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

Condition(s) targeted: Transthyretin Amyloidosis

Intervention: Doxycycline + Tauroursodeoxycholic acid (Drug)

Phase: Phase 2

Status: Recruiting

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 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.

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

Secondary outcome:

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

neurologic response

Incidence of patients discontinuing from the study because of clinical or laboratory adverse events

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Amyloid Research and Treatment Centre, Biotechnology Research Laboratories, Pavia 27100, Italy; Recruiting
Laura Obici, MD, Phone: +39 0382 50, Ext: 2983, Email: l.obici@smatteo.pv.it
Leda Roggeri, Bsc, Phone: +39 0382 50, Ext: 2967, Email: leda78@gmail.com
Giampaolo Merlini, MD, Principal Investigator
Laura Obici, MD, Sub-Investigator

Related publications:

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