Transthyretin Amyloidosis
Conditions
Keywords
amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid
Brief summary
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.
Interventions
DRUGDoxycycline + Tauroursodeoxycholic acid
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months
Sponsors
Fondazione IRCCS Policlinico San Matteo di Pavia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response rate to doxycycline + tauroursodeoxycholic acid treatment | One year | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in quality of life | Every six months | SF-36 scale |
| doxycycline pharmacokinetics (PK) | Every three months | — |
| Number of patients experiencing treatment-emergent adverse events | One year | — |
| neurologic response | One year | response assessed by motor and sensory nerves conduction studies |
| Incidence of patients discontinuing from the study because of clinical or laboratory adverse events | One year | — |
| response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement | One year | response assessed according to the Kumamoto Scale score |
Countries
Italy
Outcome results
None listed