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Tuberculosis, PulmonaryPhase 2NCT03174184

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

A Phase 2 study testing Rifampin, MEROPENEM 2 grams TID and MEROPENEM 1 gram TID in people with Tuberculosis, Pulmonary, run by Johns Hopkins University at 1 site in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Tuberculosis, Pulmonary
What is being tested?
Rifampin, MEROPENEM 2 grams TID and MEROPENEM 1 gram TID
Could I receive a placebo?
No, everyone receives an active treatment
How many people
112 participants
Where
1 siteSouth Africa
Study dates
23 Aug 2017to 13 May 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 19Show fewer
  • 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'

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

South Africa1 site

  • Task Applied Science and Stellenbosch University

    Stellenbosch, 7505

Other trials in South Africa

About this study

Official title: 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

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.

Read the 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.

Being tested
Rifampin, MEROPENEM 2 grams TID, MEROPENEM 1 gram TID, MEROPENEM 3 grams QD, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Medical subject headings
Tuberculosis, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RifampinDrug

    Also called Rifamycins

    Oral administration of rifampin at a dosage of 20 mg/kg daily

  • MEROPENEM 2 grams TIDDrug

    Also called Merrem

    Intravenous administration at a dosage of 2 grams thrice daily

  • MEROPENEM 1 gram TIDDrug

    Also called Merrem

    Intravenous administration at a dosage of 1 gram thrice daily

  • MEROPENEM 3 grams QDDrug

    Also called Merrem

    Intravenous administration at a dosage of 3 grams once daily

  • Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral TabletDrug

    Also called Augmentin

    Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily

  • Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral TabletDrug

    Also called Augmentin

    Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily

Study groups in NCT03174184
Study groupRoleWhat they receive
Rifampin resistant AExperimentalParticipants with the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive RIFAMPIN 20mg/kg once daily (QD), MEROPENEM 2 grams (G) thrice daily (TID) intravenously, Amoxicillin/Clavulanate Potassium 500 milligrams (MG)-125 MG Oral Tablet once daily for 14 days
Receives: Drug: Rifampin; Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Rifampin resistant BExperimentalParticipants with the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 2 grams TID (thrice daily) intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
Receives: Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Rifampin susceptible CExperimentalParticipants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive RIFAMPIN 20mg/kg once daily, MEROPENEM 2 grams TID (thrice daily) intravenously, Amx/Clv orally at a dose of 500 mg/125 mg thrice daily for 14 days
Receives: Drug: Rifampin; Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Rifampin susceptible DExperimentalParticipants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 2 grams TID intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
Receives: Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Rifampin susceptible EExperimentalParticipants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 1 gram TID intravenously, Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet once daily for 14 days
Receives: Drug: MEROPENEM 1 gram TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet
Rifampin susceptible FExperimentalParticipants without the presence of rifampin resistance-conferring rpoB mutations in M. tuberculosis who will receive MEROPENEM 3 grams QD intravenously, Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet once daily for 14 days
Receives: Drug: MEROPENEM 3 grams QD; Drug: Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Estimate of the 14-day Early Bactericidal Activity (EBA), Based on Colony Forming Unit Counts, of the Combination of Meropenem and Amoxicillin/Clavulanate, Without Versus With Rifampin

    The Early Bactericidal Activity (EBA) over a 14 days period (EBA0-14), as determined by the median rate of change in log10 Colony Forming Units (CFU) per mL sputum. A non-linear mixed effects model of log10 CFU/mL sputum on time was developed using aggregated participant data for each treatment arm. A basic model was developed based on mono- or bi-exponential bacterial killing functions. Afterwards, covariate modelling to identify relationships between demographics, disease severity, secondary pharmacokinetic summary indices (area under the curve from time 0 to last measured concentration (AUC0-last) and maximum observed plasma concentration (Cmax), and model parameters describing log10 CFU/mL sputum over time was performed. Finally, the treatment regimen was tested using different functions supported by the graphical analysis.

    Measured: 14 days

  2. AUC for Rifampin

    Rifampin AUC0-last in Arms A and C

    Measured: 14 days

Secondary outcomes (3)

  1. Frequency of Grade 2 or Higher Adverse Events

    Grade 2 or higher Adverse Events (AE) that constitute any untoward medical occurrence in a study participant and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

    Measured: From the time a study participant receives the first dose of study drug through the final study visit, up to 28 days

  2. Distribution of Minimum Inhibitory Concentration (MIC) of Rifampin

    The distribution of rifampin MIC in the drug-resistant arms

    Measured: 14 days

  3. Estimate the Antimycobacterial Activity Based on Liquid Culture Time-to-positivity

    Change in time-to-positivity in Mycobacteria Growth Indicator Tube (MGIT) liquid media over 14 days of treatment (EBA0-14(TTP)) (time to positivity) for the study treatments. The Early Bactericidal Activity (EBA) over a 14 days period (EBA0-14), as determined by the median rate of change in TTP (expressed in log10 hours/day). A non-linear mixed effects model of log10 hours/day on time was developed using aggregated participant data for each treatment arm. A basic model was developed based on mono- or bi-exponential bacterial killing functions. Afterwards, covariate modelling to identify relationships between demographics, disease severity, secondary pharmacokinetic summary indices (area under the curve from time 0 to last measured concentration (AUC0-last) and maximum observed plasma concentration (Cmax), and model parameters describing TTP over time was performed. Finally, the treatment regimen was tested using different functions supported by the graphical analysis.

    Measured: 14 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jun 2017
  2. Study start23 Aug 2017
  3. Primary completion13 May 2022
  4. Study completion13 May 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
112 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03174184
Sponsor's protocol ID
IRB00119017
Other IDs
FD-R-05724
Status last verified
Jun 2023
First submitted
30 May 2017
Last updated
19 Jul 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • de Jager V, Mockeliunas L, You H, Simonsson USH, Collings T, Upton CM, Bezuidenhout JA, Gupte N, Dorman SE, Nuermberger E, Lamichhane G, Diacon AH, Dooley KE. A Phase 2a Study of the Early Bactericidal Activity of Rifampicin in Combination With Meropenem Plus Amoxicillin/Clavulanate Among Adults With Rifampicin-Resistant Pulmonary Tuberculosis. Clin Infect Dis. 2025 Dec 24;81(5):e393-e400. doi: 10.1093/cid/ciaf276.

    PubMed 40455216

  • De Jager V, Gupte N, Nunes S, Barnes GL, van Wijk RC, Mostert J, Dorman SE, Abulfathi AA, Upton CM, Faraj A, Nuermberger EL, Lamichhane G, Svensson EM, Simonsson USH, Diacon AH, Dooley KE. Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial. Am J Respir Crit Care Med. 2022 May 15;205(10):1228-1235. doi: 10.1164/rccm.202108-1976OC.

    PubMed 35258443

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rifampin, MEROPENEM 2 grams TID and MEROPENEM 1 gram TID in people with Tuberculosis, Pulmonary, run by Johns Hopkins University at 1 site in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Estimate of the 14-day Early Bactericidal Activity (EBA), Based on Colony Forming Unit Counts, of the Combination of Meropenem and Amoxicillin/Clavulanate, Without Versus With Rifampin (time frame: 14 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03174184, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jul 2023.

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