Clinical trial NCT02175004: Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)
Official title: An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: 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: 2014-06-26
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Detailed description: Familial Amyloid Polyneuropathy (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.

IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.

This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Eligibility criteria: Inclusion Criteria:

* Satisfactory completion of dosing \& efficacy assessments in ISIS 420915-CS2

Exclusion Criteria:

* Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study

Primary outcomes:
measure: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Change From Baseline in Vital Signs
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Change From Baseline in Weight
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
timeFrame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
measure: Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Secondary outcomes:
measure: Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
measure: Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
measure: Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
measure: Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
measure: Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
measure: Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
measure: Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
measure: Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
timeFrame: Baseline, Weeks 78 and 156
measure: Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score
timeFrame: Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
measure: Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
timeFrame: Baseline, Weeks 78 and 156
measure: Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
timeFrame: Weeks 78 and 156
measure: Change From Baseline in Transthyretin (TTR) Level
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
measure: Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
timeFrame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
measure: Ctrough: Trough Plasma Concentration of ISIS 420915
timeFrame: Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5
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: 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: 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 Clinic
city: London
country: United Kingdom
facility: University College London - National Amyloidosis Centre
Study officials:
References:
citation: Brannagan TH, Coelho T, Wang AK, Polydefkis MJ, Dyck PJ, Berk JL, Drachman B, Gorevic P, Whelan C, Conceicao I, Plante-Bordeneuve V, Merlini G, Obici L, Plana JMC, Gamez J, Kristen AV, Mazzeo A, Gentile L, Narayana A, Olugemo K, Aquino P, Benson MD, Gertz M; NEURO-T. T. R. Open-Label Extension Investigators. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol. 2022 Dec;269(12):6416-6427. doi: 10.1007/s00415-022-11276-8. Epub 2022 Jul 31.
citation: 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.
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: Brannagan TH, Wang AK, Coelho T, Waddington Cruz M, Polydefkis MJ, Dyck PJ, Plante-Bordeneuve V, Berk JL, Barroso F, Merlini G, Conceicao I, Hughes SG, Kwoh J, Jung SW, Guthrie S, Pollock M, Benson MD, Gertz M; NEURO-TTR open-label extension investigators. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. 2020 Aug;27(8):1374-1381. doi: 10.1111/ene.14285. Epub 2020 May 29.