Safety and Effect of Doxycycline in Patients With Amyloidosis

• ClinicalTrials.gov Identifier: NCT01677286
• Recruitment Status: Completed
• First Posted: September 3, 2012
• Results First Posted: June 6, 2017
• Last Update Posted: August 1, 2017
• Sponsor: Boston University
• Information provided by (Responsible Party): John L. Berk, Boston University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Amyloidosis	Drug: Doxycycline 100 mg po bid x 12 months	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Doxycycline in Patients With Amyloidosis
• Actual Study Start Date: July 2012
• Actual Primary Completion Date: May 22, 2015
• Actual Study Completion Date: December 15, 2015

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. 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
4. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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. doi: 10.1096/fj.02-0764com.

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.

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.

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.

• Responsible Party: John L. Berk, Assistant Director, Amyloidosis Center, Boston University
• ClinicalTrials.gov Identifier: NCT01677286
• Other Study ID Numbers: H-31546
• First Posted: September 3, 2012
• Results First Posted: June 6, 2017
• Last Update Posted: August 1, 2017
• Last Verified: July 2017

Individual Participant Data (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.

• 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

Keywords provided by John L. Berk, 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; Proteostasis Deficiencies; Metabolic Diseases; Doxycycline; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents