A Pilot Study of Inflammatory Markers in Alzheimer's Disease

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2009 by McMaster University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
The Physicians' Services Incorporated Foundation
Information provided by:
McMaster University
ClinicalTrials.gov Identifier:
NCT00715858
First received: July 11, 2008
Last updated: February 3, 2009
Last verified: February 2009
  Purpose

The purpose of this study is to examine the cerebrospinal fluid (CSF) of patients with Alzheimer's disease for biomarkers of inflammation and their response to the antibiotics doxycycline and rifampin. The results of this preliminary analysis will be used in defining the direction of further research.


Condition Intervention Phase
Alzheimer's Disease
Drug: doxycycline
Drug: rifampin
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Pilot Study Comparing Inflammatory Biomarkers in Blood and CSF in Patients With Alzheimer's Disease and Age-Matched Controls

Resource links provided by NLM:


Further study details as provided by McMaster University:

Primary Outcome Measures:
  • IL-1beta [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]
  • TNF-alpha [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]
  • MCP-1 [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]
  • IL-4 [ Time Frame: baseline and 12 month ] [ Designated as safety issue: No ]
  • IL-10 [ Time Frame: baseline and 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Other inflammatory markers. [ Time Frame: Baseline and 12 month ] [ Designated as safety issue: No ]

Estimated Enrollment: 21
Study Start Date: May 2008
Estimated Study Completion Date: October 2009
Estimated Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1 AD doxycycline + rifampin
Participants with AD allocated to doxycycline 100 mg bid od and rifampin 300 mg od for 12 months
Drug: doxycycline
capsule, 100 mg, b.i.d., 12 months
Other Name: Apo-doxy
Drug: rifampin
capsule, 300 mg, od, 12 months
Other Names:
  • rifampicin
  • Rofact
  • Rifadin
Active Comparator: 2 AD doxycycline Drug: doxycycline
capsule, 100 mg, b.i.d., 12 months
Other Name: Apo-doxy
Drug: placebo
placebo matched to rifampin; placebo matched to doxycycline
Active Comparator: 3 AD rifampin
Participants with AD allocated to rifampin 300 mg od od and placebo matched to doxycycline bid for 12 months
Drug: rifampin
capsule, 300 mg, od, 12 months
Other Names:
  • rifampicin
  • Rofact
  • Rifadin
Drug: placebo
placebo matched to rifampin; placebo matched to doxycycline
Placebo Comparator: 4 AD placebo
Participants with AD allocated to placebo matched to doxycycline and placebo matched to rifampin for 12 months
Drug: placebo
placebo matched to rifampin; placebo matched to doxycycline
No Intervention: 5 Control
Age-matched cognitively healthy participants (untreated)

Detailed Description:

Doxycycline and rifampicin are two antibiotics which may be useful in the treatment of Alzheimer's disease (AD). Besides their antimicrobial effects they may also decrease specific contributors to AD pathology including: 1. amyloid beta, 2. inflammatory mediators, 3. proteolytic enzymes, and 4. metal ions. Evidence indicates an inflammatory response in AD. This includes complement activation, elevated C-reactive protein (CRP), elevated pro-inflammatory cytokines (including IL-1-beta, IL-6, TNF-α, TGF-β, S100-β), chemokine alterations (IL-8, MIP-1-alpha, MIP-1-beta, MCP-1), and microglial activation. In our previous study of AD patients treated with combined doxycycline and rifampicin versus placebo, we demonstrated that antibiotic treatment significantly delayed progression of clinical impairment. Treatment also reduced blood CRP levels suggesting an anti-inflammatory role of these antibiotics. In this study we suggest analysis of biomarkers including both pro and anti-inflammatory cytokines TNF-alpha, IL-1beta, IL-4, IL-10,the chemokine MCP-1 and other inflammatory markers in both the cerebrospinal fluid (CSF) and blood from AD patients and age-matched controls.

AD patients are participants in a 12 month randomized clinical trial of doxycyline and rifampin or placebo (DARAD) for treatment of AD. Each patient is asked if they wish to contribute a sample of CSF and blood at baseline and at 12 months when treatment is completed. About half the patients are consenting to this. Since consent is given to the lumbar puncture before the double-blinded DARAD treatment is initiated, we expect the distribution of samples collected to be random among the four treatment groups. We will compare CSF biomarker levels among the four treatment groups. Ten age-matched healthy controls are also being asked to contribute CSF and blood samples for comparison. The controls are not participants in the DARAD trial.

We feel that this is an important pilot study to determine whether there are any differences in blood or CSF concentrations of commonly studied cytokines between AD patients and normal controls. As such, this study could contribute to the search for a diagnostic biomarker. Also, it could provide a solid foundation for future studies aimed at elucidating the effects of antibiotics on various biomarkers in the blood and CSF of AD patients. From this, we may be able to correlate previous findings that antibiotics delay progression of clinical outcome in AD with changes in blood or CSF biomarker levels.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Giving informed consent to lumbar puncture
  • Participation in the DARAD clinical trial which requires the following:
  • diagnosis of probable Alzheimer's disease
  • SMMSE 14-26 inclusive
  • community-dwelling
  • age 50 or greater
  • caregiver to monitor study medication and report on ADLs, behaviour, etc.
  • adequate English literacy to complete neuropsychological testing
  • generally stable level of health

Exclusion Criteria:

  • Contraindication to lumbar puncture
  • DARAD exclusion criteria as follows:
  • dementia due to other neurodegenerative diseases
  • cognitive impairment due to head trauma, etc.
  • stroke or significant cerebrovascular disease
  • clinically significant cardiac disease such as recent MI, uncontrolled hypertension
  • taking other anti-dementia treatments or investigational drugs
  • allergy to doxycycline or rifampin
  • significant psychiatric conditions like depression
  • cancer
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00715858

Contacts
Contact: D. William Molloy, MB 905-777-3837 ext 12440 wmolloy@stpetes.ca
Contact: Timothy I Standish, MA 905-777-3837 ext 12442 tstandish@stpetes.ca

Locations
Canada, Ontario
St.Peter's Hospital Recruiting
Hamilton, Ontario, Canada, L8M1W9
Principal Investigator: D. William Molloy, MB         
Sponsors and Collaborators
McMaster University
The Physicians' Services Incorporated Foundation
Investigators
Study Chair: D.William Molloy, MB, MRCPI, FRCPC McMaster University
Principal Investigator: Brandon M Kucher, PhD, MD McMaster University
Study Director: Shucui Jiang, MD,PhD McMaster University
Study Director: Michel P Rathbone, MB, PhD McMaster University
  More Information

Additional Information:
Publications:
Responsible Party: William Molloy, McMaster University
ClinicalTrials.gov Identifier: NCT00715858     History of Changes
Other Study ID Numbers: R07-63
Study First Received: July 11, 2008
Last Updated: February 3, 2009
Health Authority: Canada: Health Canada

Keywords provided by McMaster University:
Alzheimer's disease
dementia
inflammation
cytokine
biomarker
cerebrospinal fluid
serum
doxycycline
rifampin

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Dementia
Mental Disorders
Nervous System Diseases
Neurodegenerative Diseases
Tauopathies
Doxycycline
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Antitubercular Agents
Enzyme Inhibitors
Leprostatic Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014