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

This study is currently recruiting participants.
Verified April 2011 by IRCCS Policlinico S. Matteo
Sponsor:
Information provided by:
IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier:
NCT01171859
First received: July 27, 2010
Last updated: April 25, 2011
Last verified: April 2011
History of Changes
  Purpose

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.


Condition Intervention Phase
Transthyretin Amyloidosis
 Drug: Doxycycline + Tauroursodeoxycholic acid
 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Amyloidosis
U.S. FDA Resources

Further study details as provided by IRCCS Policlinico S. Matteo:

Primary Outcome Measures:
  • Response rate to doxycycline + tauroursodeoxycholic acid treatment [ Time Frame: One year ] [ Designated as safety issue: No ]

    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).


Secondary Outcome Measures:
  • Number of patients experiencing treatment-emergent adverse events [ Time Frame: One year ] [ Designated as safety issue: Yes ]
  • Change in quality of life [ Time Frame: Every six months ] [ Designated as safety issue: No ]
    SF-36 scale

  • doxycycline pharmacokinetics (PK) [ Time Frame: Every three months ] [ Designated as safety issue: No ]
  • response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement [ Time Frame: One year ] [ Designated as safety issue: No ]
    response assessed according to the Kumamoto Scale score

  • neurologic response [ Time Frame: One year ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 40
Study Start Date: July 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Doxycycline + Tauroursodeoxycholic acid Drug: Doxycycline + Tauroursodeoxycholic acid
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01171859

Locations
Italy
Amyloid Research and Treatment Centre, Biotechnology Research Laboratories Recruiting
Pavia, Italy, 27100
Contact: Laura Obici, MD     +39 0382 50 ext 2983     l.obici@smatteo.pv.it    
Contact: Leda Roggeri, Bsc     +39 0382 50 ext 2967     leda78@gmail.com    
Principal Investigator: Giampaolo Merlini, MD            
Sub-Investigator: Laura Obici, MD            
Sponsors and Collaborators
IRCCS Policlinico S. Matteo
Investigators
Principal Investigator: Giampaolo Merlini, MD IRCCS Policlinico San Matteo
  More Information

Publications:

Responsible Party: Prof. Giampaolo Merlini, Director, Amyloid Centre, Biotechnoogy Research Laboratories, Fondazione Policlinico San Matteo
ClinicalTrials.gov Identifier: NCT01171859     History of Changes
Other Study ID Numbers: DOXYTUDCA2010, 2010-020422-17
Study First Received: July 27, 2010
Last Updated: April 25, 2011
Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health

Keywords provided by IRCCS Policlinico S. Matteo:
amyloidosis
transthyretin
doxycycline
Tauroursodeoxycholic acid

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Doxycycline
Doxycycline hyclate
Tauroursodeoxycholic acid
Taurochenodeoxycholic Acid
Anti-Bacterial Agents
Anti-Infective Agents
 Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Cholagogues and Choleretics
Gastrointestinal Agents
Antiviral Agents

ClinicalTrials.gov processed this record on October 17, 2012