Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy

NCT01737398 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: ISIS 420915-CS2
• Study Type: interventional
• Target: 173
• Locations: 10 countries
• Sites: 24

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).

Conditions

FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis

Keywords

FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis

Outcome Measures

Primary Outcomes (2)

• Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at 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

  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 Outcomes (17)

• Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66

  Baseline and Week 66

• Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66

  Baseline and Week 66

• Change From Baseline In Modified Body Mass Index (mBMI) at Week 65

  Baseline and Week 65

• Change From Baseline In Body Mass Index (BMI) at Week 65

  Baseline and Week 65

• Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66

  Baseline and Week 66

Study Arms (2)

Inotersen

ACTIVE COMPARATOR

300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks

Drug: Inotersen

Placebo

ACTIVE COMPARATOR

Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks

Drug: Placebo

Interventions

Inotersen DRUG

Also known as: TEGSEDI, IONIS-TTR Rx, ISIS 420915

Inotersen

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 82 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (24)

University of California, Irvine

Orange, California, 92868, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University Bayview Medical Center

Baltimore, Maryland, 21205, United States

Location

Boston University School of Medicine - Amyloid Treatment & Research Program

Boston, Massachusetts, 02118, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Columbia University Medical Center - The Neurological Institute

New York, New York, 10032, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Penn Presbyterian Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

FLENI

Buenos Aires, Argentina

Location

Federal University of Rio de Janeiro - University Hospital

Rio de Janeiro, CEP 21941913, Brazil

Location

AACD

São Paulo, Brazil

Location

UNIFESP

São Paulo, Brazil

Location

CHU Henri Mondor - Department of Neurology

Créteil, 94000, France

Location

CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network

Le Kremlin-Bicêtre, 94275, France

Location

UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin

Münster, 48149, Germany

Location

Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"

Messina, Sicily, 98124, Italy

Location

Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Auckland City Hospital

Auckland, New Zealand

Location

CHLN - Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

CHP-HGSA, Unidade Clinica de Paramiloidose

Porto, 4099-001, Portugal

Location

Hospital Universitari Vall D' Hebron

Barcelona, 08035, Spain

Location

Hospital Clínic

Barcelona, 08036, Spain

Location

University College London - National Amyloidosis Centre

London, NW3 2PF, United Kingdom

Location

Related Publications (11)

• 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.

  PMID: 29972757 RESULT

• 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.

  PMID: 35799473 DERIVED

• 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.

  PMID: 35766224 DERIVED

• 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.

  PMID: 34355354 DERIVED

• 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.

  PMID: 34125267 DERIVED

• 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.

  PMID: 32833564 DERIVED

• 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.

  PMID: 32654212 DERIVED

• 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.

  PMID: 32654156 DERIVED

• 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.

  PMID: 31853709 DERIVED

• 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.

  PMID: 30219500 DERIVED

• 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.

  PMID: 30169969 DERIVED

MeSH Terms

Conditions

Amyloid Neuropathies, Familial; Amyloidosis

Interventions

Inotersen

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Amyloid Neuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amyloidosis, Familial; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Proteostasis Deficiencies

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

patients@ionisph.com

800-679-4747

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 27, 2012
• First Posted: November 29, 2012
• Study Start: March 15, 2013
• Primary Completion: March 3, 2017
• Study Completion: November 7, 2017
• Last Updated: July 17, 2019
• Results First Posted: January 23, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2); PT (2); AR (1); NZ (1); US (9); FR (2); BR (3); ES (2); DE (1); GB (1)