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Essentiality of INH in TB Therapy

Essentiality of Isoniazid in Tuberculosis Therapy

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01589497
Enrollment
69
Registered
2012-05-02
Start date
2015-06-30
Completion date
2016-02-10
Last updated
2018-04-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Tuberculosis

Brief summary

Tuberculosis (TB) disease is caused by bacteria that have infected the lung. TB bacteria are very small living agents that are spread by coughing and can be killed by taking TB drugs. To kill these TB bacteria TB patients have to take a combination of four drugs for 2 months and then two drugs for a further 4 months. During the first 2 months patients take rifampicin, isoniazid, ethambutol, and pyrazinamide. After that patients take only isoniazid and rifampicin for a further 4 months, making a total of 6 months therapy. In A5307 the investigators wanted to test a new combination of drugs to see if the investigators could treat TB faster in the future. Studies in animals have suggested that one of the four drugs, isoniazid, only works for a few days and may not be needed after the first two doses of TB treatment to kill the TB bacteria. After that its effects wear off to the point that it may even interfere with the other drugs. The investigators wanted to see if stopping isoniazid early, or using moxifloxacin, a different drug, instead could treat TB faster. This study was the first time that this type of regimen without isoniazid had been tested in humans. If the investigators could show that isoniazid stops working after a few days, the investigators could then try to see if they could possibly make a better tuberculosis treatment in the future.

Detailed description

This was a Phase IIa open label, randomized clinical trial comparing the early bactericidal activity (EBA) of four anti-tuberculosis regimens. Participants with acid fast bacilli (AFB) smear-positive pulmonary tuberculosis were hospitalized from screening through Day 15 of the study, during which time, sputum, blood, and urine were collected. Participants returned to the clinic on Day 28 for the final visit. The study duration was 29 days. The purpose of the study was to estimate the primary outcome within each study arm and the study was not designed for between arm comparisons.

Interventions

DRUGRifampicin

Participants with body weight \</= 50kg were administered one 450 mg tablet orally once daily. Participants with body weight \>50kg were administered one 600 mg tablet orally once daily.

DRUGIsoniazid

Participants were administered three 100 mg tablets or one 300 mg tablet once daily.

DRUGPyrazinamide

Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily. Participants with a body weight of 56-75 kg were administered three 500 mg tablets orally once daily. Participants with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily.

DRUGEthambutol

Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily. Participants with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily. Participants with a body weight of 76-90 kg were administered four 400 mg tablets orally once daily.

DRUGMoxifloxacin

Participants were administered one 400 mg tablet orally once a day.

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)
CollaboratorNIH
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Lead SponsorNETWORK

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* Absence of HIV-1 infection within 30 days prior to study entry OR * HIV-1 infection * Sputum positive for acid fast bacilli (AFB) by smear-microscopy ≥1+ on the WHO/IUALTD scale within 1 day prior to study entry. * Isoniazid and rifampin sensitivity, based on Hain GenoType MTBDR Plus assay performed within 7 days prior to study entry. * Body weight: 40 kg to 90 kg, inclusive * Age ≥ 18 years at study entry. * Certain laboratory values, as defined in the protocol, obtained within 30 days prior to entry * For HIV-positive candidates only: CD4+ cell count of \> 200 cells/mm\^3, determined within 7 days prior to study entry at a DAIDS approved laboratory. * For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to entry. * Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (ie, condoms, with a spermicidal agent; a diaphragm, or cervical cap with spermicide; or an IUD) while receiving study medications. * Radiographic findings consistent with pulmonary TB from a chest x-ray performed within 14 days prior to entry. * Ability and willingness of study candidate or legal guardian/representative to provide informed consent. * Willingness to be hospitalized for approximately 3 weeks. * Ability to provide at least 10mL of sputum during an overnight collection prior to study entry. NOTE: Candidates who do not produce an overnight sputum sample of sufficient quality and quantity will be considered screen failures. However, if a candidate's failure to produce sufficient sputum appears to be due to poor technique rather than low volume of sputum production, this evaluation may be repeated.

Exclusion criteria

* Receipt of INH prophylaxis or any tuberculosis therapy within 7 days prior to study entry or for more than 7 cumulative days in the last 6 months, or receipt of any fluoroquinolone in the 1 month prior to entry. * Currently on anti-retroviral treatment (ART), has been on ART within 30 days, or is expected to initiate ART within 2 weeks after study entry. * Breastfeeding. * Known intolerance to any of the study drugs. * Resistance to rifampicin determined by GeneXpert within 7 days prior to study entry. * Known history of resistance to isoniazid or rifampin or known close exposure (i.e., household exposure) to someone with MDR TB or known study candidate default on previous TB treatment (ie, the study candidate was diagnosed with TB, started TB treatment but did not complete that treatment). * Known allergy to any fluoroquinolone antibiotic. * History of prolonged QT syndrome or a QTc of \> 450 ms (using Fridericia's correction).. * Current or planned therapy with quinidine, procainamide, amiodarone, sotalol, or ziprasidone during the 2 weeks of on-study tuberculosis treatment. * Current or prior diagnosis of pulmonary silicosis. * Advanced disease as defined by Karnofsky score ≤ 70 at screening. * Any of the following current comorbidities, complications, or underlying medical conditions: * poorly controlled diabetes, as determined by the site investigator * currently uncontrolled hypertension (ie, requiring acute medical treatment or immediate hospitalization) * miliary TB * neurological TB (including TB of the spine, TB meningitis) * peripheral neuropathy ≥ Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry * Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. * Estimated overnight sputum production of \< 10 mL. * Requirement for concomitant medications that may potentially interact with study drugs.

Design outcomes

Primary

MeasureTime frameDescription
Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14Pre-entry, Day 0 and Day 14The daily decrease was calculated as follows: EBA0-14(CFU)= \[baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 14\]/14. For a CFU/ml count of 0, the log10 CFU/mL was set to 0. No formal statistical testing was conducted to compare the arms. Please refer to the explanation in the Protocol Section.

Secondary

MeasureTime frameDescription
Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2Pre-entry, Day 0 and Day 2The daily change in log10 CFU/mL sputum was calculated as follows: EBA0-2(CFU) = (baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 2)/2. For a CFU/mL count of 0, the log10 CFU/mL was set to 0.
Daily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 14Day 2 and day 14The daily change in log10 CFU/mL sputum was calculated as follows: EBA2-14(CFU) = (log10 CFU/mL at day 2 - log10 CFU/mL at day 14)/12. For a CFU/mL count of 0, the log10 CFU/mL was set to 0.
Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2Pre-entry, Day 0 and Day 2The daily change in TTP was calculated as follows: EBA0-2(TTP) = (baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 2)/2.
Daily Change in Time to Positivity (TTP) From Day 2 to Day 14Day 2 and Day 14The daily change in TTP was calculated as follows: EBA2-14(TTP) = (TTP at day 2 - TTP at day 14)/12.
Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Pre-entry, Day 0 and Day 14The log10 CFU count per mL from sputum samples processed by standard method or decontaminated method.
Correlation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mLPre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14Pearson correlation coefficient was used to examine the correlation between TTP and log10 CFU among all qualified samples obtained on study
Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUCs) of Rifampicin from 0 to 24 hours obtained at Day 1 and Day 14
Rifampicin PK Parameter Clearance (CL/F)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14Rifampicin PK parameter Clearance (CL/F) obtained Day 1 and Day 14
Rifampicin PK Parameter Maximum Plasma Concentration (Cmax)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14Rifampicin PK parameter Parameter Maximum Plasma Concentration (Cmax) obtained Day 1 and Day 14
Rifampicin PK Parameter Last Concentration (CLast)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14Rifampicin (RIF) PK parameter Last Concentration (CLast) obtained Day 1 and Day 14. The lower limit of quantification of the assay (LLOQ) for RIF was 40 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 20 ng/mL.
AUC0-24hour for Isoniazid (INH) at Day 1-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1PK AUCs of Isoniazid (INH) from 0 to 24 hours obtained at Day 1
Isoniazid PK Parameter CL/F at Day 1-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1Isoniazid PK parameter CL/F obtained Day 1
Isoniazid PK Parameter Cmax at Day 1-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1Isoniazid PK parameter Cmax obtained Day 1
Isoniazid PK Parameter CLast at Day 1-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1Isoniazid (INH) PK parameter CLast obtained Day 1. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.
AUC0-24hour for Isoniazid at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14PK AUCs of Isoniazid from 0 to 24 hours obtained at Day 14
Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14Pre-entry, Day 0 and Day 14The daily change in TTP was calculated as follows: EBA0-14(TTP) = \[baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 14\]/14.
Isoniazid PK Parameter Cmax at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14Isoniazid PK parameter Cmax obtained Day 14
Isoniazid PK Parameter CLast at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14Isoniazid (INH) PK parameter CLast obtained Day 14. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.
AUC0-24hour for Pyrazinamide (PZA)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14PK AUCs of Pyrazinamide (PZA) from 0 to 24 hours obtained at Day 1 and Day 14
Pyrazinamide PK Parameter CL/F-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14Pyrazinamide PK parameter CL/F obtained Day 1 and Day 14
Pyrazinamide PK Parameter Cmax-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14
Pyrazinamide PK Parameter CLast-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14Pyrazinamide PK parameter CLast obtained Day 1 and Day 14
AUC0-24hour for Ethambutol (EMB)-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14PK AUCs of Ethambutol (EMB) from 0 to 24 hours obtained at Day 1 and Day 14
Ethambutol PK Parameter CL/F-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14Ethambutol PK parameter CL/F obtained Day 1 and Day 14
Ethambutol PK Parameter Cmax-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14Ethambutol PK parameter Cmax obtained Day 1 and Day 14
Ethambutol PK Parameter CLast-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14Ethambutol PK parameter CLast obtained Day 1 and Day 14
AUC0-24hour for Moxifloxacin (Mox) at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14PK AUCs of Moxiflozacin (Mox) from 0 to 24 hours obtained at Day 14
Moxifloxacin PK Parameter CL/F at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14Moxifloxacin PK parameter CL/F obtained Day 14
Moxifloxacin PK Parameter Cmax at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14Moxifloxacin PK parameter Cmax obtained Day 14
Moxifloxacin PK Parameter CLast at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14Moxifloxacin PK parameter CLast obtained Day 14
Isoniazid PK Parameter CL/F at Day 14-0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14Isoniazid PK parameter CL/F obtained Day 14

Countries

South Africa

Participant flow

Recruitment details

Recruited at two AIDS Clinical Trials Units in South Africa. Recruitment occurred between June 30, 2015 (date of first participant was randomized) and January 13, 2016 (date of last participant was randomized).

Pre-assignment details

69 were randomized 1:1:1:1 to 4 treatment arms. Among the 69 participants, 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

Participants by arm

ArmCount
RHZE-RHZE
Participants were administered RHZE from Day 1 to Day 14.
18
RHZE-RZE
Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.
17
RHZE-RMZE
Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
16
RZE-RZE
Participants were administered only RZE from Day 1 through Day 14.
18
Total69

Withdrawals & dropouts

PeriodReasonFG000FG001FG002FG003
Overall StudyDeath1000
Overall StudyPre-entry overnight sputum< 10ML0010
Overall StudyWithdrawal by Subject0101

Baseline characteristics

CharacteristicRHZE-RZERHZE-RMZERHZE-RHZERZE-RZETotal
Age, Continuous31 years33.5 years28.5 years32 years31 years
Age, Customized
<20
0 Participants1 Participants2 Participants1 Participants4 Participants
Age, Customized
20-29
4 Participants6 Participants7 Participants5 Participants22 Participants
Age, Customized
30-39
11 Participants2 Participants5 Participants5 Participants23 Participants
Age, Customized
40-49
1 Participants4 Participants2 Participants6 Participants13 Participants
Age, Customized
50-59
1 Participants3 Participants2 Participants1 Participants7 Participants
BMI19.4 kg/m^219.8 kg/m^218.5 kg/m^218.7 kg/m^218.9 kg/m^2
Ethnicity (NIH/OMB)
Hispanic or Latino
1 Participants0 Participants0 Participants0 Participants1 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
15 Participants16 Participants18 Participants18 Participants67 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants0 Participants0 Participants0 Participants1 Participants
HIV status
HIV negative
16 participants15 participants16 participants18 participants65 participants
HIV status
HIV positive
1 participants1 participants2 participants0 participants4 participants
Karnofsky score90 scores on a scale90 scores on a scale90 scores on a scale90 scores on a scale90 scores on a scale
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Black or African American
17 Participants16 Participants18 Participants18 Participants69 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
0 Participants0 Participants0 Participants0 Participants0 Participants
Sex: Female, Male
Female
1 Participants3 Participants5 Participants3 Participants12 Participants
Sex: Female, Male
Male
16 Participants13 Participants13 Participants15 Participants57 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
1 / 180 / 170 / 160 / 18
other
Total, other adverse events
6 / 185 / 173 / 165 / 18
serious
Total, serious adverse events
1 / 181 / 171 / 160 / 18

Outcome results

Primary

Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14

The daily decrease was calculated as follows: EBA0-14(CFU)= \[baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 14\]/14. For a CFU/ml count of 0, the log10 CFU/mL was set to 0. No formal statistical testing was conducted to compare the arms. Please refer to the explanation in the Protocol Section.

Time frame: Pre-entry, Day 0 and Day 14

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 140.134 log10 CFU/ mL
RHZE-RZEDaily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 140.096 log10 CFU/ mL
RHZE-RMZEDaily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 140.136 log10 CFU/ mL
RZE-RZEDaily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 140.119 log10 CFU/ mL
Secondary

AUC0-24hour for Ethambutol (EMB)

PK AUCs of Ethambutol (EMB) from 0 to 24 hours obtained at Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 111918.8 h*ng/mL
RHZE-RHZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 1416414.9 h*ng/mL
RHZE-RZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 1416675.9 h*ng/mL
RHZE-RZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 111145.8 h*ng/mL
RHZE-RMZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 111322.4 h*ng/mL
RHZE-RMZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 1415181.2 h*ng/mL
RZE-RZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 110716.8 h*ng/mL
RZE-RZEAUC0-24hour for Ethambutol (EMB)EMB AUC0-24hour at Day 1416574.6 h*ng/mL
Secondary

AUC0-24hour for Isoniazid at Day 14

PK AUCs of Isoniazid from 0 to 24 hours obtained at Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RHZE-RZE and RHZE-RMZE arms did not receive INH from Day 3 through Day 14 and the participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEAUC0-24hour for Isoniazid at Day 149797.2 h*ng/mL
Secondary

AUC0-24hour for Isoniazid (INH) at Day 1

PK AUCs of Isoniazid (INH) from 0 to 24 hours obtained at Day 1

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEAUC0-24hour for Isoniazid (INH) at Day 110725.8 h*ng/mL
RHZE-RZEAUC0-24hour for Isoniazid (INH) at Day 17970.6 h*ng/mL
RHZE-RMZEAUC0-24hour for Isoniazid (INH) at Day 17165.1 h*ng/mL
Secondary

AUC0-24hour for Moxifloxacin (Mox) at Day 14

PK AUCs of Moxiflozacin (Mox) from 0 to 24 hours obtained at Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. Only the participants in the RHZE-RMZE arm received Mox from Day 3 through Day 14

ArmMeasureValue (MEDIAN)
RHZE-RHZEAUC0-24hour for Moxifloxacin (Mox) at Day 1422498.4 h*ng/mL
Secondary

AUC0-24hour for Pyrazinamide (PZA)

PK AUCs of Pyrazinamide (PZA) from 0 to 24 hours obtained at Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 1301214.5 h*ng/mL
RHZE-RHZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 14249879.1 h*ng/mL
RHZE-RZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 14201389.7 h*ng/mL
RHZE-RZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 1255283.0 h*ng/mL
RHZE-RMZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 1292078.2 h*ng/mL
RHZE-RMZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 14280071.0 h*ng/mL
RZE-RZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 1272853.9 h*ng/mL
RZE-RZEAUC0-24hour for Pyrazinamide (PZA)PZA AUC0-24hour at Day 14252276.8 h*ng/mL
Secondary

Correlation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mL

Pearson correlation coefficient was used to examine the correlation between TTP and log10 CFU among all qualified samples obtained on study

Time frame: Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14

Population: Participants with qualified sputum samples who had results available at least one time point specified in the time-frame

ArmMeasureValue (NUMBER)
RHZE-RHZECorrelation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mL-0.75 correlation coefficient
Secondary

Daily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 14

The daily change in log10 CFU/mL sputum was calculated as follows: EBA2-14(CFU) = (log10 CFU/mL at day 2 - log10 CFU/mL at day 14)/12. For a CFU/mL count of 0, the log10 CFU/mL was set to 0.

Time frame: Day 2 and day 14

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 140.143 log10 CFU/ mL
RHZE-RZEDaily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 140.093 log10 CFU/ mL
RHZE-RMZEDaily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 140.123 log10 CFU/ mL
RZE-RZEDaily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 140.104 log10 CFU/ mL
Secondary

Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2

The daily change in log10 CFU/mL sputum was calculated as follows: EBA0-2(CFU) = (baseline log10 CFU/mL sputum (mean of log10 CFU/mL at pre-entry and day 0) - log10 CFU/mL at day 2)/2. For a CFU/mL count of 0, the log10 CFU/mL was set to 0.

Time frame: Pre-entry, Day 0 and Day 2

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 20.255 log10 CFU/ mL
RHZE-RZEDaily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 20.385 log10 CFU/ mL
RHZE-RMZEDaily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 20.111 log10 CFU/ mL
RZE-RZEDaily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 20.034 log10 CFU/ mL
Secondary

Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14

The daily change in TTP was calculated as follows: EBA0-14(TTP) = \[baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 14\]/14.

Time frame: Pre-entry, Day 0 and Day 14

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14-12 hours
RHZE-RZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14-12 hours
RHZE-RMZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14-13 hours
RZE-RZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14-11 hours
Secondary

Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2

The daily change in TTP was calculated as follows: EBA0-2(TTP) = (baseline TTP (mean of TTP at pre-entry and day 0) - TTP at day 2)/2.

Time frame: Pre-entry, Day 0 and Day 2

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2-31 hours
RHZE-RZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2-30 hours
RHZE-RMZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2-29 hours
RZE-RZEDaily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2-25 hours
Secondary

Daily Change in Time to Positivity (TTP) From Day 2 to Day 14

The daily change in TTP was calculated as follows: EBA2-14(TTP) = (TTP at day 2 - TTP at day 14)/12.

Time frame: Day 2 and Day 14

Population: Participants with qualified sputum samples who had results available at all time points specified in the time-frame

ArmMeasureValue (MEDIAN)
RHZE-RHZEDaily Change in Time to Positivity (TTP) From Day 2 to Day 14-9 hours
RHZE-RZEDaily Change in Time to Positivity (TTP) From Day 2 to Day 14-9 hours
RHZE-RMZEDaily Change in Time to Positivity (TTP) From Day 2 to Day 14-12 hours
RZE-RZEDaily Change in Time to Positivity (TTP) From Day 2 to Day 14-9 hours
Secondary

Ethambutol PK Parameter CLast

Ethambutol PK parameter CLast obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEEthambutol PK Parameter CLastEMB CLast at Day 186.5 ng/mL
RHZE-RHZEEthambutol PK Parameter CLastEMB CLast at Day 14205.0 ng/mL
RHZE-RZEEthambutol PK Parameter CLastEMB CLast at Day 14176 ng/mL
RHZE-RZEEthambutol PK Parameter CLastEMB CLast at Day 185 ng/mL
RHZE-RMZEEthambutol PK Parameter CLastEMB CLast at Day 140 ng/mL
RHZE-RMZEEthambutol PK Parameter CLastEMB CLast at Day 14164 ng/mL
RZE-RZEEthambutol PK Parameter CLastEMB CLast at Day 186 ng/mL
RZE-RZEEthambutol PK Parameter CLastEMB CLast at Day 14159 ng/mL
Secondary

Ethambutol PK Parameter CL/F

Ethambutol PK parameter CL/F obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEEthambutol PK Parameter CL/FEMB CL/F Day 193.6 L/hour
RHZE-RHZEEthambutol PK Parameter CL/FEMB CL/F Day 1457.9 L/hour
RHZE-RZEEthambutol PK Parameter CL/FEMB CL/F Day 1463.5 L/hour
RHZE-RZEEthambutol PK Parameter CL/FEMB CL/F Day 185.4 L/hour
RHZE-RMZEEthambutol PK Parameter CL/FEMB CL/F Day 183.8 L/hour
RHZE-RMZEEthambutol PK Parameter CL/FEMB CL/F Day 1456.8 L/hour
RZE-RZEEthambutol PK Parameter CL/FEMB CL/F Day 176.5 L/hour
RZE-RZEEthambutol PK Parameter CL/FEMB CL/F Day 1460.1 L/hour
Secondary

Ethambutol PK Parameter Cmax

Ethambutol PK parameter Cmax obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEEthambutol PK Parameter CmaxEMB Cmax at Day 12650 ng/mL
RHZE-RHZEEthambutol PK Parameter CmaxEMB Cmax at Day 142980 ng/mL
RHZE-RZEEthambutol PK Parameter CmaxEMB Cmax at Day 143090 ng/mL
RHZE-RZEEthambutol PK Parameter CmaxEMB Cmax at Day 12040 ng/mL
RHZE-RMZEEthambutol PK Parameter CmaxEMB Cmax at Day 12470 ng/mL
RHZE-RMZEEthambutol PK Parameter CmaxEMB Cmax at Day 142780 ng/mL
RZE-RZEEthambutol PK Parameter CmaxEMB Cmax at Day 12220 ng/mL
RZE-RZEEthambutol PK Parameter CmaxEMB Cmax at Day 142920 ng/mL
Secondary

Isoniazid PK Parameter CLast at Day 1

Isoniazid (INH) PK parameter CLast obtained Day 1. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter CLast at Day 150 ng/mL
RHZE-RZEIsoniazid PK Parameter CLast at Day 150 ng/mL
RHZE-RMZEIsoniazid PK Parameter CLast at Day 150 ng/mL
Secondary

Isoniazid PK Parameter CLast at Day 14

Isoniazid (INH) PK parameter CLast obtained Day 14. The lower limit of quantification of the assay (LLOQ) for INH was 100 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 50 ng/mL.

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RHZE-RZE and RHZE-RMZE arms did not receive INH from Day 3 through Day 14 and the participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter CLast at Day 1450 ng/mL
Secondary

Isoniazid PK Parameter CL/F at Day 1

Isoniazid PK parameter CL/F obtained Day 1

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter CL/F at Day 128.0 L/hour
RHZE-RZEIsoniazid PK Parameter CL/F at Day 137.6 L/hour
RHZE-RMZEIsoniazid PK Parameter CL/F at Day 141.9 L/hour
Secondary

Isoniazid PK Parameter CL/F at Day 14

Isoniazid PK parameter CL/F obtained Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RHZE-RZE and RHZE-RMZE arms did not receive INH from Day 3 through Day 14 and the participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter CL/F at Day 1430.6 L/hour
Secondary

Isoniazid PK Parameter Cmax at Day 1

Isoniazid PK parameter Cmax obtained Day 1

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter Cmax at Day 13165 ng/mL
RHZE-RZEIsoniazid PK Parameter Cmax at Day 12920 ng/mL
RHZE-RMZEIsoniazid PK Parameter Cmax at Day 12760 ng/mL
Secondary

Isoniazid PK Parameter Cmax at Day 14

Isoniazid PK parameter Cmax obtained Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. The participants in the RHZE-RZE and RHZE-RMZE arms did not receive INH from Day 3 through Day 14 and the participants in the RZE-RZE arm did not receive INH from Day 1 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEIsoniazid PK Parameter Cmax at Day 143130 ng/mL
Secondary

Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14

The log10 CFU count per mL from sputum samples processed by standard method or decontaminated method.

Time frame: Pre-entry, Day 0 and Day 14

Population: Participants with qualified sputum samples who had results available at least one time point specified in the time-frame

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Pre-entry5.80 log10 CFU/ mL
RHZE-RHZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Day 05.68 log10 CFU/ mL
RHZE-RHZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Day 144.01 log10 CFU/ mL
RHZE-RZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Pre-entry5.89 log10 CFU/ mL
RHZE-RZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Day 05.58 log10 CFU/ mL
RHZE-RZELog10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14Day 143.74 log10 CFU/ mL
Secondary

Moxifloxacin PK Parameter CLast at Day 14

Moxifloxacin PK parameter CLast obtained Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. Only the participants in the RHZE-RMZE arm received Mox from Day 3 through Day 14.

ArmMeasureValue (MEDIAN)
RHZE-RHZEMoxifloxacin PK Parameter CLast at Day 14178 ng/mL
Secondary

Moxifloxacin PK Parameter CL/F at Day 14

Moxifloxacin PK parameter CL/F obtained Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. Only the participants in the RHZE-RMZE arm received Mox from Day 3 through Day 14

ArmMeasureValue (MEDIAN)
RHZE-RHZEMoxifloxacin PK Parameter CL/F at Day 1417.8 L/hour
Secondary

Moxifloxacin PK Parameter Cmax at Day 14

Moxifloxacin PK parameter Cmax obtained Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis. Only the participants in the RHZE-RMZE arm received Mox from Day 3 through Day 14

ArmMeasureValue (MEDIAN)
RHZE-RHZEMoxifloxacin PK Parameter Cmax at Day 143010 ng/mL
Secondary

Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)

Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUCs) of Rifampicin from 0 to 24 hours obtained at Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 137358.8 h*ng/mL
RHZE-RHZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 1431361.4 h*ng/mL
RHZE-RZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 1427161.7 h*ng/mL
RHZE-RZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 142062.6 h*ng/mL
RHZE-RMZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 151434.1 h*ng/mL
RHZE-RMZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 1426751.2 h*ng/mL
RZE-RZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 139294.0 h*ng/mL
RZE-RZEPharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)RIF AUC0-24hour at Day 1430521.0 h*ng/mL
Secondary

Pyrazinamide PK Parameter CLast

Pyrazinamide PK parameter CLast obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEPyrazinamide PK Parameter CLastPZA CLast at Day 13370 ng/mL
RHZE-RHZEPyrazinamide PK Parameter CLastPZA CLast at Day 141955.0 ng/mL
RHZE-RZEPyrazinamide PK Parameter CLastPZA CLast at Day 141280 ng/mL
RHZE-RZEPyrazinamide PK Parameter CLastPZA CLast at Day 12850 ng/mL
RHZE-RMZEPyrazinamide PK Parameter CLastPZA CLast at Day 13130 ng/mL
RHZE-RMZEPyrazinamide PK Parameter CLastPZA CLast at Day 141790 ng/mL
RZE-RZEPyrazinamide PK Parameter CLastPZA CLast at Day 12710 ng/mL
RZE-RZEPyrazinamide PK Parameter CLastPZA CLast at Day 141770 ng/mL
Secondary

Pyrazinamide PK Parameter CL/F

Pyrazinamide PK parameter CL/F obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEPyrazinamide PK Parameter CL/FPZA CL/F Day 14.1 L/hour
RHZE-RHZEPyrazinamide PK Parameter CL/FPZA CL/F Day 144.5 L/hour
RHZE-RZEPyrazinamide PK Parameter CL/FPZA CL/F Day 145.4 L/hour
RHZE-RZEPyrazinamide PK Parameter CL/FPZA CL/F Day 14.8 L/hour
RHZE-RMZEPyrazinamide PK Parameter CL/FPZA CL/F Day 14.7 L/hour
RHZE-RMZEPyrazinamide PK Parameter CL/FPZA CL/F Day 144.7 L/hour
RZE-RZEPyrazinamide PK Parameter CL/FPZA CL/F Day 14.2 L/hour
RZE-RZEPyrazinamide PK Parameter CL/FPZA CL/F Day 144.7 L/hour
Secondary

Pyrazinamide PK Parameter Cmax

Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis.

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 127650 ng/mL
RHZE-RHZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 1429300 ng/mL
RHZE-RZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 1427000 ng/mL
RHZE-RZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 127000 ng/mL
RHZE-RMZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 128800 ng/mL
RHZE-RMZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 1429300 ng/mL
RZE-RZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 125800 ng/mL
RZE-RZEPyrazinamide PK Parameter CmaxPZA Cmax at Day 1428000 ng/mL
Secondary

Rifampicin PK Parameter Clearance (CL/F)

Rifampicin PK parameter Clearance (CL/F) obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 114.0 L/hour
RHZE-RHZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 1418.0 L/hour
RHZE-RZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 1422.1 L/hour
RHZE-RZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 112.5 L/hour
RHZE-RMZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 110.5 L/hour
RHZE-RMZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 1421.5 L/hour
RZE-RZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 114.3 L/hour
RZE-RZERifampicin PK Parameter Clearance (CL/F)RIF CL/F Day 1417.0 L/hour
Secondary

Rifampicin PK Parameter Last Concentration (CLast)

Rifampicin (RIF) PK parameter Last Concentration (CLast) obtained Day 1 and Day 14. The lower limit of quantification of the assay (LLOQ) for RIF was 40 ng/mL. The results below the lower limit of quantification were assigned as one-half the value of the LLOQ, which was 20 ng/mL.

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 1420 ng/mL
RHZE-RHZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 174.5 ng/mL
RHZE-RZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 1420 ng/mL
RHZE-RZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 120 ng/mL
RHZE-RMZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 1133 ng/mL
RHZE-RMZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 1420 ng/mL
RZE-RZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 1420 ng/mL
RZE-RZERifampicin PK Parameter Last Concentration (CLast)RIF CLast at Day 120 ng/mL
Secondary

Rifampicin PK Parameter Maximum Plasma Concentration (Cmax)

Rifampicin PK parameter Parameter Maximum Plasma Concentration (Cmax) obtained Day 1 and Day 14

Time frame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14

Population: 63 with qualified samples were included in the primary and secondary analyses including PK analysis

ArmMeasureGroupValue (MEDIAN)
RHZE-RHZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 15565 ng/mL
RHZE-RHZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 147145 ng/mL
RHZE-RZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 146960 ng/mL
RHZE-RZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 16060 ng/mL
RHZE-RMZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 18660 ng/mL
RHZE-RMZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 147370 ng/mL
RZE-RZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 14880 ng/mL
RZE-RZERifampicin PK Parameter Maximum Plasma Concentration (Cmax)RIF Cmax at Day 148350 ng/mL

Source: ClinicalTrials.gov · Data processed: Feb 18, 2026