Safety and Effect of Doxycycline in Patients With Amyloidosis - Full Text View

Purpose

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.

Condition	Intervention	Phase
Amyloidosis	Drug: Doxycycline 100 mg po bid x 12 months	Phase 2


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Study of Doxycycline in Patients With Amyloidosis

Resource links provided by NLM:

Genetics Home Reference related topics: lattice corneal dystrophy type II

MedlinePlus related topics: Amyloidosis

Drug Information available for: Doxycycline Doxycycline monohydrate Doxycycline hyclate Doxycycline calcium

Genetic and Rare Diseases Information Center resources: AL Amyloidosis Amyloidosis AA Hereditary Amyloidosis

U.S. FDA Resources

Further study details as provided by Boston University:

Primary Outcome Measures:

Composite measures specific to the organ system affected by amyloidosis at study entry [ Time Frame: 12 months ] [ Designated as safety issue: No ]
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:
1. airway -- PFTs, CT imaging, endoscopic visualization
2. gastrointestinal -- endoscopic visualization
3. bladder -- CT imaging, cystoscopy, urodynamics
4. skin -- direct measures of disease

Secondary Outcome Measures:

Quality of Life [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Quality of Life (SF-36)
Kumamoto neurologic score [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Motor, sensory, autonomic measures of neuropathy


Estimated Enrollment:	60
Study Start Date:	July 2012
Estimated Study Completion Date:	December 2015
Estimated Primary Completion Date:	June 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.	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

Eligibility


Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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%

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01677286

Locations


United States, Massachusetts
Boston University
Boston, Massachusetts, United States, 02118

Sponsors and Collaborators

Boston University

Investigators


Principal Investigator:	John L Berk, M.D.	Boston University

More Information

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.

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. Journal of Translational Medicine. 2010;8:74.


Responsible Party:	John L. Berk, Clinical Director, Amyloid Treatment & Research Program, Boston University
ClinicalTrials.gov Identifier:	NCT01677286 History of Changes
Other Study ID Numbers:	H-31546
Study First Received:	August 21, 2012
Last Updated:	January 2, 2015
Health Authority:	United States: Institutional Review Board

Keywords provided by Boston University:


AL Amyloidosis Primary Amyloidosis Hereditary Amyloidosis Familial Amyloidosis SSA Amyloidosis	Senile Systemic Amyloidosis AA Amyloidosis Secondary Amyloidosis Localized Amyloidosis Systemic Amyloidosis

Additional relevant MeSH terms:


Amyloidosis Metabolic Diseases Proteostasis Deficiencies Doxycycline Anti-Bacterial Agents Anti-Infective Agents	Antimalarials Antiparasitic Agents Antiprotozoal Agents Pharmacologic Actions Therapeutic Uses

ClinicalTrials.gov processed this record on February 25, 2015