Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
- Conditions
- Transthyretin Amyloidosis
- Interventions
- Registration Number
- NCT01171859
- Lead Sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Brief 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Doxycycline + Tauroursodeoxycholic acid Doxycycline + Tauroursodeoxycholic acid -
- Primary Outcome Measures
Name Time Method Response rate to doxycycline + tauroursodeoxycholic acid treatment One year A responder is a subject with:
* a modified body mass index (mBMI) reduction of less than 10% and a change in the Neurologic Impairment Score-Lower Limbs (NIS-LL) \<2 (in subjects with peripheral neuropathy);
* a modified body mass index (mBMI) reduction of less than 10% and an increase in N-terminal natriuretic peptide type B (NT-proBNP) concentration of less than 30% or \< 300 pg/mL (in subjects with isolated cardiomyopathy).
- Secondary Outcome Measures
Name Time Method Number of patients experiencing treatment-emergent adverse events One year Change in quality of life Every six months SF-36 scale
doxycycline pharmacokinetics (PK) Every three months response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement One year response assessed according to the Kumamoto Scale score
neurologic response One year response assessed by motor and sensory nerves conduction studies
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events One year
Trial Locations
- Locations (1)
Amyloid Research and Treatment Centre, Biotechnology Research Laboratories
🇮🇹Pavia, Italy