Efficacy and Safety of ISIS TTR Rx in Familial Amyloid Polyneuropathy - Full Text View

Purpose

The purpose of this study is to evaluate the efficacy and safety of ISIS TTR Rx given for 65 weeks in patients with Familial Amyloid Polyneuropathy

Condition	Intervention	Phase
Familial Amyloid Polyneuropathy	Drug: ISIS TTR Rx Drug: Placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: transthyretin amyloidosis

U.S. FDA Resources

Further study details as provided by Isis Pharmaceuticals:

Primary Outcome Measures:

Efficacy of ISIS TTR Rx as measured by change from baseline in the modified Neuropathy Impairment Score +7 [ Time Frame: 65 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Efficacy of ISIS TTR Rx based on the change from baseline in the following measures: [ Time Frame: 65 weeks ] [ Designated as safety issue: No ]
- Norfolk Quality of Life Diabetic Neuropathy questionnaire
- Modified Body Mass Index and Body Mass Index
- Individual components of the mNIS+7
- NIS+7
- NIS
Pharmacodynamic effect of ISIS TTR Rx based on the change from baseline in transthyretin and retinol binding protein 4 [ Time Frame: 65 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	195
Study Start Date:	December 2012
Estimated Study Completion Date:	March 2017
Estimated Primary Completion Date:	November 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: ISIS TTR Rx	Drug: ISIS TTR Rx 300 mg ISIS TTR Rx administered subcutaneously 3 times on alternate days in the first week and then once-weekly for 64 weeks.
Active Comparator: Placebo	Drug: Placebo Placebo administered subcutaneously 3 times on alternate days in the first week and then once-weekly for 64 weeks.

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.

ISIS TTR Rx is an antisense drug that decreases 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.

The purpose of this study is to determine if ISIS TTR Rx can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP patients. Patients will receive either ISIS TTR Rx or placebo for 65 weeks.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Stage 1 and Stage 2 FAP patients with the following:
1. NIS score >15 and <85
2. Ability to walk unaided or with the use of no more than one stick/cane
3. Documented transthyretin variant by genotyping
4. Documented amyloid deposit by biopsy
Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. Males must be surgically sterile, abstinent, or if engaged in sexual relations of child-bearing potential, must use 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 (e.g., autoimmune disease)
If previously treated with Vyndaqel®, must have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, must 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 yr 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
Have any other conditions in the opinion of the investigator which could interfere with the patient participating in or completing the study

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01737398

Contacts

Contact: Isis Pharmaceuticals

800-679-4747

info@isisph.com

Locations

United States, California
University of California, Irvine	Recruiting
Orange, California, United States, 92868
Principal Investigator: Annabel Wang, MD
United States, Indiana
Indiana University School of Medicine	Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Merrill Benson, MD 317-278-3426 mdbenson@iupui.edu
Principal Investigator: Merrill Benson, MD
United States, Maryland
Johns Hopkins University Bayview Medical Center	Not yet recruiting
Baltimore, Maryland, United States, 21205
Principal Investigator: Michael Polydefkis, MD
United States, Massachusetts
Boston University School of Medicine - Amyloid Treatment & Research Program	Not yet recruiting
Boston, Massachusetts, United States, 02118
Contact: Liz Hankinson 617-638-4494 hankea4@bu.edu
Principal Investigator: John Berk, MD
United States, Minnesota
Mayo Clinic	Not yet recruiting
Rochester, Minnesota, United States, 55905
Principal Investigator: Morie Gertz, MD
United States, New York
Columbia University Medical Center - The Neurological Institute	Recruiting
New York, New York, United States, 10032
Principal Investigator: Thomas Brannagan, MD
France
CHU Henri Mondor - Department of Neurology	Not yet recruiting
Creteil, France, 94000
Principal Investigator: Plante-Bordeneuve Violaine, MD, Ph.D.
CHU Bicetre Aphp French Referral Center for FAF/Cornamyl Network	Not yet recruiting
Le Kremlin Bicetre, France, 94275
Principal Investigator: David Adams, MD, Ph.D.
Portugal
CHLN - Hospital de Santa Maria	Not yet recruiting
Lisbon, Portugal, 1649-035
Principal Investigator: Isabel Conceicao, MD
CHP-HGSA, Unidade Clinica de Paramiloidose	Not yet recruiting
Porto, Portugal, 4099-001
Principal Investigator: Teresa Coelho, MD
United Kingdom
University College London - National Amyloidosis Centre	Not yet recruiting
London, United Kingdom, NW3 2PF
Principal Investigator: Carol Whelan, MD

Sponsors and Collaborators

Isis Pharmaceuticals

GlaxoSmithKline

More Information

No publications provided

Responsible Party:	Isis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01737398 History of Changes
Other Study ID Numbers:	ISIS 420915-CS2
Study First Received:	November 27, 2012
Last Updated:	April 30, 2013
Health Authority:	United States: Food and Drug Administration United Kingdom: Medicines and Healthcare Products Regulatory Agency France: Ministry of Health Portugal: National Pharmacy and Medicines Institute

Keywords provided by Isis Pharmaceuticals:

FAP
Familial Amyloid Polyneuropathy

Additional relevant MeSH terms:

Amyloid Neuropathies, Familial
Amyloidosis, Familial
Polyneuropathies
Amyloid Neuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases

Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Metabolic Diseases
Amyloidosis
Proteostasis Deficiencies

ClinicalTrials.gov processed this record on May 16, 2013