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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Transthyretin (TTR)-Mediated Amyloidosis, Familial Amyloidotic Polyneuropathy (FAP), ATTR Amyloidosis, Familial Amyloid Neuropathies

Intervention / Treatment
-----------------
* Drug: Revusiran


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FAP, Familial Amyloidotic Polyneuropathy, ATTR Amyloidosis, Orthotopic Liver Transplant, RNAi therapeutic