Amyloidosis
Conditions
Keywords
AL Amyloidosis, Primary Amyloidosis, Hereditary Amyloidosis, Familial Amyloidosis, SSA Amyloidosis, Senile Systemic Amyloidosis, AA Amyloidosis, Secondary Amyloidosis, Localized Amyloidosis, Systemic Amyloidosis
Brief summary
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
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.
Interventions
DRUGDoxycycline 100 mg po bid x 12 months
100mg by mouth twice daily for 1 year.
Sponsors
Boston University
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
* 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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amyloid Cardiomyopathy: BNP | 12 months | Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported |
| Amyloid Cardiomyopathy: Troponin I | 12 months | Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported |
| Amyloid Nephropathy: Creatinine Clearance | 12 months | 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 |
| Amyloid Nephropathy: Proteinuria | Data were assessed at baseline, 6 and 12 months, with change at end of study reported | Patients with predominant amyloid kidney involvement at enrollment. |
Countries
United States
Participant flow
Recruitment details
Patients referred to an amyloidosis center and no longer requiring active treatment to control progressive disease were recruited to the study.
Participants by arm
| Arm | Count |
|---|---|
| Doxycycline 100 mg po Bid x 12 Months Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | Doxycycline 100 mg po Bid x 12 Months |
|---|---|
| Age, Continuous | 65 Years |
| Brain Natriuretic Peptide (BNP) | 385 pg/mL STANDARD_DEVIATION 294 |
| Creatinine Clearance (mL/min) | 83.3 mL/min STANDARD_DEVIATION 36.5 |
| Proteinuria (g/day) | 5.99 g/day STANDARD_DEVIATION 3.15 |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Not hispanic or latino | 24 Participants |
| Race/Ethnicity, Customized Unknown/not reported | 1 Participants |
| Race/Ethnicity, Customized White | 24 Participants |
| Region of Enrollment United States | 25 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 19 Participants |
| Troponin I | 0.11 ng/mL STANDARD_DEVIATION 0.07 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 21 / 25 |
| serious Total, serious adverse events | 12 / 25 |
Outcome results
Primary
Amyloid Cardiomyopathy: BNP
Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported
Time frame: 12 months
Population: Analysis is limited to the patients with predominant amyloid heart involvement at enrollment. Mixed models analyses of change from baseline levels of cardiac biomarkers (BNP, Troponin I) were performed to include all collected data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiomyopathy | Amyloid Cardiomyopathy: BNP | 883 pg/mL | Standard Deviation 703 |
Comparison: BNP pg/mL, baseline versus end study valuesp-value: 0.03595% CI: [14.1, 328]Mixed Models Analysis
Primary
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
Time frame: 12 months
Population: Patients with predominant amyloid involvement of the heart.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiomyopathy | Amyloid Cardiomyopathy: Troponin I | 0.15 ng/mL | Standard Deviation 0.07 |
Comparison: Troponin I ng/mL, baseline versus end study levels.p-value: 0.3495% CI: [-0.009, 0.0234]Mixed Models Analysis
Primary
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
Time frame: 12 months
Population: Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all collected data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiomyopathy | Amyloid Nephropathy: Creatinine Clearance | 82.4 ml/min | Standard Deviation 48 |
Comparison: Creatinine clearance, baseline versus end study levels.p-value: 0.01795% CI: [-13.12, -1.67]Mixed Models Analysis
Primary
Amyloid Nephropathy: Proteinuria
Patients with predominant amyloid kidney involvement at enrollment.
Time frame: Data were assessed at baseline, 6 and 12 months, with change at end of study reported
Population: Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all data collected at baseline, 6 and 12 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cardiomyopathy | Amyloid Nephropathy: Proteinuria | 5.91 g/day | Standard Deviation 3.85 |
Comparison: Proteinuria (g/24 hours), baseline versus end study levels.p-value: 0.60395% CI: [-0.285, 0.466]Mixed Models Analysis