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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.

Study Description
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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).

Condition or disease Intervention/treatment Phase
FAP Familial Amyloid Polyneuropathy TTR Transthyretin Amyloidosis Drug: Inotersen Drug: Placebo Phase 2 Phase 3

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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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 173 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : March 15, 2013
Actual Primary Completion Date : March 3, 2017
Actual Study Completion Date : November 7, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Inotersen

Arms and Interventions
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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
 Drug: Inotersen
Other Names:
  • TEGSEDI
  • IONIS-TTR Rx
  • ISIS 420915
Active Comparator: Placebo
Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
 Drug: Placebo


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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

  4. Change From Baseline In Body Mass Index (BMI) at Week 65 [ Time Frame: Baseline and Week 65 ]
  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. Change From Baseline in Transthyretin (TTR) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
  11. Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 [ Time Frame: Baseline and Week 65 ]
  12. Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  13. Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  14. Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  15. Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  16. Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 [ Time Frame: Week 65 ]
  17. Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 [ Time Frame: Week 65 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 82 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01737398


Locations
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Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
  Study Documents (Full-Text)

Documents provided by Ionis Pharmaceuticals, Inc.:
Study Protocol  [PDF] May 13, 2016
Statistical Analysis Plan  [PDF] April 21, 2017

More Information
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Publications of Results:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01737398    
Other Study ID Numbers: ISIS 420915-CS2
First Posted: November 29, 2012    Key Record Dates
Results First Posted: January 23, 2019
Last Update Posted: July 17, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ionis Pharmaceuticals, Inc.:
FAP
Familial Amyloid Polyneuropathy
TTR
Transthyretin
Amyloidosis
Additional relevant MeSH terms:
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Polyneuropathies
Amyloid Neuropathies
Amyloid Neuropathies, Familial
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
 Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Amyloidosis, Familial
Metabolism, Inborn Errors