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.

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.