24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients

NCT03702829 | Terminated Phase 2 DMC FDA Drug

• 1 other identifier: 2018P001436
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

Transthyretin is a protein produced in the liver that transports thyroid hormone and vitamin A. A single substitution of an amino acid in the structure of TTR can result in a relatively unstable protein, the breakdown products of which (predominantly monomers) aggregate abnormally and produce proteinaceous deposits in nerves and the heart. These deposits are known as amyloid and produce progressive nerve and heart damage. Amyloidosis due to a mutant TTR is usually an autosomal dominant and hence is a familial condition. Wild-type TTR is also capable of producing amyloid deposits which predominantly involves the heart (rather than the nervous system) resulting in a progressive decrease in cardiac function with increasing signs of heart failure. This study aims to determine whether subcutaneous injection of an antisense oligonucleotide drug, known as inotersen, that has been specifically designed to reduce production of the protein transthyretin by the liver, can slow or stop the progression of TTR amyloid cardiomyopathy as compared to historical controls, using advanced echocardiography and cardiac MRI. The study also aims to determine the tolerability and safety of this drug when administered over a 24-month period to patients with TTR amyloid cardiomyopathy.

Conditions

Amyloidosis

Keywords

wild-type transthyretin amyloidosis; TTR amyloidosis; familial amyloid cardiomyopathy; mutant transthyretin amyloidosis

Outcome Measures

Primary Outcomes (1)

• Systolic strain imaging by echocardiographic

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

  Month 6

Secondary Outcomes (9)

• Systolic strain evaluation by echocardiography

  Month 12

• Systolic strain evaluation by echocardiography

  Month 18

• Systolic strain evaluation by echocardiography

  Month 24

• LV mass measurement by Cardiac MRI (cMRI) (units = grams)

  Month 6

• LV mass measurement by Cardiac MRI (cMRI) (units = grams)

  Month 12

Study Arms (1)

Experimental Drug

EXPERIMENTAL

Inotersen, a transthyretin (TTR) antisense oligonucleotide. Administered subcutaneously weekly. Each dose shall contain 300 mg of active drug. Subsequent visits will occur at 3, 6, 12, 18 and 24 months. Every 2 weeks, blood will be monitored for renal function and platelet count and urine will be tested by dipstick for proteinuria.

Drug: Inotersen

Interventions

Inotersen DRUG

Open Label Study

Also known as: Antisense Oligonucleotide

Experimental Drug

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have ATTR amyloidosis, defined as is defined as an echocardiographic appearance of left ventricular wall thickness of 13 mm or more, in the absence of uncontrolled hypertension, and with EITHER a positive biopsy for amyloid, which also stains positive for TTR by immunochemistry or mass spectrometry OR a positive cardiac technetium pyrophosphate scan with isotope uptake in the heart equal or greater to rib uptake and with no evidence of a plasma cell dyscrasia.
• For patients meeting the above criteria, wild-type TTR amyloidosis (ATTRwt)will be defined as having transthyretin genetic sequencing negative for a mutation. Mutant/hereditary TTR (ATTRh) will be defined as TTR amyloid cardiomyopathy with TTR sequencing showing an amyloidogenic mutation. A positive biopsy can be from any organ, providing that the echocardiographic appearance is typical of amyloidosis.
• 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 18-85 years
• Male, or non-pregnant, non-lactating females. If a woman is premenopausal, or 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
• If diagnosis is made by tissue biopsy histochemical diagnosis (positive stains for TTR in absence of staining for light chains, or AA amyloid) in the presence of green birefringent material in Congo red-stained tissue specimens or sulfated Alcian blue stain typical for amyloid deposition. NB. All patients will have had a definitive diagnosis of TTR amyloidosis made prior to study entry, either by tissue biopsy or positive PYP scan, and all will have been genotyped. No further diagnostic testing will need to be done at or after study entry.
• If diagnosis is made by nuclear imaging, a positive technetium pyrophosphate scan, characterized by isotope uptake in the heart of an intensity equal to or greater than, rib uptake.
• 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.
• Willingness to take daily oral Vitamin A supplementation throughout the study and for 3 months thereafter.

You may not qualify if:

• Patients with NYHA class 4 congestive heart failure despite optimal heart failure management.
• 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), or ongoing non-cardiac disease that, in the opinion of the investigator, will likely need hospitalization over the next 2 years (e.g. active cancer) .
• Prior liver transplantation or liver transplantation anticipated in less than 6 months
• ALT and/or AST 2 x ULN and/or Alkaline phosphatase 2 x UNL; Or bilirubin greater than 1.5 times UL (patients with bilirubin ≥1.5 x ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and genetic testing confirming Gilbert's disease)
• Glomerular filtration rate (EGFR) \< 45 ml/min/1.73m2
• A history of glomerulonephritis,
• Platelets less than 125×109/L
• TSH values outside normal range in subjects untreated for thyroid disease, unless mildly elevated with normal T4, and deemed by current standards not to need treatment.
• Uncontrolled hypertension (blood pressure \>160/100)
• Acute coronary syndrome or major surgery within 3 months of screening
• Anticipated survival less than 2 years
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to first dose of study drug
• Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or prostate that has been successfully treated
• Positive test result for HIV, hepatitis B, or hepatitis C
• Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study

Sponsors & Collaborators

• Brigham and Women's Hospital: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Amyloidosis

Interventions

Inotersen; 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 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: October 9, 2018
• First Posted: October 11, 2018
• Study Start: February 28, 2019
• Primary Completion: December 31, 2021
• Study Completion: January 15, 2022
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)