Safety and Effect of Doxycycline in Patients With Amyloidosis

Amyloidosis Clinical Trial

Official title:

A Phase II Study of Doxycycline in Patients With Amyloidosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01677286
• Other study ID #: H-31546
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 21, 2012
• Last updated: January 2, 2015
• Start date: July 2012
• Est. completion date: December 2015

Study information

• Verified date: January 2015
• Source: Boston University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: December 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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%

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyloidosis

Intervention

Drug:
• Doxycycline 100 mg po bid x 12 months
100mg by mouth twice daily for 1 year.

Locations

Country	Name	City	State
United States	Boston University	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Boston University

Country where clinical trial is conducted

United States, 

References & Publications (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. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite measures specific to the organ system affected by amyloidosis at study entry	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	12 months	No
Secondary	Quality of Life	Quality of Life (SF-36)	12 months	No
Secondary	Kumamoto neurologic score	Motor, sensory, autonomic measures of neuropathy	12 months	No