Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
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.
|Transthyretin Amyloidosis||Drug: Doxycycline + Tauroursodeoxycholic acid||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Single Center, Twelve-month, Open-label, Prospective Study Followed by a Six-month Withdrawal Period to Evaluate the Efficacy, Tolerability, Safety and Pharmacokinetics of Doxycycline in Combination With Tauroursodeoxycholic Acid in Transthyretin Amyloidosis|
- Response rate to doxycycline + tauroursodeoxycholic acid treatment [ Time Frame: 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).
- Number of patients experiencing treatment-emergent adverse events [ Time Frame: One year ]
- Change in quality of life [ Time Frame: Every six months ]SF-36 scale
- doxycycline pharmacokinetics (PK) [ Time Frame: Every three months ]
- response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement [ Time Frame: One year ]response assessed according to the Kumamoto Scale score
- neurologic response [ Time Frame: 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 [ Time Frame: One year ]
|Study Start Date:||July 2010|
|Study Completion Date:||October 2015|
|Primary Completion Date:||April 2015 (Final data collection date for primary outcome measure)|
|Experimental: Doxycycline + Tauroursodeoxycholic acid||
Drug: Doxycycline + Tauroursodeoxycholic acid
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months
Please refer to this study by its ClinicalTrials.gov identifier: NCT01171859
|Amyloid Research and Treatment Centre, Biotechnology Research Laboratories|
|Pavia, Italy, 27100|
|Principal Investigator:||Giampaolo Merlini, MD||IRCCS Policlinico San Matteo|