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

• ClinicalTrials.gov Identifier: NCT01171859
• Recruitment Status: Completed
• First Posted: July 29, 2010
• Last Update Posted: February 25, 2016
• Sponsor: IRCCS Policlinico S. Matteo
• Information provided by (Responsible Party): Giampaolo Merlini, IRCCS Policlinico S. Matteo

Tracking Information

• First Submitted Date: July 27, 2010
• First Posted Date: July 29, 2010
• Last Update Posted Date: February 25, 2016
• Study Start Date: July 2010
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 2010)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 25, 2011)

• 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 ]

Original Secondary Outcome Measures (submitted: July 28, 2010)

• tolerability and safety of doxycycline + tauroursodeoxycholic acid treatment [ 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: 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

Study Arms

Experimental: Doxycycline + Tauroursodeoxycholic acid

Intervention: Drug: Doxycycline + Tauroursodeoxycholic acid

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. doi: 10.1096/fj.05-4509com.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 28, 2010): 40
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: October 2015
• Actual Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT01171859
• Other Study ID Numbers: DOXYTUDCA2010; 2010-020422-17 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Giampaolo Merlini, IRCCS Policlinico S. Matteo
• Original Responsible Party: Prof. Giampaolo Merlini, Director, Amyloid Centre, Biotechnoogy Research Laboratories, Fondazione Policlinico San Matteo
• Current Study Sponsor: IRCCS Policlinico S. Matteo
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Giampaolo Merlini, MD; IRCCS Policlinico San Matteo

• PRS Account: IRCCS Policlinico S. Matteo
• Verification Date: February 2016