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

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

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.

Study Overview

• Status: Completed
• Conditions: Transthyretin Amyloidosis; Cardiomyopathy
• Intervention / Treatment: Drug: Doxycycline; Drug: Ursodeoxycholic acid

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Piteå, Sweden, SE-941 28
    • Dept of Clinical Medicin, Ptieå Hospital
  • Skellefteå, Sweden, SE-931 86
    • Dept of clinical medicin, Skellefteå Hospital
  • Umeå, Sweden, SE-90185
    • Dept of Clinical Medicine, Umeå University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At 12 month treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Body Mass Index (mBMI) reduction	mBMI-reduction of less than 10%	12 month
Increase of septum thickness	Increase of septum thickness ≤ 2 mm	12 month
Neurologic Kumamoto Scale	To assess the change from baseline in the neurologic Kumamoto Scale	6, 12 and 18 month
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.	During 12 month treatment and during 6 month follow-up
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.	18 months

Collaborators and Investigators

• Sponsor: Umeå University
• Investigators: Principal Investigator: Ole B Suhr, MD PhD Prof, Dept of Clinical Medicine and public Health, Umeå University

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: April 19, 2012
• First Submitted That Met QC Criteria: December 13, 2013
• First Posted (Estimate): December 20, 2013

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: May 11, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Cardiomyopathy; ATTR; neuropathy; Transthyretin amyloidosis
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Disease Attributes; Proteostasis Deficiencies; Disease Progression; Amyloidosis; Cardiomyopathies; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Cholagogues and Choleretics; Doxycycline; Ursodeoxycholic Acid
• Other Study ID Numbers: EudraCT No:2011-005236-25