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

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ClinicalTrials.gov Identifier: NCT02627820
Recruitment Status : Withdrawn
First Posted : December 11, 2015
Last Update Posted : August 10, 2016
Sponsor:
Collaborators:
GlaxoSmithKline
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Rodney H. Falk, MD, 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.

Condition or disease Intervention/treatment Phase
Amyloidosis Drug: Isis 420915/GSK 299872 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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)
Study Start Date : January 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Experimental Drug
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
Open label study in comparison to historic control.
Other Name: Antisense oligonucleotide




Primary Outcome Measures :
  1. Systolic strain imaging by echocardiographic speckle tracking [ Time Frame: 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 :
  1. Systolic strain evaluation by echocardiography [ Time Frame: Secondary analysis will occur at 18 months ]
    The primary echocardiographic parameter measured will be longitudinal left ventricular (LV) strain (units = %).

  2. Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm) [ Time Frame: 12 months ]
  3. Echocardiographic determination of Mean thickness of LV septum and posterior wall (units = mm) [ Time Frame: 18 months ]
  4. Echocardiographic determination of LV ejection fraction (units = %) [ Time Frame: 12 months ]
  5. Echocardiographic determination of LV ejection fraction (units = %) [ Time Frame: 18 months ]
  6. LV mass measurement by Cardiac MRI (cMRI) (units = grams) [ Time Frame: 18 months ]
  7. LV cellular component as determined by cMRI (units = % of total LV mass) [ Time Frame: 12 months ]
  8. LV cellular component as determined by cMRI (units = % of total LV mass) [ Time Frame: 18 months ]
  9. LV extracellular component as determined by cMRI (units = % of total LV mass) [ Time Frame: 12 months ]
  10. LV extracellular component as determined by cMRI (units = % of total LV mass) [ Time Frame: 18 months ]
  11. Extent of cMRI late gadolinium enhancement of the LV (unites = % of area) [ Time Frame: 12 months ]
  12. Extent of cMRI late gadolinium enhancement of the LV (unites = % of area) [ Time Frame: 18 months ]
  13. LV mass measurement by Cardiac MRI (cMRI) (units = grams) [ Time Frame: Month 12 ]


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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02627820


Sponsors and Collaborators
Brigham and Women's Hospital
GlaxoSmithKline
Ionis Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Rodney H Falk, MD Brigham and Women's Hospital

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Responsible Party: Rodney H. Falk, MD, Director, Brigham and Women's Cardiac Amyloidosis Program, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT02627820     History of Changes
Other Study ID Numbers: 2015-P001574
First Posted: December 11, 2015    Key Record Dates
Last Update Posted: August 10, 2016
Last Verified: January 2016

Keywords provided by Rodney H. Falk, MD, Brigham and Women's Hospital:
Senile
ATTRwt
wild-type transthyretin amyloidosis

Additional relevant MeSH terms:
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Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases