Clinical trial NCT01171859: Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Transthyretin Amyloidosis
Keywords: amyloidosis
transthyretin
doxycycline
Tauroursodeoxycholic acid
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
First posted: 2010-07-29
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Response rate to doxycycline + tauroursodeoxycholic acid treatment
timeFrame: One year
Secondary outcomes:
measure: Number of patients experiencing treatment-emergent adverse events
timeFrame: One year
measure: Change in quality of life
timeFrame: Every six months
measure: doxycycline pharmacokinetics (PK)
timeFrame: Every three months
measure: response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
timeFrame: One year
measure: neurologic response
timeFrame: One year
measure: Incidence of patients discontinuing from the study because of clinical or laboratory adverse events
timeFrame: One year
Other outcomes:
Locations:
city: Pavia
country: Italy
facility: Amyloid Research and Treatment Centre, Biotechnology Research Laboratories
Study officials:
affiliation: IRCCS Policlinico San Matteo
name: Giampaolo Merlini, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1096/fj.05-4509com.
citation: 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. doi: 10.1016/j.bbadis.2008.05.005. Epub 2008 Jun 3.
citation: 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. doi: 10.1186/1479-5876-8-74.