Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of inotersen given for 65 weeks in participants with Familial Amyloid Polyneuropathy (FAP).

Detailed Description
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FAP is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP. Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein would result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression. The purpose of this study is to determine if inotersen can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP participants. Participants will receive either inotersen or placebo for 65 weeks.

Official Title
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A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (NEURO-TTR Study)

Conditions
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FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis

Intervention / Treatment
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* Drug: Inotersen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage 1 and Stage 2 FAP participants with the following: NIS score within protocol criteria Documented transthyretin variant by genotyping Documented amyloid deposit by biopsy Females of child-bearing potential must use appropriate contraception and be non-pregnant and non-lactating. Males engaging in relations of child-bearing potential are to use appropriate contraception Exclusion Criteria: Low Retinol level at screen Karnofsky performance status ≤50 Poor Renal function Known type 1 or type 2 diabetes mellitus Other causes of sensorimotor or autonomic neuropathy (for example, autoimmune disease) If previously treated with Vyndaqel®, will need to have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, will need to have discontinued treatment for 3 days prior to Study Day 1 Previous treatment with any oligonucleotide or siRNA within 12 months of screening Prior liver transplant or anticipated liver transplant within 1 year of screening New York Heart Association (NYHA) functional classification of ≥3 Acute Coronary Syndrome or major surgery within 3 months of screening Known Primary or Leptomeningeal Amyloidosis Anticipated survival less than 2 years Any other conditions in the opinion of the investigator which interfere with the participant participating in or completing the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 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 |
| --- | --- |
| Active Comparator: Inotersen<br>300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks | Drug: Inotersen<br> <br> * Other names: ISIS 420915;|
| Active Comparator: Placebo<br>Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66 | The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function. | Baseline and Week 66 | 
| Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 | The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher Norfolk QoL-DN score indicates poorer QoL. | Baseline and Week 66 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66 | The Norfolk QoL-DN symptoms score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN symptoms domain score has a range of 0-32, and a higher Norfolk QoL-DN score indicates poorer QoL. | Baseline and Week 66 | 
| Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66 | The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer QoL. | Baseline and Week 66 | 
| Change From Baseline In Modified Body Mass Index (mBMI) at Week 65 | The mBMI is the BMI multiplied by the serum albumin g/L | Baseline and Week 65 | 
| Change From Baseline In Body Mass Index (BMI) at Week 65 |  | Baseline and Week 65 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66 | The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. | Baseline and Week 66 | 
| Change From Baseline in Modified +7 at Week 66 | The Modified +7 score is a version of the NIS score that is a measure of neurologic impairment. The Modified +7 Score has a range of -22.32 to 102.32 and a higher NIS score indicates lower function. | Baseline and Week 66 | 
| Change From Baseline in NIS+7 at Week 66 | The NIS+7 score is a version of the NIS score that is a measure of neurologic impairment. The NIS+7 Score has a range of -26.04 to 270.04 and a higher NIS score indicates lower function. | Baseline and Week 66 | 
| Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set | GLS by ECHO is a measure of cardiac systolic function | Baseline and Week 65 | 
| Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup | GLS by ECHO is a measure of cardiac systolic function | Baseline and Week 65 | 
| Change From Baseline in Transthyretin (TTR) Level at Week 65 |  | Baseline and Week 65 | 
| Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 |  | Baseline and Week 65 | 
| Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 |  | Week 65 | 
| Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 |  | Week 65 | 
| Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 |  | Week 65 | 
| Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 |  | Week 65 | 
| Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 |  | Week 65 | 
| Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 |  | Week 65 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis