A Pilot Study of Inflammatory Markers in Alzheimer's Disease

February 3, 2009 updated by: McMaster University

A Pilot Study Comparing Inflammatory Biomarkers in Blood and CSF in Patients With Alzheimer's Disease and Age-Matched Controls

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

21

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, L8M1W9
        • Recruiting
        • St.Peter's Hospital
        • Principal Investigator:
          • D. William Molloy, MB

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: FACTORIAL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Apo-doxy
Drug: rifampin
capsule, 300 mg, od, 12 months
Other Names:
  • Rifadin
  • Rofact
  • rifampicin
ACTIVE_COMPARATOR: 2 AD doxycycline
Drug: doxycycline
capsule, 100 mg, b.i.d., 12 months
Other Names:
  • 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:
  • Rifadin
  • Rofact
  • rifampicin
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
IL-1beta
Time Frame: baseline and 12 months
baseline and 12 months
TNF-alpha
Time Frame: baseline and 12 months
baseline and 12 months
MCP-1
Time Frame: baseline and 12 months
baseline and 12 months
IL-4
Time Frame: baseline and 12 month
baseline and 12 month
IL-10
Time Frame: baseline and 12 months
baseline and 12 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Other inflammatory markers.
Time Frame: Baseline and 12 month
Baseline and 12 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster University

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2008

Primary Completion (ANTICIPATED)

August 1, 2009

Study Completion (ANTICIPATED)

October 1, 2009

Study Registration Dates

First Submitted

July 11, 2008

First Submitted That Met QC Criteria

July 11, 2008

First Posted (ESTIMATE)

July 15, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

February 4, 2009

Last Update Submitted That Met QC Criteria

February 3, 2009

Last Verified

February 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R07-63

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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