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Safety and Efficacy Study of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis (Dox/Urso)

Primary Purpose

Transthyretin Amyloidosis, Cardiomyopathy

Status
Completed
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Doxycycline
Ursodeoxycholic acid
Sponsored by
Umeå University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Transthyretin Amyloidosis focused on measuring Transthyretin amyloidosis, Cardiomyopathy, ATTR, neuropathy

Eligibility Criteria

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

Inclusion Criteria:

  • Cardiomyopathy with septal thickness > 15 mm and/or S-NT-ProBNP > 300 ng/
  • Age >50 years
  • Male and females after menopause. Menopause is defined as 6 to 12 months of amenorrhea in a woman over 45 years of age.
  • Written informed consent to be obtained prior to any study procedure
  • Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, and typing of amyloid deposits as TTR and identification of amyloid fibril type.
  • Molecular definition of the TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody
  • New York Heart Association (NYHA) class <III
  • Systolic blood pressure >100 mmHg (standing)
  • Must have symptomatic organ involvement with amyloid to justify therapy

Exclusion Criteria:

  • Liver transplantation in the previous 6 months or liver transplantation anticipated in less than 6 months;
  • ALT and/or AST > 2 x upper normal limit (UNL);
  • Creatinine clearance < 30 ml/min (Cockcroft -Gault Formula)
  • Any other lab values, illness or condition that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
  • 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

  • Dept of Clinical Medicin, Ptieå Hospital
  • Dept of clinical medicin, Skellefteå Hospital
  • Dept of Clinical Medicine, Umeå University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Doxycycline and UDCA

Arm Description

Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously)

Outcomes

Primary Outcome Measures

The efficacy on serum N terminal proBNP (NT-proBNP)
The primary endpoint of the study is the response rate to doxycycline + UDCA treatment at month 12. A responder is an ATTR subject with: - a reduction of, or an increase in serum NT-proBNP concentration of less than 30% of pre-treatment level will be regarded as consistent with treatment efficacy

Secondary Outcome Measures

Modified Body Mass Index (mBMI) reduction
mBMI-reduction of less than 10%
Increase of septum thickness
Increase of septum thickness ≤ 2 mm
Neurologic Kumamoto Scale
To assess the change from baseline in the neurologic Kumamoto Scale
Number of patients with adverse events
To assess the tolerability and safety of the treatment, the number of patients with adverse reactions will be recorded. Monthly phone contacts will be performed for monitoring of the treatment safety. The safety profile of doxycycline + UDCA will be assessed through the recording, reporting and analysis of baseline medical conditions, physical examination findings including vital signs and laboratory tests. These will be compared to analysis results observed during the study.
Blood work for potential drug-related adverse events
To assess the tolerability and safety of the treatment, blood work [e.g.complete blood count, creatinine and aspartate transaminase (AST), alkaline phosphatase(ALT)] for potential drug-related adverse events will be drawn at 1, 3, 6, 9, 12 and 18 month. The safety profile of doxycycline + UDCA will be assessed through the recording, reporting and analysis of baseline medical conditions, physical examination findings including vital signs and laboratory tests. These will be compared to analysis results observed during the study.

Full Information

First Posted
April 19, 2012
Last Updated
May 11, 2016
Sponsor
Umeå University
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1. Study Identification

Unique Protocol Identification Number
NCT02016365
Brief Title
Safety and Efficacy Study of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis
Acronym
Dox/Urso
Official Title
A Phase II Multicenter Pilot Study of the Safety and Efficacy of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Umeå University

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary objective for this study is to evaluate the efficacy of doxycycline + ursodeoxycholic acid (UDCA) on disease progression in Transthyretin Amyloidosis (ATTR) subjects with cardiomyopathy with or without neuropathy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Transthyretin Amyloidosis, Cardiomyopathy
Keywords
Transthyretin amyloidosis, Cardiomyopathy, ATTR, neuropathy

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Doxycycline and UDCA
Arm Type
Experimental
Arm Description
Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously)
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Other Intervention Name(s)
Doxyferm
Intervention Description
200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks in combination with UDCA
Intervention Type
Drug
Intervention Name(s)
Ursodeoxycholic acid
Other Intervention Name(s)
Ursofalk
Intervention Description
750 mg/day (500 mg +250mg orally) continuously
Primary Outcome Measure Information:
Title
The efficacy on serum N terminal proBNP (NT-proBNP)
Description
The primary endpoint of the study is the response rate to doxycycline + UDCA treatment at month 12. A responder is an ATTR subject with: - a reduction of, or an increase in serum NT-proBNP concentration of less than 30% of pre-treatment level will be regarded as consistent with treatment efficacy
Time Frame
At 12 month treatment
Secondary Outcome Measure Information:
Title
Modified Body Mass Index (mBMI) reduction
Description
mBMI-reduction of less than 10%
Time Frame
12 month
Title
Increase of septum thickness
Description
Increase of septum thickness ≤ 2 mm
Time Frame
12 month
Title
Neurologic Kumamoto Scale
Description
To assess the change from baseline in the neurologic Kumamoto Scale
Time Frame
6, 12 and 18 month
Title
Number of patients with adverse events
Description
To assess the tolerability and safety of the treatment, the number of patients with adverse reactions will be recorded. Monthly phone contacts will be performed for monitoring of the treatment safety. The safety profile of doxycycline + UDCA will be assessed through the recording, reporting and analysis of baseline medical conditions, physical examination findings including vital signs and laboratory tests. These will be compared to analysis results observed during the study.
Time Frame
During 12 month treatment and during 6 month follow-up
Title
Blood work for potential drug-related adverse events
Description
To assess the tolerability and safety of the treatment, blood work [e.g.complete blood count, creatinine and aspartate transaminase (AST), alkaline phosphatase(ALT)] for potential drug-related adverse events will be drawn at 1, 3, 6, 9, 12 and 18 month. The safety profile of doxycycline + UDCA will be assessed through the recording, reporting and analysis of baseline medical conditions, physical examination findings including vital signs and laboratory tests. These will be compared to analysis results observed during the study.
Time Frame
18 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cardiomyopathy with septal thickness > 15 mm and/or S-NT-ProBNP > 300 ng/ Age >50 years Male and females after menopause. Menopause is defined as 6 to 12 months of amenorrhea in a woman over 45 years of age. Written informed consent to be obtained prior to any study procedure Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, and typing of amyloid deposits as TTR and identification of amyloid fibril type. Molecular definition of the TTR mutation or immunohistochemical staining of amyloid fibrils with anti TTR antibody New York Heart Association (NYHA) class <III Systolic blood pressure >100 mmHg (standing) Must have symptomatic organ involvement with amyloid to justify therapy Exclusion Criteria: Liver transplantation in the previous 6 months or liver transplantation anticipated in less than 6 months; ALT and/or AST > 2 x upper normal limit (UNL); Creatinine clearance < 30 ml/min (Cockcroft -Gault Formula) Any other lab values, illness or condition that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study; 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
Ole B Suhr, MD PhD Prof
Organizational Affiliation
Dept of Clinical Medicine and public Health, Umeå University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dept of Clinical Medicin, Ptieå Hospital
City
Piteå
ZIP/Postal Code
SE-941 28
Country
Sweden
Facility Name
Dept of clinical medicin, Skellefteå Hospital
City
Skellefteå
ZIP/Postal Code
SE-931 86
Country
Sweden
Facility Name
Dept of Clinical Medicine, Umeå University Hospital
City
Umeå
ZIP/Postal Code
SE-90185
Country
Sweden

12. IPD Sharing Statement

Learn more about this trial

Safety and Efficacy Study of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis

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