NCT03174184

Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB

A Phase 2a Study of the Early Bactericidal Activity of Rifampin (RIF) in Combination With Meropenem Plus Amoxicillin/Clavulanate Among Adults With Rifampin-resistant or Rifampin-susceptible Pulmonary Tuberculosis

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 112 (actual)
• Sponsor: Johns Hopkins University · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Tuberculosis, Pulmonary

Interventions

Type	Name	Description
DRUG	Rifampin	Oral administration of rifampin at a dosage of 20 mg/kg daily
DRUG	MEROPENEM 2 grams TID	Intravenous administration at a dosage of 2 grams thrice daily
DRUG	MEROPENEM 1 gram TID	Intravenous administration at a dosage of 1 gram thrice daily
DRUG	MEROPENEM 3 grams QD	Intravenous administration at a dosage of 3 grams once daily
DRUG	Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet	Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily
DRUG	Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet	Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily

Timeline

• Start date: 2017-08-23
• Primary completion: 2022-05-13
• Completion: 2022-05-13
• First posted: 2017-06-02
• Last updated: 2023-07-19
• Results posted: 2023-07-19

Locations

1 site across 1 country: South Africa

Regulatory

• FDA-regulated drug study