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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| doxycycline 100 mg po bid x 12 months | Experimental | Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Doxycycline 100 mg po bid x 12 months | Drug | 100mg by mouth twice daily for 1 year. |
|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John L Berk, M.D. | Boston University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Boston University | Boston | Massachusetts | 02118 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12724338 | Background | Cardoso I, Merlini G, Saraiva MJ. 4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 2003 May;17(8):803-9. doi: 10.1096/fj.02-0764com. | |
| 16449795 | Background | Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com. |
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Primary manuscript reporting outcomes is in preparation. Once completed, we will consider IPD sharing plan.
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Patients referred to an amyloidosis center and no longer requiring active treatment to control progressive disease were recruited to the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Amyloid Cardiomyopathy: BNP | Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported | 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. | Posted | Mean | Standard Deviation | pg/mL | 12 months |
|
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Doxycycline 100 mg po Bid x 12 Months | Open-label doxycycline 100 mg twice daily by mouth was administered to subjects for 12 months, if tolerated. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fluid overload | Cardiac disorders | Systematic Assessment | SOB, edema |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Skin disruption | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John Berk, MD | Boston Medical Center | 617-638-4494 | jberk@bu.edu |
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| ID | Term |
|---|---|
| D000686 | Amyloidosis |
| D000075363 | Immunoglobulin Light-chain Amyloidosis |
| D028226 | Amyloidosis, Familial |
| C000718787 | AA amyloidosis |
| ID | Term |
|---|---|
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D054219 | Neoplasms, Plasma Cell |
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| ID | Term |
|---|---|
| D004318 | Doxycycline |
| ID | Term |
|---|---|
| D013754 | Tetracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| 11163366 | Background | Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 2001 Jan 5;487(3):404-7. doi: 10.1016/s0014-5793(00)02380-2. |
| 21998211 | Background | Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011 Dec 15;118(25):6610-7. doi: 10.1182/blood-2011-04-351643. Epub 2011 Oct 12. |
| 22551192 | Background | Obici L, Cortese A, Lozza A, Lucchetti J, Gobbi M, Palladini G, Perlini S, Saraiva MJ, Merlini G. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012 Jun;19 Suppl 1:34-6. doi: 10.3109/13506129.2012.678508. Epub 2012 May 2. |
| 21068391 | Background | Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M, Mangione P, Colombo L, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M. Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils. J Biol Chem. 2011 Jan 21;286(3):2121-31. doi: 10.1074/jbc.M110.178376. Epub 2010 Nov 10. |
| 20673327 | Background | Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74. |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Brain Natriuretic Peptide (BNP) | Study participants with predominant cardiac amyloid involvement. | Patients with predominant amyloid cardiomyopathy constituted the "cardiac group" (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression. | Mean | Standard Deviation | pg/mL |
|
| Troponin I | Study participants with predominant cardiac amyloid involvement. | Patients with predominant amyloid cardiomyopathy constituted the "cardiac group" (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression. | Mean | Standard Deviation | ng/mL |
|
| Creatinine Clearance (mL/min) | Study participants with predominant renal amyloid involvement. | Patients with predominant amyloid nephropathy constituted the "renal group" (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression. | Mean | Standard Deviation | mL/min |
|
| Proteinuria (g/day) | Study participants with predominant renal amyloid involvement. | Patients with predominant amyloid nephropathy constituted the "renal group" (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression. | Mean | Standard Deviation | g/day |
|
|
|
|
| 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 | Patients with predominant amyloid involvement of the heart. | Posted | Mean | Standard Deviation | ng/mL | 12 months |
|
|
|
|
| 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 | 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. | Posted | Mean | Standard Deviation | ml/min | 12 months |
|
|
|
|
| Primary | Amyloid Nephropathy: Proteinuria | Patients with predominant amyloid kidney involvement at enrollment. | 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. | Posted | Mean | Standard Deviation | g/day | Data were assessed at baseline, 6 and 12 months, with change at end of study reported |
|
|
|
|
| 0 |
| 25 |
| 12 |
| 25 |
| 21 |
| 25 |
| Sun hypersensitivity | Skin and subcutaneous tissue disorders | Systematic Assessment | Burns/desquamation induced by sun hypersensitivity |
|
| Bloating | Gastrointestinal disorders | Systematic Assessment | Abdominal distension |
|
| Urinary retention | Renal and urinary disorders | Systematic Assessment |
|
| osteonecrosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Orthopedic issues | Surgical and medical procedures | Non-systematic Assessment |
|
| Deep vein thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Arrhythmia | Cardiac disorders | Non-systematic Assessment | Ventricular trachycardia |
|
| Hip disease | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Cytomegalovirus infection | Infections and infestations | Non-systematic Assessment |
|
| Skin cancer | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Hernia | Gastrointestinal disorders | Non-systematic Assessment |
|
| GI disorder | Gastrointestinal disorders | Systematic Assessment |
|
| Infection | Infections and infestations | Non-systematic Assessment |
|
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| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D010265 | Paraproteinemias |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |