Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03174184 |
Other study ID # |
IRB00119017 |
Secondary ID |
FD-R-05724 |
Status |
Completed |
Phase |
Phase 2
|
First received |
|
Last updated |
|
Start date |
August 23, 2017 |
Est. completion date |
May 13, 2022 |
Study information
Verified date |
June 2023 |
Source |
Johns Hopkins University |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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 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.