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Safety and Effect of Doxycycline in Patients With Amyloidosis

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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:
Information provided by (Responsible Party):
John L. Berk, Boston University

Tracking Information
First Submitted Date  ICMJE August 21, 2012
First Posted Date  ICMJE September 3, 2012
Results First Submitted Date  ICMJE March 19, 2017
Results First Posted Date  ICMJE June 6, 2017
Last Update Posted Date August 1, 2017
Actual Study Start Date  ICMJE July 2012
Actual Primary Completion Date May 22, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (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  ICMJE Safety and Effect of Doxycycline in Patients With Amyloidosis
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Amyloidosis
Intervention  ICMJE 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  ICMJE 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 *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 10, 2017)
25
Original Estimated Enrollment  ICMJE
 (submitted: August 31, 2012)
60
Actual Study Completion Date  ICMJE December 15, 2015
Actual Primary Completion Date May 22, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01677286
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: Undecided
Plan Description: Primary manuscript reporting outcomes is in preparation. Once completed, we will consider IPD sharing plan.
Responsible Party John L. Berk, Boston University
Study Sponsor  ICMJE Boston University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: John L Berk, M.D. Boston University
PRS Account Boston University
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP