Trial of Faropenem and Cefadroxil (in Combination With Amoxicillin/Clavulanic Acid and Standard TB Drugs) in Patients With Pulmonary Tuberculosis: Measurement of Early Bactericidal Activity and Effects on Novel Biomarkers

Study Overview
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Brief Summary
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This trial aims to determine whether the early bactericidal activity of rifampicin given with faropenem or cefadroxil (each given with amoxicillin/clavulanic acid) is greater than the activity of rifampicin alone in patients with pulmonary TB. The trial will also investigate potential new biomarkers of sterilising activity.

Detailed Description
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Tuberculosis (TB) remains one of the leading causes of mortality from an infectious disease worldwide with approximately 2 million deaths annually. There is an urgent need to identify new drugs, especially drugs with activity against persistent organisms that may enable shorter treatment regimens. Beta-lactam antibiotics have activity against TB in vitro and in animal models and there is evidence of synergy with rifampicin, one of the standard TB drugs. Amongst oral beta-lactam antibiotics, two appear to have optimal properties and optimal synergy with rifampicin and may be candidates for adjunctive treatment of drug-sensitive TB: faropenem (an oral penem, closely related to the carbapenem class) and cefadroxil (a first generation cephalosporin). Both drugs are used widely for the treatment of bacterial infections. They have in vitro activity against Mycobacterium tuberculosis, which is augmented when administered with rifampicin. This is a Phase II randomised, controlled, open-label, early bactericidal activity trial. We will recruit patients between the ages of 18 and 70 with newly-diagnosed smear positive pulmonary TB, who have not yet started TB therapy. Patients will be randomised into one of 3 arms to take faropenem (with amoxicillin/clavulanic acid) plus rifampicin, or cefadroxil (with amoxicillin/ clavulanic acid) plus rifampicin, or rifampicin alone for the first two days of the study. Patients will start standard TB therapy on the third day of the study and continue with the beta lactam antibiotics for the remaining 5 days of the study. Following the completion of the 7 days of study medication, the study will end and patients will continue standard combination TB therapy under normal clinical follow-up.

Official Title
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Trial of Faropenem and Cefadroxil (in Combination With Amoxicillin/Clavulanic Acid and Standard TB Drugs) in Patients With Pulmonary Tuberculosis: Measurement of Early Bactericidal Activity and Effects on Novel Biomarkers

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: Faropenem
* Drug: Amoxicillin/clavulanic acid
* Drug: Cefadroxil
* Drug: Rifampicin


Participation Criteria
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Eligibility Criteria
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Patient inclusion criteria: Aged 18 to 70 years Clinical features compatible with pulmonary TB Sputum smear graded at least 1 + Estimated to be producing at least 5ml of sputum per day Willing to comply with study procedures and able to provide written informed consent. Patient exclusion criteria: Suspected miliary TB or TB meningitis Patients receiving any TB treatment within the previous 6 months Patients too ill to tolerate a 2-3 day delay in standard therapy Concurrent bacterial pneumonia Known hypersensitivity to beta-lactam drugs (penicillins, carbapenems) or rifampicin History of severe allergies or severe asthma Receiving loop diuretics Estimated creatinine clearance < 80 ml/min on screening blood test ALT > 2.5 times upper limit of normal on screening blood test. Presence of rifampicin resistance on GeneXpert (or alternative molecular test). Women who are currently pregnant or breastfeeding. Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial. Participation in other clinical intervention trial or research protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Faropenem<br>Faropenem 600mg (with amoxicillin/clavulanic acid, 500mg/125mg) given three times daily for 7 days PLUS Rifampicin 10mg/kg once daily alone for the first 2 days then standard combination therapy (rifampicin, isoniazid, pyrazinamide, ethambutol, adjusted for body weight) for the following 5 days | Drug: Faropenem<br>* Faropenem 600mg<br>* Other names: Farobact 200;Drug: Amoxicillin/clavulanic acid<br>* Amoxicillin 500mg/ clavulanic acid 125mg<br>* Other names: Co-amoxiclav;|
| Experimental: Cefadroxil<br>Cefadroxil 1g (with amoxicillin/clavulanic acid, 500mg/125mg) given twice daily for 7 days PLUS Rifampicin 10mg/kg once daily alone for the first 2 days then standard combination therapy (rifampicin, isoniazid, pyrazinamide, ethambutol, adjusted for body weight) for the following 5 days | Drug: Amoxicillin/clavulanic acid<br>* Amoxicillin 500mg/ clavulanic acid 125mg<br>* Other names: Co-amoxiclav;Drug: Cefadroxil<br>* Cefadroxil 1g<br>|
| Active Comparator: Control<br>Rifampicin 10mg/kg once daily alone for the first 2 days then standard combination therapy (rifampicin, isoniazid, pyrazinamide, ethambutol, adjusted for body weight) for the following 5 days | Drug: Rifampicin<br>* Rifampicin 10mg/kg<br>* Other names: Rifampin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change of time to positivity (TTP) in liquid culture from day 0 to day 2 |  | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change of TTP in liquid culture from day 0 to day 7 |  | 7 days | 
| Change in CFU/ml in solid culture from Day 0 to Day 2 |  | 2 days | 
| Change in CFU/ml in solid culture from Day 0 to Day 7 |  | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta lactams, adjunctive therapy, drug-sensitive tuberculosis