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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Isis Pharmaceuticals
Information provided by (Responsible Party):
Isis Pharmaceuticals
ClinicalTrials.gov Identifier:
First received: November 27, 2012
Last updated: August 21, 2014
Last verified: August 2014

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: 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:

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 ]
  • Efficacy of ISIS-TTR Rx as measured by change from baseline in the Norfolk Quality of Life Diabetic Neuropathy questionnaire [ 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 ]
    • Modified Body Mass Index and Body Mass Index
    • Individual components of the mNIS+7
    • NIS+7

  • 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.


Ages Eligible for Study:   18 Years to 82 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Stage 1 and Stage 2 FAP patients with the following:

    1. NIS score within protocol criteria
    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 of child-bearing potential must use appropriate contraception and must be non-pregnant and non-lactating. Males engaged in relations of child-bearing potential must 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 (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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Contact: Isis Pharmaceuticals 800-679-4747 patients@isisph.com

United States, California
University of California, Irvine Recruiting
Orange, California, United States, 92868
Contact: Veronica Martin    714-456-7760    vero@uci.edu   
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 Recruiting
Baltimore, Maryland, United States, 21205
Contact: Kathy Burks    410-502-6006    kburks1@jhmi.edu   
Principal Investigator: Michael Polydefkis, MD         
United States, Massachusetts
Boston University School of Medicine - Amyloid Treatment & Research Program Recruiting
Boston, Massachusetts, United States, 02118
Contact: Victoria Lattanzi    617-638-4494    vlattanz@bu.edu   
Principal Investigator: John Berk, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Morie Gertz, MD    507-284-2511    Gertz.morie@mayo.edu   
Principal Investigator: Morie Gertz, MD         
United States, New York
Columbia University Medical Center - The Neurological Institute Recruiting
New York, New York, United States, 10032
Contact: Thomas Brannagan    212-305-0405    tb2325@cumc.columbia.edu   
Principal Investigator: Thomas Brannagan, MD         
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10029
Contact: Ghimja Berhanu    212-241-1617    ghimja.berhanu@mssm.edu   
Principal Investigator: Peter Gorevic, MD         
CHU Henri Mondor - Department of Neurology Recruiting
Creteil, France, 94000
Contact: Prof Plante    +33 6 62 32 83 91    vplante@free.fr   
Principal Investigator: Violaine Plante-Bordeneuve, MD, Ph.D.         
CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network Recruiting
Le Kremlin Bicetre, France, 94275
Contact: Prof David Adams    +33 1 45 21 27 11    david.adams@bct.aphp.fr   
Principal Investigator: David Adams, MD, Ph.D.         
UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin Recruiting
Munster, Germany, 48149
Contact: Hartmut Schmidt, Prof.    +49 251 83 57935    hepar@ukmuenster.de   
Principal Investigator: Hartmut Schmidt, Prof.         
Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo Recruiting
Pavia, Italy, 27100
Contact: Giampaolo Merlini, Prof.    +39(0)382-502994    gmerlini@unipv.it   
Principal Investigator: Giampaolo Merlini, Prof.         
CHLN - Hospital de Santa Maria Recruiting
Lisbon, Portugal, 1649-035
Contact: Dra. Conceicao    +351 217 930 629    imsconceicao@gmail.com   
Principal Investigator: Isabel Conceicao, MD         
CHP-HGSA, Unidade Clinica de Paramiloidose Recruiting
Porto, Portugal, 4099-001
Contact: Dra. Teresa Coelho    +351 226 068 114    tcoelho@netcabo.pt   
Principal Investigator: Teresa Coelho, MD         
United Kingdom
University College London - National Amyloidosis Centre Recruiting
London, United Kingdom, NW3 2PF
Contact: Thirusha Lane    020 7433 2759    t.lane@ucl.ac.uk   
Principal Investigator: Carol Whelan, MD         
Sponsors and Collaborators
Isis Pharmaceuticals
  More Information

Additional 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: August 21, 2014
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
Germany: Ministry of Health
Italy: Ministry of Health

Keywords provided by Isis Pharmaceuticals:
Familial Amyloid Polyneuropathy

Additional relevant MeSH terms:
Amyloid Neuropathies, Familial
Amyloidosis, Familial
Amyloid Neuropathies
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on September 18, 2014