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

NCT03174184 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: IRB00119017FD-R-05724
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Tuberculosis, Pulmonary

Outcome Measures

Primary Outcomes (2)

• 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.

  14 days

• AUC for Rifampin

  Rifampin AUC0-last in Arms A and C

  14 days

Secondary Outcomes (3)

• Frequency of Grade 2 or Higher Adverse Events

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

• Distribution of Minimum Inhibitory Concentration (MIC) of Rifampin

  14 days

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

  14 days

Study Arms (6)

Rifampin resistant A

EXPERIMENTAL

Participants 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

Drug: Rifampin; Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet

Rifampin resistant B

EXPERIMENTAL

Participants 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

Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet

Rifampin susceptible C

EXPERIMENTAL

Participants 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

Drug: Rifampin; Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet

Rifampin susceptible D

EXPERIMENTAL

Participants 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

Drug: MEROPENEM 2 grams TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet

Rifampin susceptible E

EXPERIMENTAL

Participants 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

Drug: MEROPENEM 1 gram TID; Drug: Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet

Rifampin susceptible F

EXPERIMENTAL

Participants 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

Drug: MEROPENEM 3 grams QD; Drug: Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet

Interventions

Rifampin DRUG

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

Also known as: Rifamycins

Rifampin resistant A; Rifampin susceptible C

MEROPENEM 2 grams TID DRUG

Intravenous administration at a dosage of 2 grams thrice daily

Also known as: Merrem

Rifampin resistant A; Rifampin resistant B; Rifampin susceptible C; Rifampin susceptible D

MEROPENEM 1 gram TID DRUG

Intravenous administration at a dosage of 1 gram thrice daily

Also known as: Merrem

Rifampin susceptible E

MEROPENEM 3 grams QD DRUG

Intravenous administration at a dosage of 3 grams once daily

Also known as: Merrem

Rifampin susceptible F

Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet DRUG

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

Also known as: Augmentin

Rifampin resistant A; Rifampin resistant B; Rifampin susceptible C; Rifampin susceptible D; Rifampin susceptible E

Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet DRUG

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

Also known as: Augmentin

Rifampin susceptible F

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

Task Applied Science and Stellenbosch University

Stellenbosch, 7505, South Africa

Location

Related Publications (1)

• 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.

  PMID: 35258443 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Rifampin; Rifamycins; Meropenem; Amoxicillin; Clavulanic Acid; Amoxicillin-Potassium Clavulanate Combination

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Ampicillin; Penicillin G; Penicillins; Sulfur Compounds; Clavulanic Acids; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Kelly Dooley, MD, PhD
• Organization: Vanderbilt University Medical Center

kelly.e.dooley@vumc.org

6153228972

Study Officials

• Kelly Dooley, MD

  Associate Professor of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2017
• First Posted: June 2, 2017
• Study Start: August 23, 2017
• Primary Completion: May 13, 2022
• Study Completion: May 13, 2022
• Last Updated: July 19, 2023
• Results First Posted: July 19, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)