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

Study Overview
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Brief Summary
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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.

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

Conditions
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Transthyretin Amyloidosis, Cardiomyopathy

Intervention / Treatment
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* Drug: Doxycycline
* Drug: Ursodeoxycholic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline and UDCA<br>Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously) | Drug: Doxycycline<br>* 200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks in combination with UDCA<br>* Other names: Doxyferm;Drug: Ursodeoxycholic acid<br>* 750 mg/day (500 mg +250mg orally) continuously<br>* Other names: Ursofalk;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transthyretin amyloidosis, Cardiomyopathy, ATTR, neuropathy