Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
Information source: IRCCS Policlinico S. Matteo
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Transthyretin Amyloidosis
Intervention: Doxycycline + Tauroursodeoxycholic acid (Drug)
Phase: Phase 2
Sponsored by: IRCCS Policlinico S. Matteo
Official(s) and/or principal investigator(s):
Giampaolo Merlini, MD, Principal Investigator, Affiliation: IRCCS Policlinico San Matteo
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
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.
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
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Response rate to doxycycline + tauroursodeoxycholic acid treatment
Number of patients experiencing treatment-emergent adverse events
Change in quality of life
doxycycline pharmacokinetics (PK)
response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events
Minimum age: 18 Years.
Maximum age: N/A.
- 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.
Locations and Contacts
Amyloid Research and Treatment Centre, Biotechnology Research Laboratories, Pavia 27100, Italy; Recruiting
Laura Obici, MD, Phone: +39 0382 50, Ext: 2983, Email: firstname.lastname@example.org
Leda Roggeri, Bsc, Phone: +39 0382 50, Ext: 2967, Email: email@example.com
Giampaolo Merlini, MD, Principal Investigator
Laura Obici, MD, Sub-Investigator
Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9.
Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta. 2008 Sep;1782(9):517-22. Epub 2008 Jun 3.
Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74.
Starting date: July 2010
Last updated: April 25, 2011