Safety and Effect of Doxycycline in Patients With Amyloidosis

Study Overview
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Brief Summary
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The tetracycline antibiotic doxycycline disrupts A beta amyloid fibrils (AB) in Alzheimer's disease, transthyretin (ATTR) amyloid fibrils in familial amyloidotic polyneuropathy, and immunoglobulin light chain (AL) amyloid fibrils in transgenic mouse models of disease. If untreated, amyloid deposits impair organ function, affecting the morbidity and mortality of patients. This single-center, twelve-month, open-label, prospective, pilot phase II study aims to determine whether doxycycline reduces amyloid deposits and improves organ function in patients with systemic or localized amyloidosis. The investigators plan to enroll patients with measurable amyloid disease according to internationally-accepted diagnostic criteria. Patients must have stable organ function at enrollment. Eligible subjects not receiving active treatments for amyloidosis affecting their kidneys, heart, aerodigestive tracts, peripheral or autonomic nervous system(s), lungs, eyes, skin, bladder, or breasts will undergo evaluations at baseline, 6 months, and 12 months - or more frequently as clinically indicated. Over 45 years experience indicates doxycycline is a safe, well tolerated antibiotic. The investigators will use standard grading systems to assess doxycycline response following twelve months of treatment.

Detailed Description
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In transgenic animal models of disease, the tetracycline antibiotic doxycycline disrupts A beta amyloid fibrils (AB) in Alzheimer's disease, transthyretin (ATTR) amyloid fibrils in familial amyloidotic polyneuropathy, and immunoglobulin light chain (AL) amyloid fibrils. The aim of this single-center, 12-month open label, prospective phase II study was to determine a) the safety and tolerability of prolonged full dose doxycycline in patients with amyloidosis, and b) the effect of doxycycline treatment on amyloid-induced organ dysfunction. We enrolled 25 patients with measurable organ dysfunction caused by amyloid deposition who were not receiving active treatment to control their amyloid production. All 25 subjects received doxycycline 100 mg by both twice daily for up to 12 months depending on their tolerance of the antibiotic. The primary endpoint, defined by the organ most affected by amyloid, was measured at baseline, 6 and 12 months along with safety laboratory values.

Official Title
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A Phase II Study of Doxycycline in Patients With Amyloidosis

Conditions
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Amyloidosis

Intervention / Treatment
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* Drug: Doxycycline 100 mg po bid x 12 months


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older Biopsy-proven amyloidosis Biochemical or clinical evidence of amyloid induced end-organ dysfunction Exclusion Criteria: Concurrent use of other tetracyclines Ongoing active treatment for amyloidosis Pregnancy or unwillingness to use contraception by women of childbearing age Doxycycline drug allergy/hypersensitivity ECOG performance status > 3 NYHA class > 3 Renal insufficiency (estimated creatinine clearance < 25 ml/min) Transaminitis (AST or ALT > 5 times upper limit of normal) Diabetes mellitus or hemoglobin A1C > 6.2%

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 100 mg po bid x 12 months<br>Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months. | Drug: Doxycycline 100 mg po bid x 12 months<br>* 100mg by mouth twice daily for 1 year.<br>* Other names: CAS: 564-25-0; ATC code: J01AA02 A01AB22; PubChem: CID 11256;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amyloid Cardiomyopathy: BNP | Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported | 12 months | 
| Amyloid Cardiomyopathy: Troponin I | Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported | 12 months | 
| Amyloid Nephropathy: Creatinine Clearance | Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported | 12 months | 
| Amyloid Nephropathy: Proteinuria | Patients with predominant amyloid kidney involvement at enrollment. | Data were assessed at baseline, 6 and 12 months, with change at end of study reported | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AL Amyloidosis, Primary Amyloidosis, Hereditary Amyloidosis, Familial Amyloidosis, SSA Amyloidosis, Senile Systemic Amyloidosis, AA Amyloidosis, Secondary Amyloidosis, Localized Amyloidosis, Systemic Amyloidosis