The BLAST- 1 Trial - Cephalexin+Amoxicillin-clavulanate for Tuberculosis

Study Overview
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Brief Summary
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The goal of this randomized controlled trial is to study the early bactericidal activity in adult patients with smear-positive pulmonary tuberculosis. The main question it aims to answer are if cephalexin, in combination with amoxicillin-clavulanate, is effective in the treatment of tuberculosis. Participants with smear-positive tuberculosis will be randomized to either of two groups: Intervention group: cephalexin and amoxicillin-clavulanate. Control group: Standard of care TB treatment. The study period is 2 weeks and participants will be asked to submit multiple sputum samples to measure the bacterial sputum load. They will also submit saliva samples for estimation of drug concentrations in the body. Researchers will compare the intervention group with the control group to see if the trial drugs result in a reduced bacterial sputum load Overall aim: To study the early bactericidal activity of cephalexin, in combination with amoxicillin-clavulanate, in comparison to standard treatment in patients with active pulmonary tuberculosis during the first 2 weeks of treatment. Primary aim: To evaluate the early bactericidal activity (measured as 'time to culture positivity') of cephalexin-clavulanate in comparison, to standard TB treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol). Secondary aim: To asses safety and tolerability of cephalexin together with amoxicillin-clavulanate. To determine key pharmacokinetic (PK) parameters of cephalexin, especially half-life and drug exposure (maximal concentration; Cmax and area under the concentration versus time curve, AUC).

Detailed Description
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Given the need for alternative and well-tolerated tuberculosis (TB) treatment options, there is scope to re-assess the potential value of already approved drugs that are known to be safe, cheap and widely available. Cephalexin, in combination with amoxicillin-clavulanate, have shown high in vitro efficacy against the TB bacteria. Both cephalexin and amoxicillin-clavulanate are Therapeutic Goods Administration (TGA) approved and are widely used in Australia for common infections. In order to compare the bacterial killing effect of cephalexin, in combination with amoxicillin-clavulanate, with current standard of care TB treatment, we will perform an open-label randomized controlled trial. Eligible and consenting study participants with bacteriologically confirmed sputum-smear positive pulmonary TB will be randomised to an intervention or control arm in a 1:1 ratio (15 patients in each arm) for the two weeks duration of the trial. Intervention arm: cephalexin 1g thrice daily + amoxicillin-clavulanate 500/125 mg thrice daily. Control arm: standard of care treatment for TB (rifampicin, isoniazid, ethambutol and pyrazinamide) The primary outcome is the fall in bacterial load measured by 'time to positive culture' using the BACTEC MGIT system with automated detection. Multiple sputum samples (10 in total) will be collected during the first 2 weeks of TB treatment. Six saliva samples will be collected after 4 days of treatment, in order to estimate the drug concentrations of cephalexin in the body (intervention arm only). For a small subset of patients receiving cephalexin (n=5), a more intensive simultaneous blood and saliva sampling will be done in order to calculate the saliva:plasma ratio, in order to facilitate the estimation of plasma drug concentrations from saliva samples.

Official Title
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Early Bactericidal Activity of Cephalexin and Amoxicillin-clavulanate for Susceptible Tuberculosis - BLAST 1 Trial

Conditions
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Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: Cephalexin
* Drug: Amoxicillin-Clavulanate 500 Mg-125 Mg Oral Tablet
* Other: Standard of care treatment of tuberculosis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consenting adults (≥18 years) ≥40 kg Smear-positive patients with active tuberculosis, confirmed by sputum smear, TB PCR and/or GeneXpert. Exclusion Criteria: On TB treatment for >1 day Condition affecting ability of an informed consent (i.e. dementia, delirium etc). Pregnancy or breast-feeding HIV Known allergy or sensitivity to any of the study drugs Drug-resistant TB (resistance to rifampicin and/or isoniazid) Poor general condition or severe infection such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated TB with concomitant central nervous system and/or cardiac involvement. Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study. Use of metformin, probenecid or allopurinol Known previous Clostridium difficile infection due to the risk of colitis. (In case no medical records are available, it should be suspected in elderly patients reporting severe gastrointestinal infections in relation to courses of antibiotics)

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized-controlled early bactericidal activity trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care TB<br>Standard of care treatment for TB (rifampicin, isoniazid, ethambutol and pyrazinamide according to WHO) | Other: Standard of care treatment of tuberculosis<br>* The control group will be given standard of care treatment of tuberculosis consisting of rifampicin, isoniazid, pyrazinamide and ethambutol<br>* Other names: HREZ;|
| Experimental: Cephalexin + amoxicillin-clavulanate<br>Intervention arm: cephalexin 1g thrice daily + amoxicillin-clavulanate 500/125 mg thrice daily. | Drug: Cephalexin<br>* Participants in intervention group will receive a combination of cephalexin and amoxicillin-clavulanate for the first 2 weeks of TB treatment<br>* Other names: Keflex;Drug: Amoxicillin-Clavulanate 500 Mg-125 Mg Oral Tablet<br>* Participants in the intervention group will receive a combination of cephalexin and amoxicillin-clavulanate for the first 2 weeks of TB treatment<br>* Other names: Augmentin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to positivity (TTP) | Early bactericidal activity measured as fall in time to positivity (TTP) 1. The primary outcome is fall in bacterial load in sputum, measured as the rate of change in Time to Sputum Culture Positivity (TTP). TTP is the time to a positive culture when sputum samples are incubated in BACTEC MGIT for automated detection of M. tuberculosis. Measuring the fall in bacterial load is standard choice of outcome for studies evaluating the effect (kill) of drug on TB bacteria. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Tolerability - frequency, categorization and grade of adverse events according to CTCAE (Common Terminology Criteria for Adverse Events) | 2 weeks | 
| Area under the concentration versus time curve (AUC) of cephalexin | Estimation of the pharmacokinetic parameter area under the concentration versus time curve (AUC) of cephalexin in saliva. | 2 weeks | 
| Cmax of cephalexin | Estimation of the pharmacokinetic parameter maximum concentration (Cmax) of cephalexin saliva. | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized controlled trial, Early bactericidal activity, Smear-positive TB, Betalactam antibiotics, Cephalosporin, Time to positivity