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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01737398
Registration number
NCT01737398
Ethics application status
Date submitted
27/11/2012
Date registered
29/11/2012
Titles & IDs
Public title
Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy
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Scientific 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)
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Secondary ID [1]
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ISIS 420915-CS2
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
FAP
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Familial Amyloid Polyneuropathy
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TTR
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Transthyretin
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Amyloidosis
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Condition category
Condition code
Neurological
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Other neurological disorders
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Neurological
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Neurodegenerative diseases
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Metabolic and Endocrine
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Metabolic disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Metabolic and Endocrine
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Other metabolic disorders
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
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
Active comparator: Placebo - Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Week 66
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Primary outcome [2]
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Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline and Week 66
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Secondary outcome [1]
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Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66
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Assessment method [1]
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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.
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Timepoint [1]
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Baseline and Week 66
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Secondary outcome [2]
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Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66
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Assessment method [2]
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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.
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Timepoint [2]
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Baseline and Week 66
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Secondary outcome [3]
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Change From Baseline In Modified Body Mass Index (mBMI) at Week 65
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Assessment method [3]
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The mBMI is the BMI multiplied by the serum albumin g/L
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Timepoint [3]
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Baseline and Week 65
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Secondary outcome [4]
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Change From Baseline In Body Mass Index (BMI) at Week 65
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Assessment method [4]
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Timepoint [4]
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Baseline and Week 65
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Secondary outcome [5]
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Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline and Week 66
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Secondary outcome [6]
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Change From Baseline in Modified +7 at Week 66
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline and Week 66
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Secondary outcome [7]
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Change From Baseline in NIS+7 at Week 66
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline and Week 66
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Secondary outcome [8]
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Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set
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Assessment method [8]
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GLS by ECHO is a measure of cardiac systolic function
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Timepoint [8]
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Baseline and Week 65
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Secondary outcome [9]
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Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup
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Assessment method [9]
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GLS by ECHO is a measure of cardiac systolic function
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Timepoint [9]
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Baseline and Week 65
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Secondary outcome [10]
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Change From Baseline in Transthyretin (TTR) Level at Week 65
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Assessment method [10]
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Timepoint [10]
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Baseline and Week 65
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Secondary outcome [11]
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Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65
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Assessment method [11]
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Timepoint [11]
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Baseline and Week 65
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Secondary outcome [12]
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Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
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Assessment method [12]
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Timepoint [12]
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Week 65
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Secondary outcome [13]
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Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65
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Assessment method [13]
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Timepoint [13]
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Week 65
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Secondary outcome [14]
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Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65
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Assessment method [14]
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Timepoint [14]
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Week 65
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Secondary outcome [15]
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Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65
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Assessment method [15]
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Timepoint [15]
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Week 65
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Secondary outcome [16]
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Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65
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Assessment method [16]
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Timepoint [16]
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Week 65
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Secondary outcome [17]
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Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65
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Assessment method [17]
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Timepoint [17]
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Week 65
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Eligibility
Key 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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Minimum age
18
Years
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Maximum age
82
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
15/03/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
7/11/2017
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Sample size
Target
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Accrual to date
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Final
173
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
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United States of America
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State/province [1]
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California
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United States of America
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State/province [2]
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Indiana
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United States of America
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State/province [3]
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Maryland
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Country [4]
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United States of America
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State/province [4]
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Massachusetts
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Country [5]
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United States of America
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State/province [5]
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Minnesota
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Country [6]
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United States of America
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State/province [6]
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New York
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Country [7]
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United States of America
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State/province [7]
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Oregon
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Country [8]
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United States of America
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State/province [8]
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Pennsylvania
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Country [9]
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Argentina
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State/province [9]
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Buenos Aires
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Country [10]
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Brazil
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State/province [10]
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Rio de Janeiro
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Country [11]
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Brazil
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State/province [11]
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Sao Paulo
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Country [12]
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France
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State/province [12]
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Creteil
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Country [13]
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France
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State/province [13]
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Le Kremlin Bicetre
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Germany
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State/province [14]
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Munster
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Country [15]
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Italy
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State/province [15]
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Sicily
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Italy
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State/province [16]
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Pavia
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New Zealand
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State/province [17]
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Auckland
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Country [18]
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Portugal
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State/province [18]
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Lisbon
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Portugal
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State/province [19]
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Porto
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Spain
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Barcelona
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Country [21]
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United Kingdom
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State/province [21]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Ionis Pharmaceuticals, Inc.
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/study/NCT01737398
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Trial related presentations / publications
Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793. Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4. Karam C, Brown D, Yang M, Done N, Dieye I, Bozas A, Vera Llonch M, Signorovitch J. Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen. Muscle Nerve. 2022 Sep;66(3):319-328. doi: 10.1002/mus.27668. Epub 2022 Jul 15. Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5. Yarlas A, Lovley A, Brown D, Kosinski M, Vera-Llonch M. Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study. J Neurol. 2022 Jan;269(1):323-335. doi: 10.1007/s00415-021-10635-1. Epub 2021 Jun 14. Yu RZ, Wang Y, Norris DA, Kim TW, Narayanan P, Geary RS, Monia BP, Henry SP. Immunogenicity Assessment of Inotersen, a 2'-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety. Nucleic Acid Ther. 2020 Oct;30(5):265-275. doi: 10.1089/nat.2020.0867. Epub 2020 Aug 19. Dyck PJB, Kincaid JC, Wiesman JF, Polydefkis M, Litchy WJ, Mauermann ML, Ackermann EJ, Guthrie S, Pollock M, Jung SW, Baker BF, Dyck PJ. mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis. Muscle Nerve. 2020 Oct;62(4):502-508. doi: 10.1002/mus.27022. Epub 2020 Aug 13. Dyck PJB, Coelho T, Waddington Cruz M, Brannagan TH 3rd, Khella S, Karam C, Berk JL, Polydefkis MJ, Kincaid JC, Wiesman JF, Litchy WJ, Mauermann ML, Ackermann EJ, Baker BF, Jung SW, Guthrie S, Pollock M, Dyck PJ. Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis. Muscle Nerve. 2020 Oct;62(4):509-515. doi: 10.1002/mus.27023. Epub 2020 Aug 7. Coelho T, Yarlas A, Waddington-Cruz M, White MK, Sikora Kessler A, Lovley A, Pollock M, Guthrie S, Ackermann EJ, Hughes SG, Karam C, Khella S, Gertz M, Merlini G, Obici L, Schmidt HH, Polydefkis M, Dyck PJB, Brannagan Iii TH, Conceicao I, Benson MD, Berk JL. Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis. J Neurol. 2020 Apr;267(4):1070-1079. doi: 10.1007/s00415-019-09671-9. Epub 2019 Dec 18. Pinto MV, Dyck PJB, Gove LE, McCauley BM, Ackermann EJ, Hughes SG, Waddington-Cruz M, Dyck PJ. Kind and distribution of cutaneous sensation loss in hereditary transthyretin amyloidosis with polyneuropathy. J Neurol Sci. 2018 Nov 15;394:78-83. doi: 10.1016/j.jns.2018.08.031. Epub 2018 Aug 30. Waddington-Cruz M, Ackermann EJ, Polydefkis M, Heitner SB, Dyck PJ, Barroso FA, Wang AK, Berk JL, Dyck PJB, Monia BP, Hughes SG, Tai L, Jesse Kwoh T, Jung SW, Coelho T, Benson MD, Gertz MA. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018 Sep;25(3):180-188. doi: 10.1080/13506129.2018.1503593. Epub 2018 Aug 31.
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Public notes
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Contacts
Principal investigator
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Contact person for public queries
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/98/NCT01737398/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/98/NCT01737398/SAP_001.pdf
Results publications and other study-related documents
Type
Citations or Other Details
Journal
Benson MD, Waddington-Cruz M, Berk JL, Polydefkis ...
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Results are available at
https://clinicaltrials.gov/study/NCT01737398