Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis

• Status: Completed
• Trial end date: 2015-10-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: IRCCS Policlinico S. Matteo
• Treatments: Doxycycline; Taurochenodeoxycholic Acid; Tauroursodeoxycholic acid; Ursodoxicoltaurine

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.