- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01737398
Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy
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)
Study Overview
Status
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Expanded Access
Contacts and Locations
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
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Stage 1 and Stage 2 FAP participants with the following:
- NIS score within protocol criteria
- Documented transthyretin variant by genotyping
- 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
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:
|
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
Sponsor
Publications and helpful links
General Publications
- 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.
- 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.
- 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, 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, 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Metabolic Diseases
- Nervous System Diseases
- Genetic Diseases, Inborn
- Neuromuscular Diseases
- Neurodegenerative Diseases
- Peripheral Nervous System Diseases
- Proteostasis Deficiencies
- Metabolism, Inborn Errors
- Heredodegenerative Disorders, Nervous System
- Amyloidosis, Familial
- Amyloidosis
- Polyneuropathies
- Amyloid Neuropathies
- Amyloid Neuropathies, Familial
Other Study ID Numbers
- ISIS 420915-CS2
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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.
Clinical Trials on Amyloidosis
-
Millennium Pharmaceuticals, Inc.CompletedLight-Chain AmyloidosisUnited States, Canada, France, Germany, Italy
-
Boston UniversityCorino Therapeutics, Inc.CompletedTransthyretin Amyloidosis | Amyloidosis, Leptomeningeal, Transthyretin-RelatedUnited States
-
Chulalongkorn UniversityUnknown
-
Criterium, Inc.AmgenCompletedAmyloidosis | Systemic Light Chain AmyloidosisUnited States
-
Steen Hvitfeldt PoulsenRecruitingTransthyretin Amyloidosis | Transthyretin Cardiac Amyloidosis | Wild-Type Transthyretin-Related (ATTR)AmyloidosisDenmark
-
Peking Union Medical College HospitalXian-Janssen Pharmaceutical Ltd.Active, not recruitingAmyloidosis; SystemicChina
-
IRCCS Policlinico S. MatteoRecruiting
-
University Hospital Center of MartiniqueTerminated
-
Kaneka Medical America LLCRecruitingDialysis AmyloidosisUnited States
-
Peking Union Medical College HospitalRecruitingLight Chain (AL) Amyloidosis | Venetoclax | CCND1 TranslocationChina
Clinical Trials on Placebo
-
SamA Pharmaceutical Co., LtdUnknownAcute Bronchitis | Acute Upper Respiratory Tract InfectionKorea, Republic of
-
National Institute on Drug Abuse (NIDA)CompletedCannabis UseUnited States
-
AstraZenecaParexel; Spandauer Damm 130; 14050; Berlin, GermanyCompletedMale Subjects With Type II Diabetes (T2DM)Germany
-
Heptares Therapeutics LimitedCompletedPharmacokinetics | Safety IssuesUnited Kingdom
-
GlaxoSmithKlineCompletedPulmonary Disease, Chronic ObstructiveUnited Kingdom, Netherlands
-
ItalfarmacoCompletedBecker Muscular DystrophyNetherlands, Italy
-
Shijiazhuang Yiling Pharmaceutical Co. LtdXuanwu Hospital, BeijingCompleted
-
GlaxoSmithKlineCompletedInfections, BacterialUnited States
-
West Penn Allegheny Health SystemCompletedAsthma | Allergic RhinitisUnited States