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

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

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.

Condition or disease Intervention/treatment Phase
Transthyretin Amyloidosis Drug: Doxycycline + Tauroursodeoxycholic acid Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : July 2010
Actual Primary Completion Date : April 2015
Actual Study Completion Date : October 2015

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. 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).

Secondary Outcome Measures :
  1. Number of patients experiencing treatment-emergent adverse events [ Time Frame: One year ]
  2. Change in quality of life [ Time Frame: Every six months ]
    SF-36 scale

  3. doxycycline pharmacokinetics (PK) [ Time Frame: Every three months ]
  4. response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement [ Time Frame: One year ]
    response assessed according to the Kumamoto Scale score

  5. neurologic response [ Time Frame: One year ]
    response assessed by motor and sensory nerves conduction studies

  6. Incidence of patients discontinuing from the study because of clinical or laboratory adverse events [ Time Frame: One year ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01171859

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Amyloid Research and Treatment Centre, Biotechnology Research Laboratories
Pavia, Italy, 27100
Sponsors and Collaborators
IRCCS Policlinico S. Matteo
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Principal Investigator: Giampaolo Merlini, MD IRCCS Policlinico San Matteo
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Responsible Party: Giampaolo Merlini, Prof., IRCCS Policlinico S. Matteo
ClinicalTrials.gov Identifier: NCT01171859    
Other Study ID Numbers: DOXYTUDCA2010
2010-020422-17 ( EudraCT Number )
First Posted: July 29, 2010    Key Record Dates
Last Update Posted: February 25, 2016
Last Verified: February 2016
Keywords provided by Giampaolo Merlini, IRCCS Policlinico S. Matteo:
Tauroursodeoxycholic acid
Additional relevant MeSH terms:
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Amyloid Neuropathies, Familial
Proteostasis Deficiencies
Metabolic Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Amyloid Neuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Genetic Diseases, Inborn
Amyloidosis, Familial
Metabolism, Inborn Errors
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Antiviral Agents
Cholagogues and Choleretics
Gastrointestinal Agents