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

Transthyretin Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01171859
• Other study ID #: DOXYTUDCA2010
• Secondary ID: 2010-020422-17
• Status: Completed
• Phase: Phase 2
• First received: July 27, 2010
• Last updated: February 24, 2016
• Start date: July 2010
• Est. completion date: October 2015

Study information

• Verified date: February 2016
• Source: IRCCS Policlinico S. Matteo
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: October 2015
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyloid Neuropathies, Familial
• Amyloidosis
• Transthyretin Amyloidosis

Intervention

Drug:
• Doxycycline + Tauroursodeoxycholic acid
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months

Locations

Country	Name	City	State
Italy	Amyloid Research and Treatment Centre, Biotechnology Research Laboratories	Pavia

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS Policlinico S. Matteo

Country where clinical trial is conducted

Italy, 

References & Publications (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. doi: 10.1186/1479-5876-8-74. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response rate to doxycycline + tauroursodeoxycholic acid treatment	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).	One year	No
Secondary	Number of patients experiencing treatment-emergent adverse events		One year	Yes
Secondary	Change in quality of life	SF-36 scale	Every six months	No
Secondary	doxycycline pharmacokinetics (PK)		Every three months	No
Secondary	response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement	response assessed according to the Kumamoto Scale score	One year	No
Secondary	neurologic response	response assessed by motor and sensory nerves conduction studies	One year	No
Secondary	Incidence of patients discontinuing from the study because of clinical or laboratory adverse events		One year	Yes