The Effect of an Antisense Oligonucleotide to Lower Transthyretin (TTR) Levels on the Progression of -Wild-type TTR Involving the Heart

NCT02627820 | Withdrawn Phase 2

• 1 other identifier: 2015-P001574
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

ATTRwt (also known as senile systemic, or senile cardiac amyloidosis) is a progressive heart disease, causing congestive heart failure. It is caused by amyloid protein deposits in the heart, that are derived from a normal protein, TTR, made in the liver. The aim of the study is to determine whether lowering the blood levels of TTR, by a weekly injection of a compound designed specifically to do this, will slow the progression of the disease when treated patients are compared to previously-followed patients who were not receiving this drug. The study also aims to determine how well this drug is tolerated and the existence and severity of any drug side-effects.

Conditions

Amyloidosis

Keywords

Senile; ATTRwt; wild-type transthyretin amyloidosis

Outcome Measures

Primary Outcomes (1)

• Systolic strain imaging by echocardiographic speckle tracking

  The primary echocardiographic parameter to be measured will be longitudinal left ventricular (LV) strain (units = % LV longitudinal shortening) as compared to baseline.

  Month 12

Secondary Outcomes (13)

• Systolic strain evaluation by echocardiography

  Secondary analysis will occur at 18 months

• Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm)

  12 months

• Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm)

  18 months

• Echocardiographic determination of LV ejection fraction (units = %)

  12 months

• Echocardiographic determination of LV ejection fraction (units = %)

  18 months

Study Arms (1)

Experimental Drug

EXPERIMENTAL

Isis 420915/GSK 299872, an antisense oligonucleotide. Administered subcutaneously three times per week for the first week, and then weekly for 18 months. Each dose shall contain 300 mg of active drug.

Drug: Isis 420915/GSK 299872

Interventions

Isis 420915/GSK 299872 DRUG

Open label study in comparison to historic control.

Also known as: Antisense oligonucleotide

Experimental Drug

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients should, in the opinion of the Investigator, be in a stable state in terms of NYHA class. Class I-III patients will be recruited.
• Age 50-90 years
• Male or non-pregnant, non-lactating females. If a woman is premenopausal, or a male partners with a premenopausal woman, she/he must be willing to use the following methods of contraception: condoms, oral/hormonal contraception, Intrauterine Device, diaphragm, or abstinence
• Written informed consent to be obtained prior to study treatment
• Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens
• Molecular definition of the absence of a TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody and negative genetic testing for a TTR mutation.
• Willingness to return to the treating center for follow-up.
• Willingness and ability to self-administer, or to have spouse administer weekly subcutaneous injections of study drug.

You may not qualify if:

• Patients with NYHA class 4 congestive heart failure.
• Concomitant non-amyloid heart disease that might, in the opinion of the investigator, cause changes in strain imaging on serial follow-up (e.g. aortic stenosis of greater than mild severity, unstable coronary artery disease).
• Prior liver transplantation or liver transplantation anticipated in less than 6 months;
• ALT and/or AST ³ 2 x ULN and/or Alkaline phosphatase ³ 2 x UNL;
• Estimated glomerular filtration rate (EGFR) \< 50 ml/min;
• Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
• History of poor compliance with medications or medical treatment, based on a review of medical records.
• History of hypersensitivity to any of the ingredients of the study therapy;
• Use of any investigational drug for amyloidosis within 4 weeks prior to study entry or during the study.
• Current use of tafamidis, diflunisal, doxycycline or TUDCA for therapy of amyloidosis.

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• GlaxoSmithKline: collaborator
• Ionis Pharmaceuticals, Inc.: collaborator

MeSH Terms

Conditions

Amyloidosis

Interventions

Oligonucleotides, Antisense

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Antisense Elements (Genetics); Nucleic Acids, Nucleotides, and Nucleosides; Nucleic Acid Probes; Nucleic Acids; Oligonucleotides; Polynucleotides; Nucleotides; Molecular Probes; Laboratory Chemicals; Specialty Uses of Chemicals; Chemical Actions and Uses

Study Officials

• Rodney H Falk, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Brigham and Women's Cardiac Amyloidosis Program

Study Record Dates

• First Submitted: November 19, 2015
• First Posted: December 11, 2015
• Study Start: January 1, 2016
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: August 10, 2016

Record last verified: 2016-01