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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

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ClinicalTrials.gov Identifier: NCT02381470
Recruitment Status : Not yet recruiting
First Posted : March 6, 2015
Last Update Posted : December 18, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Pulmonary Tuberculosis Drug: Faropenem Drug: Amoxicillin/clavulanic acid Drug: Cefadroxil Drug: Rifampicin Phase 2

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 45 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : April 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

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 Name: 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 Name: Rifampin




Primary Outcome Measures :
  1. Rate of change of time to positivity (TTP) in liquid culture from day 0 to day 2 [ Time Frame: 2 days ]

Secondary Outcome Measures :
  1. Rate of change of TTP in liquid culture from day 0 to day 7 [ Time Frame: 7 days ]
  2. Change in CFU/ml in solid culture from Day 0 to Day 2 [ Time Frame: 2 days ]
  3. Change in CFU/ml in solid culture from Day 0 to Day 7 [ Time Frame: 7 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02381470


Contacts
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Contact: Claire Naftalin +65 6601 5373 claire_naftalin@nuhs.edu.sg
Contact: Jing Wang +65 6601 5374 mdcwaj@nus.edu.sg

Locations
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Philippines
De La Salle Health Institute Not yet recruiting
Cavite, Philippines
Contact: Marietto Partosa         
Principal Investigator: Marietto Partosa         
Tropical Disease Foundation Not yet recruiting
Makati City, Philippines
Contact: Thelma Tupasi         
Principal Investigator: Thelma Tupasi         
Lung Center Philippines Not yet recruiting
Quezon City, Philippines
Contact: Vincent Balanag         
Principal Investigator: Vincent Balanag         
Singapore
National University Hospital, Singapore Not yet recruiting
Singapore, Singapore
Contact: Claire Naftalin         
Principal Investigator: Nicholas Paton         
Sponsors and Collaborators
National University Hospital, Singapore
Investigators
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Principal Investigator: Nicholas Paton National University Hospital, Singapore

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Responsible Party: National University Hospital, Singapore
ClinicalTrials.gov Identifier: NCT02381470     History of Changes
Other Study ID Numbers: Faropenem_TB
First Posted: March 6, 2015    Key Record Dates
Last Update Posted: December 18, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National University Hospital, Singapore:
Beta lactams
adjunctive therapy
drug-sensitive tuberculosis

Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Amoxicillin
Rifampin
Clavulanic Acids
Clavulanic Acid
Cefadroxil
beta-Lactams
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
beta-Lactamase Inhibitors