Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

July 8, 2019 updated by: Ionis Pharmaceuticals, Inc.

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)

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).

Study Overview

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 Type

Interventional

Enrollment (Actual)

173

Phase

  • Phase 2
  • Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Buenos Aires, Argentina
        • FLENI
      • Rio de Janeiro, Brazil, CEP 21941913
        • Federal University of Rio de Janeiro - University Hospital
      • Sao Paulo, Brazil
        • AACD
      • Sao Paulo, Brazil
        • UNIFESP
      • Creteil, France, 94000
        • CHU Henri Mondor - Department of Neurology
      • Le Kremlin Bicetre, France, 94275
        • CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network
      • Munster, Germany, 48149
        • UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin
      • Pavia, Italy, 27100
        • Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo
    • Sicily
      • Messina, Sicily, Italy, 98124
        • Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"
      • Auckland, New Zealand
        • Auckland City Hospital
      • Lisbon, Portugal, 1649-035
        • CHLN - Hospital de Santa Maria
      • Porto, Portugal, 4099-001
        • CHP-HGSA, Unidade Clinica de Paramiloidose
      • Barcelona, Spain, 08036
        • Hospital Clínic
      • Barcelona, Spain, 08035
        • Hospital Universitari Vall d' Hebrón
      • London, United Kingdom, NW3 2PF
        • University College London - National Amyloidosis Centre
    • California
      • Orange, California, United States, 92868
        • University of California, Irvine
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University School of Medicine
    • Maryland
      • Baltimore, Maryland, United States, 21205
        • Johns Hopkins University Bayview Medical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02118
        • Boston University School of Medicine - Amyloid Treatment & Research Program
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • New York
      • New York, New York, United States, 10029
        • Mount Sinai Medical Center
      • New York, New York, United States, 10032
        • Columbia University Medical Center - The Neurological Institute
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Penn Presbyterian Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 82 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Inotersen
300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks
Other Names:
  • TEGSEDI
  • ISIS 420915
  • IONIS-TTR Rx
Active Comparator: Placebo
Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks

What is the study measuring?

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
Time Frame: 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.
Baseline and Week 66
Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
Time Frame: 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.
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
Time Frame: 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.
Baseline and Week 66
Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66
Time Frame: 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.
Baseline and Week 66
Change From Baseline In Modified Body Mass Index (mBMI) at Week 65
Time Frame: Baseline and 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
Time Frame: Baseline and Week 65
Baseline and Week 65
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66
Time Frame: 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.
Baseline and Week 66
Change From Baseline in Modified +7 at Week 66
Time Frame: 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.
Baseline and Week 66
Change From Baseline in NIS+7 at Week 66
Time Frame: 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.
Baseline and Week 66
Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set
Time Frame: Baseline and Week 65
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
Time Frame: Baseline and Week 65
GLS by ECHO is a measure of cardiac systolic function
Baseline and Week 65
Change From Baseline in Transthyretin (TTR) Level at Week 65
Time Frame: Baseline and Week 65
Baseline and Week 65
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65
Time Frame: Baseline and Week 65
Baseline and Week 65
Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
Time Frame: Week 65
Week 65
Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65
Time Frame: Week 65
Week 65
Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65
Time Frame: Week 65
Week 65
Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65
Time Frame: Week 65
Week 65
Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65
Time Frame: Week 65
Week 65
Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65
Time Frame: Week 65
Week 65

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2013

Primary Completion (Actual)

March 3, 2017

Study Completion (Actual)

November 7, 2017

Study Registration Dates

First Submitted

November 27, 2012

First Submitted That Met QC Criteria

November 27, 2012

First Posted (Estimate)

November 29, 2012

Study Record Updates

Last Update Posted (Actual)

July 17, 2019

Last Update Submitted That Met QC Criteria

July 8, 2019

Last Verified

July 1, 2019

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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