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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Transthyretin Amyloidosis

Intervention / Treatment
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* Drug: Doxycycline + Tauroursodeoxycholic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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 + Tauroursodeoxycholic acid<br> | Drug: Doxycycline + Tauroursodeoxycholic acid<br>* doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | One year | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid