The Study of an Investigational Drug, Revusiran (ALN-TTRSC), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis in Patients Whose Disease Has Continued to Worsen Following Liver Transplant

An Open-label Study to Evaluate the Efficacy and Safety of Revusiran in Patients With Transthyretin-mediated Familial Amyloidotic Polyneuropathy With Disease Progression Post-Orthotopic Liver Transplant

The purpose of this study was to evaluate the safety and effectiveness of revusiran (ALN-TTRSC) in adults with transthyretin-mediated amyloidosis (ATTR), whose disease has continued to worsen after liver transplantation. Dosing has been discontinued; patients are being followed-up for safety.

Study Overview

• Status: Completed
• Conditions: ATTR Amyloidosis; Transthyretin (TTR)-Mediated Amyloidosis; Familial Amyloidotic Polyneuropathy (FAP); Familial Amyloid Neuropathies
• Intervention / Treatment: Drug: Revusiran

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Clinical Trial Site
• Germany
  • Münster, Germany
    • Clinical Trial Site
• Portugal
  • Porto, Portugal
    • Clinical Trial Site
• Spain
  • Majorca, Spain
    • Clinical Trial Site
• Sweden
  • Umea, Sweden
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom
    • Clinical Trial Site

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:

• Diagnosis of FAP (familial amyloidotic polyneuropathy) with documented TTR mutation
• Received an orthotopic liver transplant ≥12 months before the date of informed consent
• An increase in polyneuropathy disability (PND) score post-transplant
• Polyneuropathy Disability score of ≤3b

Exclusion Criteria:

• New York Heart Association (NYHA) classification of >2
• Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All Patients; All patients who received at least 1 dose of revusiran (ALN-TTRSC)	Drug: Revusiran; 500mg Revusiran by subcutaneous (sc) injection; Other Names: ALN-TTRSC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Serum TTR at Month 6	A negative percentage change from baseline at Month 6 indicates a reduction in serum TTR level.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Serum TTR Over 18 Months	A negative percentage change from baseline indicates a reduction in serum TTR level.	Weeks 3, 7, 12, 18, 24, 26 (Month 6), 39 (Month 9), 52 (Month 12), 57, 78 (Month 18)
Change From Baseline in Modified Neurological Impairment Score (mNIS +7) Composite Score Over 18 Months	The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome. A negative change from baseline indicates an improvement.	Baseline, Months 6, 12, 18
Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Score	The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.	Baseline, Months 6, 12, 18
Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score	PND Scores: Stage 0: No symptoms, Stage 1: Sensory disturbances but preserved walking capabilities, Stage 2: Impaired walking capacity, but ability to walk without a stick or crutches, Stage 3A/B: Walking with help of 1 or 2 sticks or crutches, Stage 4: confined to wheel chair. For each stage (0-4) at baseline, the number of participants is presented at their worst post-baseline score for each stage (0-4) post-baseline. Worst post-baseline is defined the highest PND classification for a participant recorded after the first dose of study drug.	Baseline, Months 6, 12, 18

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: John Vest, MD, Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): February 6, 2017
• Study Completion (Actual): February 6, 2017

Study Registration Dates

• First Submitted: October 30, 2015
• First Submitted That Met QC Criteria: November 2, 2015
• First Posted (Estimate): November 4, 2015

Study Record Updates

• Last Update Posted (Actual): March 28, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: RNAi therapeutic; FAP; ATTR Amyloidosis; Familial Amyloidotic Polyneuropathy; Orthotopic Liver Transplant
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis, Familial; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: ALN-TTRSC-005