# Ph2a Study: Rifampin, Merrem, Augmentin for Tuberculosis IND 129159; 12/31/2015

> **NIH FDA R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $499,999

## Abstract

Project Summary/Abstract
Tuberculosis (TB) is the single greatest infectious disease killer globally. Multidrug-resistant (MDR) TB,
caused by M. tuberculosis resistant to isoniazid and rifampin, threatens global TB control. The lengthy,
expensive treatments that can cure MDR-TB are often not accessible by patients who need them, are only
50% successful, and cause unacceptably high toxicity. Rifampin, by virtue of its sterilizing activity against
M. tuberculosis, plays an indispensable role in modern six-month `short-course' therapy for drug-susceptible
TB. In MDR-TB, it is the infecting bacteria's resistance to rifampin that is primarily responsible for the
prolonged treatment duration of 18-24 months that is required when rifampin cannot be used. Up to now,
there are simply no anti-TB drugs with demonstrated sterilizing potency equivalent to that of rifampin.
Strategies that restore rifampin activity, even partially, may have important treatment shortening effects for
MDR-TB. Strategies to potentiate rifampin activity -- that is, to increase the antituberculosis effect of a given
dose of rifampin -- may also be relevant for treatment of drug-susceptible TB. Lamichhane and colleagues
at Johns Hopkins University recently showed that the combination of rifampin plus a carbapenem/β-
lactamase inhibitor is synergistic and lowers the effective rifampin MIC, even restoring the activity of
rifampin in vitro against rifampin-resistant M. tuberculosis. Further, the combination of meropenem plus
amoxicillin/clavulanate has potent antituberculosis activity in human TB and is safe and well-tolerated.
We propose a focused, proof-of-concept clinical trial to determine whether, in pulmonary TB patients, a
carbapenem/ β-lactamase inhibitor combination can serve as a rifampin `sensitizer' and thereby potentiate
the antituberculosis activity of rifampin. In this phase 2a randomized, open-label trial we will enroll patients
with rifampin-susceptible pulmonary TB as well as patients with rifampin-resistant pulmonary TB.
Participants will be randomized to receive one of 5 treatments for 7 days:
 Baseline DST Regimen Regimen Components 
Rifampin
resistant
Randomized
(1:1) to: A Rifampin Meropenem Amx/Clv
B - Meropenem Amx/Clv
Rifampin
susceptible
Randomized
(1:1:1) to: C Rifampin Meropenem Amx/Clv
D - Meropenem Amx/Clv
E Rifampin - -
Abbreviations: DST, drug-susceptibility testing; Amx/Clv, amoxicillin/clavulanate
The primary endpoint is mean daily fall in log10 colony forming units of M. tuberculosis per mL of sputum
over 7 days of treatment. Safety of the regimens will be assessed. We will incorporate intensive
pharmacokinetic (PK) and mycobacteriology assessments which, in the context of a range of M.
tuberculosis minimum inhibitor concentrations (MICs) and expected inter-individual rifampin PK variability,
will allow determination of the pharmacodynamic relationships between rifampin, rifampin area under the
concentration-time curve (AUC), and antituberculosis act...

## Key facts

- **NIH application ID:** 10014610
- **Project number:** 5R01FD005724-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kelly E. Dooley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** FDA
- **Fiscal year:** 2020
- **Award amount:** $499,999
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014610

## Citation

> US National Institutes of Health, RePORTER application 10014610, Ph2a Study: Rifampin, Merrem, Augmentin for Tuberculosis IND 129159; 12/31/2015 (5R01FD005724-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10014610. Licensed CC0.

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