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

Sponsor

Umeå University (Other)

Overall Status

Completed

CT.gov ID

NCT02016365

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

18.3

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Transthyretin Amyloidosis Cardiomyopathy	Drug: Doxycycline Drug: Ursodeoxycholic acid	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

55 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Multicenter Pilot Study of the Safety and Efficacy of Doxycycline/UrsoDeoxyCholicAcid on Disease Progression in ATTR Amyloidosis

Study Start Date :

Feb 1, 2012

Actual Primary Completion Date :

Dec 1, 2014

Actual Study Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxycycline and UDCA Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously)	Drug: Doxycycline 200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks in combination with UDCA Other Names: Doxyferm Drug: Ursodeoxycholic acid 750 mg/day (500 mg +250mg orally) continuously Other Names: Ursofalk

Arm

Intervention/Treatment

Experimental: Doxycycline and UDCA

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

Drug: Doxycycline

200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks in combination with UDCA

Other Names:

Doxyferm

Drug: Ursodeoxycholic acid

750 mg/day (500 mg +250mg orally) continuously

Other Names:

Ursofalk

Outcome Measures

Primary Outcome Measures

The efficacy on serum N terminal proBNP (NT-proBNP) [At 12 month treatment]
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 [12 month]
mBMI-reduction of less than 10%
Increase of septum thickness [12 month]
Increase of septum thickness ≤ 2 mm
Neurologic Kumamoto Scale [6, 12 and 18 month]
To assess the change from baseline in the neurologic Kumamoto Scale
Number of patients with adverse events [During 12 month treatment and during 6 month follow-up]
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 [18 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Dept of Clinical Medicin, Ptieå Hospital	Piteå	Sweden	SE-941 28
2	Dept of clinical medicin, Skellefteå Hospital	Skellefteå	Sweden	SE-931 86
3	Dept of Clinical Medicine, Umeå University Hospital	Umeå	Sweden	SE-90185