Transthyretin Amyloid Cardiopathy Clinical Trial
Official title:
An Open-Label Study of ION-682884 in Patients With TTR Amyloidosis Who Have Completed a 24-Open Label Study of Inotersen for TTR Amyloidosis Cardiomyopathy
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 ION-682884, 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. This study drug will only be administered to patients who have completed a 24-month study of a similar drug, inotersen (clinicaltrials.gov identifier NCT037028289).The study also aims to determine the tolerability and safety of this drug when administered over a 36+-month period to patients with TTR amyloid cardiomyopathy. The study duration is open-ended and will continue either until this agent is approved by the FDA, or production is discontinued based on results of ongoing double-blinded studies.
The study is limited to those patients who have completed 24 months in our single-center open-label trial of inotersen for amyloid cardiomyopathy (NCT037028289). Patients must have an estimated glomerular filtration rate of greater than 30 and a platelet count greater than 130,000. They will have either wildtype or mutant transthyretin cardiomyopathy. It is anticipated that up to 17 patients will be eligible for the study, age 65-85 years. Research design: After completion of the 24 months in the inotersen study, patients will undergo their final visit and assessment. This will include an echocardiogram, lab work, 6-minute walk test, cardiopulmonary exercise testing and, in those without a pacemaker, a cardiac MRI. If the lab work from the end of study confirms eligibility for the new study, patients will be offered the option of continuing with the TTR-lowering drug, ION-682884. After informed consent the patient will be supplied with prefilled syringes containing ION-682884 and the first injection administered. They will return for follow up visits at six weeks, 12 weeks, three months, and six months thereafter. At each six-monthly visit they will undergo the same testing as they had in the inotersen study, namely laboratory measurements, 6-minute walk test, cardiopulmonary exercise testing, echocardiogram and, unless contraindicated, cardiac MRI. The patients will remain in the study for an open-ended period of time until study ending criteria occur (reduction in the glomerular filtration rate to less than 30 or platelet count with a significant fall) or until the drug is FDA-approved or the manufacturer or principal investigator terminates the study. Because ION-682884 is an antisense oligonucleotide similar to inotersen and because inotersen has been associated with thrombocytopenia and worsening renal function, patients will have weekly lab draws done in their own home for safety monitoring. These bloods will be used to measure platelet function every week, and renal function every other week. This is currently mandated by the Food and Drug administration in the double-blinded study of ION-682884 but the frequency of blood draws may be decreased overtime depending on the interim safety analysis results from that study and FDA evaluation of that data. ;
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