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

Phase 2

Withdrawn

• Conditions: Amyloidosis
• Interventions: Drug: Isis 420915/GSK 299872

• Registration Number: NCT02627820
• Lead Sponsor: Brigham and Women's Hospital

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-11-19
• Study First Submitted QC: 2015-12-09
• Study First Posted: 2015-12-11
• Status Verified: 2016-01
• Study Start: 2016-01
• Last Update Submitted: 2016-08-09
• Last Update Posted: 2016-08-10
• Primary Completion: 2018-12
• Study Completion: 2018-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. 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.
2. Age 50-90 years
3. 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
4. Written informed consent to be obtained prior to study treatment
5. Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens
6. 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.
7. Willingness to return to the treating center for follow-up.
8. Willingness and ability to self-administer, or to have spouse administer weekly subcutaneous injections of study drug.

Exclusion Criteria

1. Patients who, in the opinion of the Investigator, require further adjustment of diuretics at the time of screening to achieve optimal treatment of heart failure. Once stable for 2 weeks, patients in Class I-III will become eligible for inclusion.
2. Patients with NYHA class 4 congestive heart failure.
3. 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).
4. Prior liver transplantation or liver transplantation anticipated in less than 6 months;
5. ALT and/or AST ³ 2 x ULN and/or Alkaline phosphatase ³ 2 x UNL;
6. Estimated glomerular filtration rate (EGFR) < 50 ml/min;
7. Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
8. History of poor compliance with medications or medical treatment, based on a review of medical records.
9. History of hypersensitivity to any of the ingredients of the study therapy;
10. Use of any investigational drug for amyloidosis within 4 weeks prior to study entry or during the study.
11. Current use of tafamidis, diflunisal, doxycycline or TUDCA for therapy of amyloidosis.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental Drug	Isis 420915/GSK 299872	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.

Primary Outcome Measures

Name	Time	Method
Systolic strain imaging by echocardiographic speckle tracking	Month 12	The primary echocardiographic parameter to be measured will be longitudinal left ventricular (LV) strain (units = % LV longitudinal shortening) as compared to baseline.

Secondary Outcome Measures

Name	Time	Method
Systolic strain evaluation by echocardiography	Secondary analysis will occur at 18 months	The primary echocardiographic parameter measured will be longitudinal left ventricular (LV) strain (units = %).
Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm)	18 months
Echocardiographic determination of LV ejection fraction (units = %)	18 months
LV mass measurement by Cardiac MRI (cMRI) (units = grams)	Month 12
LV cellular component as determined by cMRI (units = % of total LV mass)	18 months
LV extracellular component as determined by cMRI (units = % of total LV mass)	18 months
Extent of cMRI late gadolinium enhancement of the LV (unites = % of area)	18 months