Clinical trial NCT01737398: Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: FAP
Familial Amyloid Polyneuropathy
TTR
Transthyretin
Amyloidosis
Keywords: FAP
Familial Amyloid Polyneuropathy
TTR
Transthyretin
Amyloidosis
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2012-11-29
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Maximum age (years): 82
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline In The Norfolk Quality Of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
timeFrame: Baseline and Week 66
Secondary outcomes:
measure: Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline In Modified Body Mass Index (mBMI) at Week 65
timeFrame: Baseline and Week 65
measure: Change From Baseline In Body Mass Index (BMI) at Week 65
timeFrame: Baseline and Week 65
measure: Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline in Modified +7 at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline in NIS+7 at Week 66
timeFrame: Baseline and Week 66
measure: Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set
timeFrame: Baseline and Week 65
measure: Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup
timeFrame: Baseline and Week 65
measure: Change From Baseline in Transthyretin (TTR) Level at Week 65
timeFrame: Baseline and Week 65
measure: Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65
timeFrame: Baseline and Week 65
measure: Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65
timeFrame: Week 65
measure: Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65
timeFrame: Week 65
measure: Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65
timeFrame: Week 65
measure: Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65
timeFrame: Week 65
measure: Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65
timeFrame: Week 65
measure: Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65
timeFrame: Week 65
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University Bayview Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine - Amyloid Treatment & Research Program
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - The Neurological Institute
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Buenos Aires
country: Argentina
facility: FLENI
city: Rio de Janeiro
country: Brazil
facility: Federal University of Rio de Janeiro - University Hospital
city: Sao Paulo
country: Brazil
facility: AACD
city: Sao Paulo
country: Brazil
facility: UNIFESP
city: Creteil
country: France
facility: CHU Henri Mondor - Department of Neurology
city: Le Kremlin Bicetre
country: France
facility: CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network
city: Munster
country: Germany
facility: UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin
city: Messina
country: Italy
facility: Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"
state: Sicily
city: Pavia
country: Italy
facility: Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Lisbon
country: Portugal
facility: CHLN - Hospital de Santa Maria
city: Porto
country: Portugal
facility: CHP-HGSA, Unidade Clinica de Paramiloidose
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D' Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic
city: London
country: United Kingdom
facility: University College London - National Amyloidosis Centre
Study officials:
References:
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.