A Pilot Study of Inflammatory Markers in Alzheimer's Disease - Full Text View

Sponsor:	McMaster University
Collaborator:	The Physicians' Services Incorporated Foundation
Information provided by:	McMaster University
ClinicalTrials.gov Identifier:	NCT00715858

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 III

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Factorial Assignment
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:

Genetics Home Reference related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease Dementia

Drug Information available for: Rifampin Doxycycline Doxycycline hyclate Doxycycline calcium

U.S. FDA Resources

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
1 AD doxycycline + rifampin: Active Comparator 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 Drug: rifampin capsule, 300 mg, od, 12 months
2 AD doxycycline: Active Comparator	Drug: doxycycline capsule, 100 mg, b.i.d., 12 months Drug: placebo placebo matched to rifampin; placebo matched to doxycycline
3 AD rifampin: Active Comparator 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 Drug: placebo placebo matched to rifampin; placebo matched to doxycycline
4 AD placebo: Placebo Comparator 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
5 Control: No Intervention 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

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:

DARAD Study clinical trial registration on ISRCTN15039674. Details provided. This link exits the ClinicalTrials.gov site

Publications:

Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson W, McDougall A, Gnarpe J, O'DONNell M, Chernesky M. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc. 2004 Mar;52(3):381-7.

Responsible Party:	McMaster University ( William Molloy )
Study ID Numbers:	R07-63
Study First Received:	July 11, 2008
Last Updated:	February 3, 2009
ClinicalTrials.gov Identifier:	NCT00715858 History of Changes
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:

Anti-Infective Agents
Antiprotozoal Agents
Molecular Mechanisms of Pharmacological Action
Alzheimer Disease
Nervous System Diseases
Central Nervous System Diseases
Enzyme Inhibitors
Brain Diseases
Neurodegenerative Diseases
Pharmacologic Actions
Antibiotics, Antitubercular
Antimalarials

Rifampin
Anti-Bacterial Agents
Antiparasitic Agents
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Therapeutic Uses
Antitubercular Agents
Dementia
Tauopathies
Nucleic Acid Synthesis Inhibitors
Doxycycline
Leprostatic Agents

ClinicalTrials.gov processed this record on November 27, 2009