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

Primary Purpose

Transthyretin Amyloidosis

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Doxycycline + Tauroursodeoxycholic acid
Sponsored by
IRCCS Policlinico S. Matteo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Transthyretin Amyloidosis focused on measuring amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Amyloid Research and Treatment Centre, Biotechnology Research Laboratories

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Doxycycline + Tauroursodeoxycholic acid

Arm Description

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Number of patients experiencing treatment-emergent adverse events
Change in quality of life
SF-36 scale
doxycycline pharmacokinetics (PK)
response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
response assessed according to the Kumamoto Scale score
neurologic response
response assessed by motor and sensory nerves conduction studies
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events

Full Information

First Posted
July 27, 2010
Last Updated
February 24, 2016
Sponsor
IRCCS Policlinico S. Matteo
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1. Study Identification

Unique Protocol Identification Number
NCT01171859
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
July 2010 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
IRCCS Policlinico S. Matteo

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Transthyretin Amyloidosis
Keywords
amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Doxycycline + Tauroursodeoxycholic acid
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Doxycycline + Tauroursodeoxycholic acid
Intervention Description
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months
Primary Outcome Measure Information:
Title
Response rate to doxycycline + tauroursodeoxycholic acid treatment
Description
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).
Time Frame
One year
Secondary Outcome Measure Information:
Title
Number of patients experiencing treatment-emergent adverse events
Time Frame
One year
Title
Change in quality of life
Description
SF-36 scale
Time Frame
Every six months
Title
doxycycline pharmacokinetics (PK)
Time Frame
Every three months
Title
response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
Description
response assessed according to the Kumamoto Scale score
Time Frame
One year
Title
neurologic response
Description
response assessed by motor and sensory nerves conduction studies
Time Frame
One year
Title
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events
Time Frame
One year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giampaolo Merlini, MD
Organizational Affiliation
IRCCS Policlinico San Matteo
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amyloid Research and Treatment Centre, Biotechnology Research Laboratories
City
Pavia
ZIP/Postal Code
27100
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
16449795
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.
Results Reference
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PubMed Identifier
18572024
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.
Results Reference
background
PubMed Identifier
20673327
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.
Results Reference
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Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis

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