeSH terms:

Amyloidosis; Immunoglobulin Light-chain Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias