Evaluating Celecoxib Activity in Mycobacterium Tuberculosis: A Whole Blood Bactericidal Activity Study in Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the bactericidal activity against Mycobacterium tuberculosis of celecoxib in combination with established drugs used to treat tuberculosis (TB). Pharmacokinetics (PK) and whole blood bactericidal activity (WBA) will be measured in healthy volunteers following administration of the study drugs alone and in combination.

Detailed Description
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The whole blood bactericidal activity (WBA) assay is an ex vivo model for measuring the combined effects of administered drugs, host factors and strain factors on mycobacterial sterilisation. If performed in parallel with PK measurements, the method can be used to evaluate the effect of drugs throughout the dosing cycle. Celecoxib is a COX-2 inhibitor with immuno-modulatory properties important in the host defence against tuberculosis (TB). The aim of this trial is to investigate the effect on WBA of manipulation of the host response to TB using celecoxib, in combination with established TB drugs.

Official Title
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Evaluating Celecoxib Activity in Mycobacterium Tuberculosis: A Whole Blood Bactericidal Activity Study in Healthy Volunteers

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Celecoxib
* Drug: Rifampicin
* Drug: Pyrazinamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged over 21 years and below 60 years old Male or female willing to comply with the study visits and procedures Willing and able to provide written informed consent Exclusion Criteria: Women who are currently pregnant or breastfeeding Body weight below 50kg Clinical signs of active TB in the opinion of the investigator Previous hypersensitivity, intolerance or allergy to rifampicin, pyrazinamide, COX-2 inhibitors, non-steroidal anti-inflammatory drugs or sulfonamides Current use of any drugs or medication known to have an interaction with rifampicin, pyrazinamide or celecoxib Current use or use in the last 2 weeks of non-steroidal anti-inflammatory drugs or COX-2 inhibitors Current use or use in the last 2 weeks of any drugs, over the counter or herbal preparations that are known or potential inhibitors or inducers of cytochrome P450 enzymes Evidence of renal or hepatic dysfunction or any clinically significant deviation from normal during screening including laboratory determinations Known hepatic disease, recent hepatitis (within last 6 months) or alcohol abuse Known cardiovascular disease, heart failure, stroke or current cardiovascular risk factors Known peptic ulcer disease, previous gastrointestinal bleed or current risk factors for gastrointestinal events Acute or previous gout, acute porphyria Any other significant condition that would, in the opinion of the investigator, compromise the volunteer's safety or outcome in the trial Current participation in other clinical intervention trial or research protocol

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Celecoxib plus rifampicin group<br>Visit 1: Celecoxib 400mg Visit 2: Rifampicin 10mg/kg Visit 3: Celecoxib 400mg PLUS rifampicin 10mg/kg | Drug: Celecoxib<br> <br> * Other names: Celebrex;Drug: Rifampicin<br> <br> * Other names: Rifampin;|
| Experimental: Celecoxib plus pyrazinamide group<br>Visit 1: Celecoxib 400mg Visit 2: Pyrazinamide 25mg/kg Visit 3: Celecoxib 400mg PLUS pyrazinamide 25mg/kg | Drug: Celecoxib<br> <br> * Other names: Celebrex;Drug: Pyrazinamide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Log change CFU.day (cumulative over 8 hours) calculated from Mycobacteria Growth Indicator Tube (MGIT) Time to Positivity | Cumulative whole blood bactericidal activity (WBA) | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of study drugs to determine the Area Under the Curve (AUC) |  | 8 hours | 
| Plasma concentrations of study drugs to determine the Maximum Plasma Concentration (Cmax) |  | 8 hours |