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Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01737398
Recruitment Status : Completed
First Posted : November 29, 2012
Results First Posted : January 23, 2019
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE November 27, 2012
First Posted Date  ICMJE November 29, 2012
Results First Submitted Date  ICMJE November 2, 2018
Results First Posted Date  ICMJE January 23, 2019
Last Update Posted Date July 17, 2019
Actual Study Start Date  ICMJE March 15, 2013
Actual Primary Completion Date March 3, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 2, 2019)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 27, 2012)
Efficacy of ISIS-TTR Rx as measured by change from baseline in the modified Neuropathy Impairment Score +7 [ Time Frame: 65 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 2, 2019)
  • 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.
  • 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.
  • 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
  • Change From Baseline In Body Mass Index (BMI) at Week 65 [ Time Frame: 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.
  • 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.
  • 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.
  • 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
  • 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
  • Change From Baseline in Transthyretin (TTR) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
  • Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
  • Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  • Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 [ Time Frame: 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 ]
  • Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  • Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  • Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 [ Time Frame: Week 65 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 27, 2012)
  • Efficacy of ISIS-TTR Rx based on the change from baseline in the following measures: [ Time Frame: 65 weeks ]
    • Norfolk Quality of Life Diabetic Neuropathy questionnaire
    • Modified Body Mass Index and Body Mass Index
    • Individual components of the mNIS+7
    • NIS+7
    • NIS
  • Pharmacodynamic effect of ISIS-TTR Rx based on the change from baseline in transthyretin and retinol binding protein 4 [ Time Frame: 65 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy
Official Title  ICMJE 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)
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • FAP
  • Familial Amyloid Polyneuropathy
  • TTR
  • Transthyretin
  • Amyloidosis
Intervention  ICMJE
  • Drug: Inotersen
    Other Names:
    • TEGSEDI
    • IONIS-TTR Rx
    • ISIS 420915
  • Drug: Placebo
Study Arms  ICMJE
  • 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
    Intervention: Drug: Inotersen
  • Active Comparator: Placebo
    Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 2, 2019)
173
Original Estimated Enrollment  ICMJE
 (submitted: November 27, 2012)
195
Actual Study Completion Date  ICMJE November 7, 2017
Actual Primary Completion Date March 3, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 82 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   France,   Germany,   Italy,   New Zealand,   Portugal,   Spain,   United Kingdom,   United States
Removed Location Countries Bulgaria
 
Administrative Information
NCT Number  ICMJE NCT01737398
Other Study ID Numbers  ICMJE ISIS 420915-CS2
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ionis Pharmaceuticals, Inc.
Study Sponsor  ICMJE Ionis Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Ionis Pharmaceuticals, Inc.
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP