safety, efficacy and pharmacokinetics of doxycycline plus tauroursodeoxycholic acid in transthyretin amyloidosis

Conditions: Transthyretin Amyloidosis

Summary: this study is being conducted to explore the potential benefits of a twelve-month doxycycline (at the best tolerated dose of 200 mg/day) and tauroursodeoxycholic acid (750 mg/day) treatment on disease progression in patients affected by transthyretin amyloidosis, including: 1) patients not eligible for liver transplantation; 2) patients eligible for liver transplantation, as a "bridge" therapy between the time of diagnosis and surgery, with the aim of stabilizing the disease; 3) patients showing disease progression after liver transplantation performed since at least 1 year. it is a phase ii, therapeutic exploratory, two-part, 18-month, single centre, prospective study. part i is a 12-month, open label treatment period in which doxycycline (200 mg/day, continuously) and tauroursodeoxycholic acid (750 mg/day continuously) are administered to 40 consenting subjects with transthyretin amyloidosis. part ii is a withdrawal period in which subjects will be monitored for disease progression. during part i, subjects will be evaluated at baseline (study day 0), and then after 3, 6, 9 and 12 months of doxycycline plus tauroursodeoxycholic acid treatment or at premature treatment discontinuation; during part ii, they will be assessed at months 15 and 18. monthly phone contacts and blood tests will be performed to monitor potential adverse events.


Eligibility criteria:
inclusion criteria: * histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in congo red-stained tissue specimens; * molecular definition of the transthyretin (ttr) mutation or immunohistochemical staining of amyloid fibrils with anti-ttr antibody; * ecog performance status (ps) 0, 1, 2; * new york heart association (nyha) class ≤iii * systolic blood pressure ≥100 mmhg (standing) * must have symptomatic organ involvement with amyloid to justify therapy; must have evidence of neuropathy and/or cardiomyopathy progression after liver transplantation performed since at least one year. * contraception for women of childbearing potential. medically approved contraception could include abstinence. a negative serum pregnancy test is required prior to initiation of treatment with study medication. exclusion criteria: * liver transplantation in the previous 12 months or liver transplantation anticipated in less than 6 months; * alt and/or ast ≥ 2 x upper normal limit (unl); * alkaline phosphatase ≥ 2 x unl; * creatinine clearance \< 30 ml/min; * any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study; * echocardiographic ejection fraction \< 50%; * other neuropathies, due to vitamin b12 deficiency, alcoholism, hypothyroidism, uremia, diabetes mellitus, vasculitides; * history of poor compliance; * history of hypersensitivity to any of the ingredients of the study therapies; * use of any investigational drug, device (or biologic) within 4 weeks prior to study entry or during the study.

Keywords: amyloidosis transthyretin doxycycline tauroursodeoxycholic acid