Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB
Condition: Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 2

Summary: 
      The overall goal of this exploratory proof-of-concept study is to determine whether, in
      participants with pulmonary tuberculosis caused by M. tuberculosis (MTB) with or without
      rifampin resistance-conferring rpoB-gene mutations, the combination of meropenem and
      amoxicillin/clavulanate with rifampin has greater early bactericidal activity (EBA) than the
      combination of meropenem and amoxicillin/clavulanate without rifampin. Funding Source- FDA
      OOPD.
    

Detailed description: 
      This is a proof-of-concept study to determine whether, in humans infected with M.
      tuberculosis that is resistant or susceptible to rifampin based on conventional drug
      susceptibility testing, the combination of meropenem, amoxicillin/clavulanate, and rifampin
      has activity that is sufficiently promising to proceed with further drug development along
      these lines. Rifampin has an incompletely understood but critical role in eradication of M.
      tuberculosis persisters and consequently the shortening of the duration of treatment for
      'rifampin susceptible' tuberculosis (TB). For Multi-Drug Resistant (MDR) / Extensively Drug
      Tuberculosis (XDR) TB, the ability to recoup rifampin's antituberculosis activity through
      rational combination with a carbapenem and a β-lactamase inhibitor with or without
      amoxicillin could transform the treatment of this disease.

      This proof-of-concept study is designed such that a negative outcome would refute the
      hypothesis that the combination of a carbapenem and amoxicillin/clavulanate with rifampin
      will have greater activity than either component alone against M. tuberculosis strains having
      Minimum Inhibitory Concentrations (MIC) in the range considered resistant to rifampin. A
      positive study outcome would catalyze further research to identify optimal dosing strategies
      for all regimen components as well as development of carbapenems optimized for TB treatment
      with respect to targets of activity, stability against hydrolysis, and oral formulation.

      The study hypothesis cannot be tested satisfactorily in traditional animal models of
      tuberculosis chemotherapy due to the rapid inactivation of carbapenems (as well as other
      beta-lactams) by dehydropeptidases that are expressed at high levels in mouse, rabbit, and
      guinea pig tissues. However, all of the study drugs are Food and Drug Administration (FDA)
      -approved for various infectious disease indications, are in routine clinical use, and have
      good safety profiles, such that proceeding with the proposed clinical trial based on in vitro
      data is justified.

      This study will also characterize the relationship between meropenem exposure (in combination
      with amoxicillin/clavulanate) and early bactericidal activity in order to identify the
      pharmacokinetic drivers of activity and pharmacokinetic targets for desired effects. This
      will inform the identification of more feasible meropenem dosing strategies in the near term,
      as well as the dose selection for novel oral carbapenems that may be available for
      tuberculosis treatment in the future. The proportion of the dosing interval for which free
      drug concentrations exceed MIC (T>MIC) is the pharmacokinetic (PK) / pharmacodynamic(PD)
      parameter most closely correlated with efficacy of carbapenems against common fast-growing
      bacteria such as Enterobacteriaceae that cause infections for which meropenem is currently
      approved. A commonly accepted target for efficacy in these infections is 40% T>MIC, which
      requires multiple daily doses to achieve. Whether this PK/PD parameter and target value is
      optimal for carbapenem treatment of infections with M. tuberculosis, which has a much longer
      doubling time, is unknown. In the trial by Diacon et al, meropenem 2 grams thrice daily plus
      amoxicillin/clavulanate resulted in a median T>MIC of 76% [90% Confidence Interval (CI):
      66-93] whereas faropenem sodium 600 mg thrice daily plus amoxicillin/clavulanate resulted in
      T>MIC of 13% (90% CI: 0-33), indicating that if T>MIC is the single parameter most strongly
      linked to efficacy in tuberculosis, then the target for bactericidal effect is between 13%
      and 76%, and lower and/or less frequent doses (or use of oral carbapenems with lower
      bioavailability) may still have significant efficacy. If T>MIC is not the efficacy-linked
      PK/PD parameter, less frequent administration of the same total dose is likely to remain
      equally effective.
    

Intervention name(s): Rifampin; MEROPENEM 2 grams TID; MEROPENEM 1 gram TID; MEROPENEM 3 grams QD; Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet; Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Oral administration of rifampin at a dosage of 20 mg/kg daily; Intravenous administration at a dosage of 2 grams thrice daily; Intravenous administration at a dosage of 1 gram thrice daily; Intravenous administration at a dosage of 3 grams once daily; Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily; Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily
Other intervention name(s): Rifamycins; Merrem; Merrem; Merrem; Augmentin; Augmentin
Intervention MeSH terms: Amoxicillin; Rifampin; Meropenem; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Rifamycins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment