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| ID | Type | Description | Link |
|---|---|---|---|
| FD-R-05724 | Other Grant/Funding Number | FDA OOPD |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifampin | Drug | Oral administration of rifampin at a dosage of 20 mg/kg daily |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kelly Dooley, MD | Associate Professor of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Task Applied Science and Stellenbosch University | Stellenbosch | 7505 | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35258443 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Rifampin Resistant A | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 8, 2016 |
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|
| 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 |
|
| 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 |
|
| MEROPENEM 2 grams TID | Drug | Intravenous administration at a dosage of 2 grams thrice daily |
|
|
| MEROPENEM 1 gram TID | Drug | Intravenous administration at a dosage of 1 gram thrice daily |
|
|
| MEROPENEM 3 grams QD | Drug | Intravenous administration at a dosage of 3 grams once daily |
|
|
| 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 |
|
|
| 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 |
|
|
| 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 | The distribution of rifampin MIC in the drug-resistant arms | 14 days |
| 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. | 14 days |
| FG001 | Rifampin Resistant B | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| FG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| FG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| FG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| FG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
| COMPLETED |
|
| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Rifampin Resistant A | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| BG001 | Rifampin Resistant B | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| BG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| BG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| BG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| BG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
| BG006 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Inter-Quartile Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
| ||||||||||||||||
| HIV positive | Count of Participants | Participants |
| ||||||||||||||||
| BMI | Median | Inter-Quartile Range | kg/m^2 |
| |||||||||||||||
| MGIT Time to Positivity | Median | Inter-Quartile Range | Days |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | EBA could not be calculated among some participants who did not complete dosing | Posted | Mean | 95% Confidence Interval | rate of change in log10 CFU/mL/day | 14 days |
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|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary | AUC for Rifampin | Rifampin AUC0-last in Arms A and C | Participants in Arms B, D, E, and F did not receive rifampicin. In Arm A, some participants dropped out prior to PK collection day | Posted | Mean | Full Range | h*mg/L | 14 days |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | 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. | Posted | Number | Events | From the time a study participant receives the first dose of study drug through the final study visit, up to 28 days |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Distribution of Minimum Inhibitory Concentration (MIC) of Rifampin | The distribution of rifampin MIC in the drug-resistant arms | Rifampin MIC was only measured in Arms A and B. Some cultures did not grow in subculture and MIC could not be assessed in Arms A and B. | Posted | Median | Full Range | mcg/mL | 14 days |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | 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. | Some participants dropped out and did not contribute enough longitudinal TTP data to contribute to these assessments | Posted | Mean | 95% Confidence Interval | rate of change in log10 hours/day | 14 days |
|
28 days
Standard AE and SAE definitions apply
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rifampin Resistant A | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily | 0 | 32 | 0 | 32 | 6 | 32 |
| EG001 | Rifampin Resistant B | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily | 0 | 20 | 0 | 20 | 2 | 20 |
| EG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily | 0 | 17 | 0 | 17 | 2 | 17 |
| EG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily | 0 | 15 | 2 | 15 | 1 | 15 |
| EG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily | 0 | 14 | 0 | 14 | 0 | 14 |
| EG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily | 0 | 14 | 0 | 14 | 0 | 14 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated ALT | Hepatobiliary disorders | Systematic Assessment | Grade 2 elevation of ALT and AST that led to prolongation of hospitalization |
| |
| Elevated AST | Hepatobiliary disorders | Systematic Assessment | Grade 2 elevation of ALT and AST that led to prolongation of hospitalization |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal side effects | Gastrointestinal disorders | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kelly Dooley, MD, PhD | Vanderbilt University Medical Center | 6153228972 | kelly.e.dooley@vumc.org |
| May 12, 2023 |
| Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D014397 | Tuberculosis, Pulmonary |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D012293 | Rifampin |
| D012294 | Rifamycins |
| D000077731 | Meropenem |
| D000658 | Amoxicillin |
| D019818 | Clavulanic Acid |
| D019980 | Amoxicillin-Potassium Clavulanate Combination |
| ID | Term |
|---|---|
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D013845 | Thienamycins |
| D015780 | Carbapenems |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000667 | Ampicillin |
| D010400 | Penicillin G |
| D010406 | Penicillins |
| D013457 | Sulfur Compounds |
| D002969 | Clavulanic Acids |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
Not provided
Not provided
| Male |
|
| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| OG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
| OG002 |
| Rifampin Susceptible C |
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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
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| OG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
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| OG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
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| OG001 | Rifampin Resistant B | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG002 | Rifampin Susceptible C | 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 Rifampin: Oral administration of rifampin at a dosage of 20 mg/kg daily MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG003 | Rifampin Susceptible D | 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 MEROPENEM 2 grams TID: Intravenous administration at a dosage of 2 grams thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG004 | Rifampin Susceptible E | 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 MEROPENEM 1 gram TID: Intravenous administration at a dosage of 1 gram thrice daily Amoxicillin/Clavulanate Potassium 500 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 500 mg/125 mg thrice daily |
| OG005 | Rifampin Susceptible F | 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 MEROPENEM 3 grams QD: Intravenous administration at a dosage of 3 grams once daily Amoxicillin/Clavulanate Potassium 875 MG-125 MG Oral Tablet: Amx/Clv will be administered orally at a dose of 875 mg/125 mg once daily |
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