Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)

NCT02175004 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: ISIS 420915-CS32013-004561-13
• Study Type: interventional
• Target: 135
• Locations: 9 countries
• Sites: 22

Brief Summary

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

Conditions

FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis

Keywords

FAP; Familial Amyloid Polyneuropathy; TTR; Transthyretin; Amyloidosis

Outcome Measures

Primary Outcomes (8)

• Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug

  An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Change From Baseline in Vital Signs

  Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Change From Baseline in Weight

  As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values

  Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10\^9/L to 400×10\^9/L.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)

  Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders

  A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes

  From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

• Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Secondary Outcomes (20)

• Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

• Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

• Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

• Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

• Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156

  Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Study Arms (2)

Previous Placebo-Inotersen 300 mg

EXPERIMENTAL

Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.

Drug: Inotersen

Previous Inotersen-Inotersen 300 mg

EXPERIMENTAL

Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.

Drug: Inotersen

Interventions

Inotersen DRUG

Inotersen SC

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

Previous Inotersen-Inotersen 300 mg; Previous Placebo-Inotersen 300 mg

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (22)

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

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

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 Clinic

Barcelona, 08036, Spain

Location

University College London - National Amyloidosis Centre

London, NW3 2PF, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 35908242 DERIVED

• 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

• 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

• 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.

  PMID: 32343462 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 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 12, 2014
• First Posted: June 26, 2014
• Study Start: June 26, 2014
• Primary Completion: September 11, 2020
• Study Completion: January 7, 2021
• Last Updated: November 18, 2023
• Results First Posted: February 9, 2023

Record last verified: 2023-11

Locations

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