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

• Register: ClinicalTrials.gov
• Last refreshed on: 22 August 2016
• Main ID: NCT02627820
• Date of registration: 19/11/2015
• Prospective Registration: Yes
• Primary sponsor: Brigham and Women's Hospital
• Public title: The Effect of an Antisense Oligonucleotide to Lower Transthyretin (TTR) Levels on the Progression of -Wild-type TTR Involving the Heart
• Scientific title: An 18 Month Open Label Study Of The Tolerability And Efficacy Of An Antisense Oligonucleotide In Patients With Wild-Type Transthyretin Amyloid Cardiomyopathy (Senile Systemic Amyloidosis)
• Date of first enrolment: January 2016
• Target sample size: 0
• Recruitment status: Withdrawn
• URL: https://clinicaltrials.gov/show/NCT02627820
• Study type: Interventional
• Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 2

Contacts

• Name: Rodney H Falk, MD
• Affiliation: Brigham and Women's Hospital

Key inclusion & exclusion criteria

All patients with documented SSA will be considered for inclusion. SSA is defined as an
echocardiographic appearance of left ventricular wall thickness of 13 mm or more, in the
absence of uncontrolled hypertension, and with a positive biopsy for amyloid, which also
stains positive for TTR by immunochemistry or mass spectrometry. For the definition of
SSA, genetic testing should be negative for a mutation. Identification of amyloid type is
standard of care for all patients seen at the Cardiac Amyloidosis Program and the presence
of a clinically -obtained positive biopsy will be a requirement for study inclusion. The
positive biopsy can be from any organ, providing that the echocardiographic appearance is
typical of amyloidosis.

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.



Age minimum: 50 Years
Age maximum: 90 Years
Gender: Both

Health Condition(s) or Problem(s) studied

Amyloidosis

Intervention(s)

Drug: Isis 420915/GSK 299872

Primary Outcome(s)

Systolic strain imaging by echocardiographic speckle tracking [Time Frame: Month 12]

Secondary Outcome(s)

LV extracellular component as determined by cMRI (units = % of total LV mass) [Time Frame: 12 months]

LV extracellular component as determined by cMRI (units = % of total LV mass) [Time Frame: 18 months]

LV mass measurement by Cardiac MRI (cMRI) (units = grams) [Time Frame: 18 months]

Systolic strain evaluation by echocardiography [Time Frame: Secondary analysis will occur at 18 months]

Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm) [Time Frame: 12 months]

Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm) [Time Frame: 18 months]

Echocardiographic determination of LV ejection fraction (units = %) [Time Frame: 18 months]

Extent of cMRI late gadolinium enhancement of the LV (unites = % of area) [Time Frame: 12 months]

LV cellular component as determined by cMRI (units = % of total LV mass) [Time Frame: 18 months]

Echocardiographic determination of LV ejection fraction (units = %) [Time Frame: 12 months]

LV cellular component as determined by cMRI (units = % of total LV mass) [Time Frame: 12 months]

Extent of cMRI late gadolinium enhancement of the LV (unites = % of area) [Time Frame: 18 months]

LV mass measurement by Cardiac MRI (cMRI) (units = grams) [Time Frame: Month 12]

Secondary ID(s)

2015-P001574

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Ionis Pharmaceuticals, Inc.

GlaxoSmithKline