A Pilot Study of Inflammatory Markers in Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00715858
Recruitment Status : Unknown
Verified February 2009 by McMaster University.
Recruitment status was:  Recruiting
First Posted : July 15, 2008
Last Update Posted : February 4, 2009
The Physicians' Services Incorporated Foundation
Information provided by:
McMaster University

Brief Summary:
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 or disease Intervention/treatment Phase
Alzheimer's Disease Drug: doxycycline Drug: rifampin Drug: placebo Phase 3

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  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Care Provider, 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
Study Start Date : May 2008
Estimated Primary Completion Date : August 2009
Estimated Study Completion Date : October 2009

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 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)

Primary Outcome Measures :
  1. IL-1beta [ Time Frame: baseline and 12 months ]
  2. TNF-alpha [ Time Frame: baseline and 12 months ]
  3. MCP-1 [ Time Frame: baseline and 12 months ]
  4. IL-4 [ Time Frame: baseline and 12 month ]
  5. IL-10 [ Time Frame: baseline and 12 months ]

Secondary Outcome Measures :
  1. Other inflammatory markers. [ Time Frame: Baseline and 12 month ]

Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00715858

Contact: D. William Molloy, MB 905-777-3837 ext 12440
Contact: Timothy I Standish, MA 905-777-3837 ext 12442

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
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

Additional Information:
Responsible Party: William Molloy, McMaster University Identifier: NCT00715858     History of Changes
Other Study ID Numbers: R07-63
First Posted: July 15, 2008    Key Record Dates
Last Update Posted: February 4, 2009
Last Verified: February 2009

Keywords provided by McMaster University:
Alzheimer's disease
cerebrospinal fluid

Additional relevant MeSH terms:
Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers