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

Phase 2

Completed

• Conditions: Pulmonary Tuberculosis
• Interventions: Drug: Faropenem; Drug: Rifampicin; Drug: Amoxicillin/clavulanic acid; Drug: Cefadroxil

• Registration Number: NCT02381470
• Lead Sponsor: National University Hospital, Singapore

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2015-03-02
• Study First Submitted QC: 2015-03-05
• Study First Posted: 2015-03-06
• Study Start: 2019-02-11
• Primary Completion: 2019-09-28
• Study Completion: 2019-10-02
• Status Verified: 2020-03
• Last Update Submitted: 2020-03-19
• Last Update Posted: 2020-03-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Faropenem	Amoxicillin/clavulanic acid	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
Cefadroxil	Amoxicillin/clavulanic acid	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
Faropenem	Faropenem	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
Cefadroxil	Cefadroxil	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
Control	Rifampicin	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

Primary Outcome Measures

Name	Time	Method
Rate of change of time to positivity (TTP) in liquid culture from day 0 to day 2	2 days

Secondary Outcome Measures

Name	Time	Method
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 7	7 days
Change in CFU/ml in solid culture from Day 0 to Day 2	2 days

Trial Locations

Locations (6)

Tropical Disease Foundation; 🇵🇭 Makati City, Philippines

De La Salle Health Institute; 🇵🇭 Cavite, Philippines

National University Hospital, Singapore; 🇸🇬 Singapore, Singapore

Infectious Diseases Institute; 🇺🇬 Kampala, Uganda

Joint Clinical Research Centre; 🇺🇬 Kampala, Uganda

Lung Center Philippines; 🇵🇭 Quezon City, Philippines