Safety and Effect of Doxycycline in Patients With Amyloidosis

NCT01677286 | Completed Phase 2 Results FDA Drug

• 1 other identifier: H-31546
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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.

Conditions

Amyloidosis

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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

Study Arms (1)

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.

Drug: Doxycycline 100 mg po bid x 12 months

Interventions

Doxycycline 100 mg po bid x 12 months DRUG

100mg by mouth twice daily for 1 year.

Also known as: CAS: 564-25-0; ATC code: J01AA02 A01AB22; PubChem: CID 11256

doxycycline 100 mg po bid x 12 months

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 or older
• Biopsy-proven amyloidosis
• Biochemical or clinical evidence of amyloid induced end-organ dysfunction

You may not qualify if:

• 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%

Sponsors & Collaborators

• Boston University: lead

Study Sites (1)

Boston University

Boston, Massachusetts, 02118, United States

Location

Related Publications (7)

• 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.

  PMID: 12724338 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.

  PMID: 16449795 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.

  PMID: 11163366 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.

  PMID: 21998211 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.

  PMID: 22551192 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.

  PMID: 21068391 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.

  PMID: 20673327 BACKGROUND

MeSH Terms

Conditions

Amyloidosis; Immunoglobulin Light-chain Amyloidosis; Amyloidosis, Familial; AA amyloidosis

Interventions

Doxycycline

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: John Berk, MD
• Organization: Boston Medical Center

jberk@bu.edu

617-638-4494

Study Officials

• John L Berk, M.D.

  Boston University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Director, Amyloidosis Center

Study Record Dates

• First Submitted: August 21, 2012
• First Posted: September 3, 2012
• Study Start: July 1, 2012
• Primary Completion: May 22, 2015
• Study Completion: December 15, 2015
• Last Updated: August 1, 2017
• Results First Posted: June 6, 2017

Record last verified: 2017-07

Locations

US (1)