Effects of Doxycycline and Rifampicin on Biomarkers of Alzheimer's Disease in the Cerebrospinal Fluid

Effects of Treatment With Doxycycline and Rifampicin on Biomarkers of Alzheimer's Disease in the Cerebrospinal Fluid

This study will determine if biomarkers found in the cerebrospinal fluid of people with Alzheimer's disease, are affected by treatment with two common antibiotics, doxycycline and rifampicin, suggesting a disease-modifying effect of those treatments.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: doxycycline; Drug: rifampicin; Drug: Placebo matched to Rifampin; Drug: Placebo matched to doxycycline

Detailed Description

Diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Potential disease-modifying drugs like the antibiotics rifampicin and doxycycline, highlight the need of improved diagnostic accuracy and offer the potential to examine how these treatments may actually exert their clinical effects.

Cerebrospinal fluid biomarkers (the 42 amino acid form of β-amyloid (Aβ), total tau, and phosphorylated tau) have been evaluated in scientific studies. Tau proteins are considered "state" markers, whereas Aβ(1-42) proteins can be used as "stage" markers. These CSF markers have high sensitivity to differentiate early AD from normal aging, depression, alcohol dementia and Parkinson's disease. When these biomarkers are used in combination with a medical history, clinical examination, laboratory tests and brain imaging, the diagnostic accuracy is improved.

Matrix metalloproteinase (MMP) dysregulation is thought to contribute to a variety of pathological conditions such as arthritis, cancer, atherosclerosis, aneurysms, nephritis, tissue ulcers, and fibrosis. In addition, MMP involvement has been demonstrated in the pathogenesis of a variety of CNS disorders, including bacterial and viral disorders, stroke, multiple sclerosis, ALS, and AD.

There is an inflammatory response in AD. This includes complement activation, elevated C-reactive protein (CRP), elevated pro-inflammatory cytokines (including IL-1-β, IL-6, TNF-α, TGF-β, S100-β), chemokine alterations (IL-8, MIP-1-α, MIP-1-β, MCP-1), and microglial.

We are measuring the biochemical markers of Aβ(1-40) and Aβ(1-42), P-tau and T-tau, matrix metalloproteinases (MMP-2, MMP-9), pro-inflammatory cytokines (IL-1beta, TNF-alpha), and anti-inflammatory cytokines (IL-4 and IL-10) at the start and one year after treatment in the multi-centered, randomized, controlled, trial of disease-modifying drugs rifampicin and/or and doxycycline to slow the progress of Alzheimer's disease by affecting the production of these biomarkers.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8M1W9
      • St.Peter's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female
• Age greater than or equal to 50 years
• Diagnosis of probable Alzheimer's disease by NINCDS-ADRDA criteria
• Standardized Mini-Mental State Examination score 14-26 inclusive
• A caregiver who consents to monitor study medications, report on patient function, bring the patient to visits, etc.
• Vision, hearing, language ability sufficient to complete standardized testing in English.
• Patient consents (or legal representative consents for patient)
• Generally stable level of health where patient may be reasonably expected to complete a 1 year trial

Exclusion Criteria:

• Other neurodegenerative diseases such as Lewy body or Parkinson's
• Cognitive impairment due to: acute trauma, subdural hematoma, hypoxic cerebral damage, B12 deficiency, infections such as AIDS or meningitis, cerebral neoplasia, endocrine deficiencies, mental retardation
• Significant cerebrovascular disease or multi-infarct dementia
• Intra-cranial pathology such as tumour
• Co-existing medical conditions such as epilepsy, major psychiatric conditions, depression (Cornell Depression in Dementia Scale score of 12 or more), significant liver, kidney, lung, metabolic or endocrine diseases
• Clinically significant cardiac disease such as uncontrolled angina or hypertension
• Anti-dementia treatments other than donepezil, galantamine, rivastigmine, memantine
• Enrollment in trials with other investigational drugs
• Antibiotic use more than one month in the last six months
• Allergy to doxycycline or rifampicin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 AD combined doxycycline + rifampin; Doxycycline 100 mg b.i.d. plus rifampin 300 mg o.d. for 12 months.	Drug: doxycycline; capsule, 100 mg, b.i.d., daily for 1 year; Drug: rifampicin; capsule, 300mg, o.d., daily for 11 months (administration starts in 2nd month of trial); Other Names: Rifadin; Rofact
Experimental: 2 AD Doxycycline only; Doxycycline 100 mg b.i.d. plus placebo matched to rifampin o.d. for 12 months.	Drug: doxycycline; capsule, 100 mg, b.i.d., daily for 1 year; Drug: Placebo matched to Rifampin; Rifampin-matched - red capsule, o.d., daily for 11 months starting at month 2.
Experimental: 3 Rifampin only; Rifampin 300 mg o.d. plus placebo matched to doxycycline b.i.d. for 12 months.	Drug: rifampicin; capsule, 300mg, o.d., daily for 11 months (administration starts in 2nd month of trial); Other Names: Rifadin; Rofact; Drug: Placebo matched to doxycycline; Doxycycline-matched - blue capsule, b.i.d.,daily for 12 months
Placebo Comparator: 4 Double Placebo; Placebo matched to Doxycycline b.i.d. plus placebo matched to rifampin o.d. for 12 months.	Drug: Placebo matched to Rifampin; Rifampin-matched - red capsule, o.d., daily for 11 months starting at month 2.; Drug: Placebo matched to doxycycline; Doxycycline-matched - blue capsule, b.i.d.,daily for 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinical Dementia Rating scale	12 months
Standardized Alzheimer's disease Assessment Scale -cognitive subscale	12 months

Collaborators and Investigators

• Sponsor: Hamilton Health Sciences Corporation
• Collaborators: The Physicians' Services Incorporated Foundation
• Investigators: Study Chair: William Molloy, MB, FRCPC, McMaster University; Principal Investigator: Tricia KW Woo, MD, FRCPC, McMaster University; Principal Investigator: David D Cowan, MD, FRCPC, McMaster University; Principal Investigator: Brandon M Kucher, PhD, McMaster University; Principal Investigator: Alwin Cunje, MD, PhD, University of Ottawa; Principal Investigator: Tim I Standish, MA, McMaster University

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: February 20, 2007
• First Submitted That Met QC Criteria: February 21, 2007
• First Posted (Estimate): February 23, 2007

Study Record Updates

• Last Update Posted (Actual): March 19, 2018
• Last Update Submitted That Met QC Criteria: March 15, 2018
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: biomarkers; tau; cerebrospinal fluid; doxycycline; rifampicin; beta amyloid
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Antiprotozoal Agents; Antiparasitic Agents; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antimalarials; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Doxycycline; Rifampin
• Other Study ID Numbers: PSI 06-47