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

Tracking Information

• First Submitted Date: August 21, 2012
• First Posted Date: 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: July 2012
• Actual Primary Completion Date: May 22, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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:

1. airway -- PFTs, CT imaging, endoscopic visualization
2. gastrointestinal -- endoscopic visualization
3. bladder -- CT imaging, cystoscopy, urodynamics
4. skin -- direct measures of disease

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Effect of Doxycycline in Patients With Amyloidosis
• Official Title: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Amyloidosis

Intervention

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 10, 2017): 25
• Original Estimated Enrollment (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

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, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01677286
• Other Study ID Numbers: 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.

• Current Responsible Party: John L. Berk, Boston University
• Original Responsible Party: John L. Berk, Boston University, Clinical Director, Amyloid Treatment & Research Program
• Current Study Sponsor: Boston University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Boston University
• Verification Date: July 2017