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

  • STATUS
    Recruiting
  • End date
    Jul 22, 2023
  • participants needed
    88
  • sponsor
    Johns Hopkins University
Updated on 22 October 2021
platelet count
cervical cap
amoxicillin
neutrophil count
rifampin
direct microscopy
acid-fast bacilli

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.

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 -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.

Details
Condition Pulmonary tuberculosis
Treatment 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
Clinical Study IdentifierNCT03174184
SponsorJohns Hopkins University
Last Modified on22 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

New or recurrent pulmonary TB with one or both of the following
sputum positive for acid-fast bacilli on direct microscopy of at least grade 1+ (International Union Against Tuberculosis and Lung Disease (IUATLD) scale) on at least one pre-treatment sputum sample
sputum positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of 'medium' or 'high' on at least one pre-treatment sputum sample
Age 18 and 65 years at study screening
Ability and willingness to provide informed consent
Body weight 40 kg to 90 kg, inclusive
Laboratory values obtained within 30 days prior to or at study screening
Absolute neutrophil count (ANC) > 750 cells/mm3
Hemoglobin 7.0 g/dL
Platelet count 50,000/mm3
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 3 X upper limit of normal (ULN)
Total bilirubin 2.5 X ULN
Creatinine < 1.5 X ULN
HIV infection must be documented as either absent or present
For HIV-positive candidates only: CD4+ cell count of 100 cells/cu mm, performed within 30 days prior to or at study screening
For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to or at study screening. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal method of contraception (condoms or an IUD), or another method (diaphragm or cervical cap) if it is approved by the national regulatory authority and used according to package insert, while receiving study medications
Willingness to be hospitalized for a minimum of 16 consecutive days
Ability to produce an overnight sputum sample of sufficient quality and quantity. As a guideline, this should be 10 ml or more during a 16-hour collection period. Volume is clinically estimated from a spot sample provided at screening and verified upon the first overnight collection (which can be repeated upon retraining)
Xpert MTB/RIF result performed on sputum within 14 days prior to or at study screening that shows EITHER 'Rifampin resistance detected' OR 'Rifampin resistance not detected'

Exclusion Criteria

Treatment with any drug active against M. tuberculosis within the 3 months prior to study screening
Breast-feeding
Known allergy or sensitivity to any of the study drugs
Participants receiving valproate sodium or probenecid
Karnofsky score < 60 OR poor general condition such that, in the opinion of the investigator at screening, any delay in initiation of definitive TB treatment cannot be tolerated
Known current neurological TB or seizure disorder
Any condition as determined by physical examination, medical history, laboratory data, or chest x-ray which, in the opinion of the investigator, would interfere with safety or endpoint assessments in the study
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