Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

Phase 2

Completed

• Conditions: FAP; Familial Amyloid Polyneuropathy; TTR; Amyloidosis; Transthyretin
• Interventions: Drug: Placebo; Drug: Inotersen

• Registration Number: NCT01737398
• Lead Sponsor: Ionis Pharmaceuticals, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2012-11-27
• Study First Submitted QC: 2012-11-27
• Study First Posted: 2012-11-29
• Study Start: 2013-03-15
• Primary Completion: 2017-03-03
• Study Completion: 2017-11-07
• Disposition First Submitted: 2018-04-25
• Disposition First Submitted QC: 2018-04-25
• Disposition First Posted: 2018-04-27
• Results First Submitted: 2018-11-02
• Results First Submitted QC: 2019-01-02
• Results First Posted: 2019-01-23
• Status Verified: 2019-07
• Last Update Submitted: 2019-07-08
• Last Update Posted: 2019-07-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 173

Inclusion Criteria

• Stage 1 and Stage 2 FAP participants with the following:

  1. NIS score within protocol criteria
  2. Documented transthyretin variant by genotyping
  3. 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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
Inotersen	Inotersen	300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks

Primary Outcome Measures

Name	Time	Method
Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66	Baseline and 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.
Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66	Baseline and 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.

Secondary Outcome Measures

Name	Time	Method
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
Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup	Baseline and Week 65	GLS by ECHO is a measure of cardiac systolic function
Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66	Baseline and 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.
Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66	Baseline and 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.
Change From Baseline In Modified Body Mass Index (mBMI) at Week 65	Baseline and Week 65	The mBMI is the BMI multiplied by the serum albumin g/L
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	Baseline and 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.
Change From Baseline in Modified +7 at Week 66	Baseline and 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.
Change From Baseline in NIS+7 at Week 66	Baseline and 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.
Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set	Baseline and Week 65	GLS by ECHO is a measure of cardiac systolic function
Change From Baseline in Transthyretin (TTR) Level at Week 65	Baseline and 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

Trial Locations

Locations (24)

CHP-HGSA, Unidade Clinica de Paramiloidose; 🇵🇹 Porto, Portugal

UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin; 🇩🇪 Munster, Germany

Hospital Universitari Vall D' Hebron; 🇪🇸 Barcelona, Spain

Hospital Clínic; 🇪🇸 Barcelona, Spain

CHLN - Hospital de Santa Maria; 🇵🇹 Lisbon, Portugal

UNIFESP; 🇧🇷 Sao Paulo, Brazil

FLENI; 🇦🇷 Buenos Aires, Argentina

Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"; 🇮🇹 Messina, Sicily, Italy

AACD; 🇧🇷 Sao Paulo, Brazil

Auckland City Hospital; 🇳🇿 Auckland, New Zealand

Federal University of Rio de Janeiro - University Hospital; 🇧🇷 Rio de Janeiro, Brazil

University College London - National Amyloidosis Centre; 🇬🇧 London, United Kingdom

Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo; 🇮🇹 Pavia, Italy

Indiana University School of Medicine; 🇺🇸 Indianapolis, Indiana, United States

Johns Hopkins University Bayview Medical Center; 🇺🇸 Baltimore, Maryland, United States

Boston University School of Medicine - Amyloid Treatment & Research Program; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Penn Presbyterian Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States

CHU Henri Mondor - Department of Neurology; 🇫🇷 Creteil, France

CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network; 🇫🇷 Le Kremlin Bicetre, France

Columbia University Medical Center - The Neurological Institute; 🇺🇸 New York, New York, United States

Oregon Health & Science University; 🇺🇸 Portland, Oregon, United States

Mount Sinai Medical Center; 🇺🇸 New York, New York, United States

University of California, Irvine; 🇺🇸 Orange, California, United States