Trial Outcomes & Findings for Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB (NCT NCT03174184)
NCT ID: NCT03174184
Last Updated: 2023-07-19
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
112 participants
Primary outcome timeframe
14 days
Results posted on
2023-07-19
Participant Flow
Participant milestones
| Measure |
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
|
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
|
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
|
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
|
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
|
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
|
|---|---|---|---|---|---|---|
|
Overall Study
STARTED
|
32
|
20
|
17
|
15
|
14
|
14
|
|
Overall Study
COMPLETED
|
23
|
15
|
12
|
12
|
12
|
12
|
|
Overall Study
NOT COMPLETED
|
9
|
5
|
5
|
3
|
2
|
2
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Early Bactericidal Activity of Rifampin + Meropenem + Amoxicillin/Clavulanate in Adults With Pulmonary TB
Baseline characteristics by cohort
| Measure |
Rifampin Resistant A
n=32 Participants
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
|
Rifampin Resistant B
n=20 Participants
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
|
Rifampin Susceptible C
n=17 Participants
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
|
Rifampin Susceptible D
n=15 Participants
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
|
Rifampin Susceptible E
n=14 Participants
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
|
Rifampin Susceptible F
n=14 Participants
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
|
Total
n=112 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|---|---|
|
Age, Continuous
|
37 years
n=5 Participants
|
37 years
n=7 Participants
|
33 years
n=5 Participants
|
36 years
n=4 Participants
|
45 years
n=21 Participants
|
34 years
n=8 Participants
|
36 years
n=8 Participants
|
|
Sex: Female, Male
Female
|
12 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
7 Participants
n=4 Participants
|
2 Participants
n=21 Participants
|
2 Participants
n=8 Participants
|
32 Participants
n=8 Participants
|
|
Sex: Female, Male
Male
|
20 Participants
n=5 Participants
|
15 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
8 Participants
n=4 Participants
|
12 Participants
n=21 Participants
|
12 Participants
n=8 Participants
|
80 Participants
n=8 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=8 Participants
|
0 Participants
n=8 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=8 Participants
|
0 Participants
n=8 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=8 Participants
|
0 Participants
n=8 Participants
|
|
Race (NIH/OMB)
Black or African American
|
13 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
2 Participants
n=4 Participants
|
5 Participants
n=21 Participants
|
7 Participants
n=8 Participants
|
39 Participants
n=8 Participants
|
|
Race (NIH/OMB)
White
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=8 Participants
|
0 Participants
n=8 Participants
|
|
Race (NIH/OMB)
More than one race
|
19 Participants
n=5 Participants
|
11 Participants
n=7 Participants
|
14 Participants
n=5 Participants
|
13 Participants
n=4 Participants
|
9 Participants
n=21 Participants
|
7 Participants
n=8 Participants
|
73 Participants
n=8 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
0 Participants
n=8 Participants
|
0 Participants
n=8 Participants
|
|
Region of Enrollment
South Africa
|
32 Participants
n=5 Participants
|
20 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
15 Participants
n=4 Participants
|
14 Participants
n=21 Participants
|
14 Participants
n=8 Participants
|
112 Participants
n=8 Participants
|
|
HIV positive
|
9 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
3 Participants
n=21 Participants
|
6 Participants
n=8 Participants
|
29 Participants
n=8 Participants
|
|
BMI
|
18.3 kg/m^2
n=5 Participants
|
17.8 kg/m^2
n=7 Participants
|
18.9 kg/m^2
n=5 Participants
|
18.7 kg/m^2
n=4 Participants
|
19.4 kg/m^2
n=21 Participants
|
18.1 kg/m^2
n=8 Participants
|
18.4 kg/m^2
n=8 Participants
|
|
MGIT Time to Positivity
|
4.8 Days
n=5 Participants
|
5.8 Days
n=7 Participants
|
4.3 Days
n=5 Participants
|
4.4 Days
n=4 Participants
|
5.7 Days
n=21 Participants
|
4.9 Days
n=8 Participants
|
4.8 Days
n=8 Participants
|
PRIMARY outcome
Timeframe: 14 daysPopulation: EBA could not be calculated among some participants who did not complete dosing
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.
Outcome measures
| Measure |
Rifampin Resistant A
n=22 Participants
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
|
Rifampin Resistant B
n=17 Participants
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
|
Rifampin Susceptible C
n=14 Participants
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
|
Rifampin Susceptible D
n=15 Participants
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
|
Rifampin Susceptible E
n=12 Participants
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
|
Rifampin Susceptible F
n=14 Participants
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
|
|---|---|---|---|---|---|---|
|
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
|
-0.06 rate of change in log10 CFU/mL/day
Interval -0.09 to -0.02
|
-0.11 rate of change in log10 CFU/mL/day
Interval -0.15 to 0.0
|
-0.14 rate of change in log10 CFU/mL/day
Interval -0.2 to -0.08
|
-0.12 rate of change in log10 CFU/mL/day
Interval -0.16 to -0.08
|
-0.05 rate of change in log10 CFU/mL/day
Interval -0.09 to -0.004
|
-0.02 rate of change in log10 CFU/mL/day
Interval -0.06 to 0.03
|
PRIMARY outcome
Timeframe: 14 daysPopulation: Participants in Arms B, D, E, and F did not receive rifampicin. In Arm A, some participants dropped out prior to PK collection day
Rifampin AUC0-last in Arms A and C
Outcome measures
| Measure |
Rifampin Resistant A
n=23 Participants
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
|
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
|
Rifampin Susceptible C
n=12 Participants
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
|
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
|
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
|
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
|
|---|---|---|---|---|---|---|
|
AUC for Rifampin
|
105 h*mg/L
Interval 52.0 to 226.0
|
—
|
109 h*mg/L
Interval 82.0 to 136.0
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: From the time a study participant receives the first dose of study drug through the final study visit, up to 28 daysGrade 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.
Outcome measures
| Measure |
Rifampin Resistant A
n=32 Participants
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
|
Rifampin Resistant B
n=20 Participants
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
|
Rifampin Susceptible C
n=17 Participants
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
|
Rifampin Susceptible D
n=15 Participants
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
|
Rifampin Susceptible E
n=14 Participants
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
|
Rifampin Susceptible F
n=14 Participants
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
|
|---|---|---|---|---|---|---|
|
Frequency of Grade 2 or Higher Adverse Events
|
28 Events
|
15 Events
|
5 Events
|
8 Events
|
3 Events
|
7 Events
|
SECONDARY outcome
Timeframe: 14 daysPopulation: 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.
The distribution of rifampin MIC in the drug-resistant arms
Outcome measures
| Measure |
Rifampin Resistant A
n=30 Participants
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
|
Rifampin Resistant B
n=16 Participants
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
|
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
|
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
|
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
|
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
|
|---|---|---|---|---|---|---|
|
Distribution of Minimum Inhibitory Concentration (MIC) of Rifampin
|
1.28 mcg/mL
Interval 0.32 to 1.28
|
1.28 mcg/mL
Interval 0.32 to 1.28
|
—
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: 14 daysPopulation: Some participants dropped out and did not contribute enough longitudinal TTP data to contribute to these assessments
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.
Outcome measures
| Measure |
Rifampin Resistant A
n=30 Participants
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
|
Rifampin Resistant B
n=18 Participants
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
|
Rifampin Susceptible C
n=15 Participants
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
|
Rifampin Susceptible D
n=15 Participants
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
|
Rifampin Susceptible E
n=13 Participants
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
|
Rifampin Susceptible F
n=14 Participants
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
|
|---|---|---|---|---|---|---|
|
Estimate the Antimycobacterial Activity Based on Liquid Culture Time-to-positivity
|
0.19 rate of change in log10 hours/day
Interval 0.08 to 0.29
|
0.31 rate of change in log10 hours/day
Interval 0.19 to 0.43
|
0.53 rate of change in log10 hours/day
Interval 0.38 to 0.68
|
0.20 rate of change in log10 hours/day
Interval 0.13 to 0.27
|
0.09 rate of change in log10 hours/day
Interval 0.03 to 0.15
|
0.09 rate of change in log10 hours/day
Interval -0.03 to 0.21
|
Adverse Events
Rifampin Resistant A
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Rifampin Resistant B
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Rifampin Susceptible C
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Rifampin Susceptible D
Serious events: 2 serious events
Other events: 1 other events
Deaths: 0 deaths
Rifampin Susceptible E
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Rifampin Susceptible F
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Rifampin Resistant A
n=32 participants at risk
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
|
Rifampin Resistant B
n=20 participants at risk
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
|
Rifampin Susceptible C
n=17 participants at risk
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
|
Rifampin Susceptible D
n=15 participants at risk
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
|
Rifampin Susceptible E
n=14 participants at risk
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
|
Rifampin Susceptible F
n=14 participants at risk
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
|
|---|---|---|---|---|---|---|
|
Hepatobiliary disorders
Elevated ALT
|
0.00%
0/32 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/20 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/17 • 28 days
Standard AE and SAE definitions apply
|
6.7%
1/15 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
|
Hepatobiliary disorders
Elevated AST
|
0.00%
0/32 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/20 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/17 • 28 days
Standard AE and SAE definitions apply
|
6.7%
1/15 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
Other adverse events
| Measure |
Rifampin Resistant A
n=32 participants at risk
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
|
Rifampin Resistant B
n=20 participants at risk
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
|
Rifampin Susceptible C
n=17 participants at risk
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
|
Rifampin Susceptible D
n=15 participants at risk
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
|
Rifampin Susceptible E
n=14 participants at risk
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
|
Rifampin Susceptible F
n=14 participants at risk
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
|
|---|---|---|---|---|---|---|
|
Gastrointestinal disorders
Gastrointestinal side effects
|
18.8%
6/32 • 28 days
Standard AE and SAE definitions apply
|
10.0%
2/20 • 28 days
Standard AE and SAE definitions apply
|
11.8%
2/17 • 28 days
Standard AE and SAE definitions apply
|
6.7%
1/15 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
0.00%
0/14 • 28 days
Standard AE and SAE definitions apply
|
Additional Information
Kelly Dooley, MD, PhD
Vanderbilt University Medical Center
Phone: 6153228972
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place