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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: doxycycline
* Drug: rifampicin
* Drug: Placebo matched to doxycycline
* Drug: Placebo matched to Rifampin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tau, doxycycline, rifampicin, cerebrospinal fluid, biomarkers, beta amyloid