ION-682884 in Patients With TTR Amyloid Cardiomyopathy (NCT04843020) | Clinical Trial Compass
WithdrawnPhase 2
ION-682884 in Patients With TTR Amyloid Cardiomyopathy
Stopped: no subjects available
United States0Started 2021-06-01
Plain-language 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 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.
Who can participate
Age range65 Years – 85 Years
SexALL
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Inclusion criteria
✓. Patients should, in the opinion of the Investigator, be in a stable state in terms of New York Heart Association (NYHA) class. Class I-III patients will be recruited.
✓. Age 65-85 years
✓. Male, or non-pregnant, non-lactating females. If a male partners with a premenopausal woman, he must be willing to use the following methods of contraception: condoms, oral/hormonal contraception, Intrauterine Device, diaphragm, or abstinence (all patients are either male of post-menopausal) (NB: There will be no premenopausal women in the proposed study)
✓. Written informed consent to be obtained prior to study treatment
✓. Willingness to return to the treating center for follow-up
✓. Willingness and ability to self-administer, or to have spouse administer subcutaneous injections of study drug every 4 weeks.
✓. Willingness to take oral Vitamin A supplementation throughout the study and for 3 months thereafter.
Exclusion criteria
✕. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) \> 2.0 × upper limit of normal (ULN)
What they're measuring
1
Echocardiographic change
Timeframe: 48 months
2
Change in cardiac MRI
Timeframe: 48 months
3
Change in cardiac MRI
Timeframe: 48 months
4
change in 6 minute walk
Timeframe: 48 months
5
change in cardiopulmonary testing
Timeframe: 48 months
6
change in the cardiac biomarker NTproBNP
Timeframe: 48 months
7
change in the cardiac biomarker high-sensitivity troponin
✕. Total bilirubin ≥ 1.5 × ULN (patients with total bilirubin ≥ 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and known to have Gilbert's disease)
✕. Platelets \< 125 × 109/L
✕. Urine protein creatinine ratio (UPCR) ≥ 750 mg/g. In the event of UPCR above this threshold ineligibility may be confirmed by a repeat random spot UPCR ≥ 750 mg/g
✕. Positive test for blood (including trace) on urinalysis that is subsequently confirmed with urine microscopy showing \> 5 red blood cells per high power field and is related to glomerulopathies. In women, this exclusion criterion must be assessed outside of menstrual period. If in the opinion of the Investigator the hematuria is not considered related to glomerulopathies the patient may be considered eligible, pending proper follow-up and a discussion with the Medical Monitor. Patients with history of bladder cancer must have been treated with curative intent and have not presented recurrence within the prior 5 years
✕. Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 at Screening. If the eGFR is thought to be underestimated, the CKD-EPI creatinine-cystatin C equation can be used for confirmation.
✕. Abnormal thyroid function tests with clinical significance per Investigator judgement
✕. Hemoglobin A1c (HbA1c) \> 9.5% 8. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For patients with CKD and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25.