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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: Faropenem; Drug: Amoxicillin/clavulanic acid; Drug: Cefadroxil; Drug: Rifampicin

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 Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Philippines
  • Cavite, Philippines
    • De La Salle Health Institute
  • Makati City, Philippines
    • Tropical Disease Foundation
  • Quezon City, Philippines
    • Lung Center Philippines
• Singapore
  • Singapore, Singapore
    • National University Hospital, Singapore
• Uganda
  • Kampala, Uganda
    • Infectious Diseases Institute
  • Kampala, Uganda
    • Joint Clinical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Patient inclusion criteria:

1. Aged 18 to 70 years
2. Clinical features compatible with pulmonary TB
3. Sputum smear graded at least 1 +
4. Estimated to be producing at least 5ml of sputum per day
5. Willing to comply with study procedures and able to provide written informed consent.

Patient exclusion criteria:

1. Suspected miliary TB or TB meningitis
2. Patients receiving any TB treatment within the previous 6 months
3. Patients too ill to tolerate a 2-3 day delay in standard therapy
4. Concurrent bacterial pneumonia
5. Known hypersensitivity to beta-lactam drugs (penicillins, carbapenems) or rifampicin
6. History of severe allergies or severe asthma
7. Receiving loop diuretics
8. Estimated creatinine clearance < 80 ml/min on screening blood test
9. ALT > 2.5 times upper limit of normal on screening blood test.
10. Presence of rifampicin resistance on GeneXpert (or alternative molecular test).
11. Women who are currently pregnant or breastfeeding.
12. Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.
13. Participation in other clinical intervention trial or research protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Faropenem; Faropenem 600mg; Other Names: Farobact 200; Drug: Amoxicillin/clavulanic acid; Amoxicillin 500mg/ clavulanic acid 125mg; Other Names: Augmentin; Co-amoxiclav
Experimental: 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	Drug: Amoxicillin/clavulanic acid; Amoxicillin 500mg/ clavulanic acid 125mg; Other Names: Augmentin; Co-amoxiclav; Drug: Cefadroxil; Cefadroxil 1g
Active Comparator: Control; 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; Rifampicin 10mg/kg; Other Names: Rifampin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Actual): September 28, 2019
• Study Completion (Actual): October 2, 2019

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: March 5, 2015
• First Posted (Estimate): March 6, 2015

Study Record Updates

• Last Update Posted (Actual): March 23, 2020
• Last Update Submitted That Met QC Criteria: March 19, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: adjunctive therapy; Beta lactams; drug-sensitive tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; beta-Lactamase Inhibitors; Rifampin; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Cefadroxil
• Other Study ID Numbers: Faropenem_TB

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No