Safety and Effect of Doxycycline in Patients With Amyloidosis

Tracking Information
First Submitted Date ICMJE	August 21, 2012
First Posted Date ICMJE	September 3, 2012
Results First Submitted Date	March 19, 2017
Results First Posted Date	June 6, 2017
Last Update Posted Date	August 1, 2017
Actual Study Start Date ICMJE	July 2012
Actual Primary Completion Date	May 22, 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: June 5, 2017)	Amyloid Cardiomyopathy: BNP [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Data were assessed at baseline, 6 and 12 months, with change at end of study reported ]Patients with predominant amyloid kidney involvement at enrollment.
Original Primary Outcome Measures ICMJE; (submitted: August 31, 2012)	Composite measures specific to the organ system affected by amyloidosis at study entry [ Time Frame: 12 months ]; Amyloid nephropathy: 24 hour urine protein excretion, creatinine clearance Amyloid cardiomyopathy: cardiac biomarkers (BNP, Troponin I), echo parameters (IVSd, longitudinal strain, diastolic indices [e/e']), ECG Amyloid peripheral neuropathy: Neurologic Impairment Score-Lower Limb (NIS-LL), modified body mass index (mBMI) Amyloid autonomic neuropathy: postural blood pressures, heart rate variability, mBMI Localized amyloidosis: airway -- PFTs, CT imaging, endoscopic visualization; gastrointestinal -- endoscopic visualization; bladder -- CT imaging, cystoscopy, urodynamics; skin -- direct measures of disease
Change History	Complete list of historical versions of study NCT01677286 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE; (submitted: August 31, 2012)	Quality of Life [ Time Frame: 12 months ]Quality of Life (SF-36); Kumamoto neurologic score [ Time Frame: 12 months ]Motor, sensory, autonomic measures of neuropathy
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Safety and Effect of Doxycycline in Patients With Amyloidosis
Official Title ICMJE	A Phase II Study of Doxycycline in Patients With 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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Amyloidosis
Intervention ICMJE	Drug: Doxycycline 100 mg po bid x 12 months; 100mg by mouth twice daily for 1 year.; Other Name: CAS: 564-25-0; ATC code: J01AA02 A01AB22; PubChem: CID 11256
Study Arms	Experimental: 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.; Intervention: Drug: Doxycycline 100 mg po bid x 12 months
Publications *	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.; 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.; 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.; 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.; 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.; 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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 10, 2017)	25
Original Estimated Enrollment ICMJE; (submitted: August 31, 2012)	60
Actual Study Completion Date	December 15, 2015
Actual Primary Completion Date	May 22, 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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%
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01677286
Other Study ID Numbers ICMJE	H-31546
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement	Plan to Share IPD: Undecided Plan Description: Primary manuscript reporting outcomes is in preparation. Once completed, we will consider IPD sharing plan.
Responsible Party	John L. Berk, Boston University
Study Sponsor ICMJE	Boston University
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: John L Berk, M.D. Boston University
PRS Account	Boston University
Verification Date	July 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP