Essentiality of INH in TB Therapy

• Sponsor: AIDS Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01589497
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 69
• Locations: 2
• Arms: 4
• Duration (Months): 7.4
• Patients Per Site: 34.5
• Patients Per Site Per Month: 4.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Moxifloxacin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Essentiality of Isoniazid in Tuberculosis Therapy
• Study Start Date: Jun 30, 2015
• Actual Primary Completion Date: Jan 28, 2016
• Actual Study Completion Date: Feb 10, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: RHZE-RHZE Participants were administered rifampin-isoniazid-pyrazinamide-ethambutol (RHZE) from Day 1 to Day 14.	Drug: Rifampicin; 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.; Drug: Isoniazid; Participants were administered three 100 mg tablets or one 300 mg tablet once daily.; Drug: Pyrazinamide; 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.; Drug: Ethambutol; 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.
Active Comparator: RHZE-RZE Participants were administered RHZE from Day 1 to Day 2, then rifampin-pyrazinamide-ethambutol (RZE) from Day 3 to Day 14.	Drug: Rifampicin; 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.; Drug: Isoniazid; Participants were administered three 100 mg tablets or one 300 mg tablet once daily.; Drug: Pyrazinamide; 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.; Drug: Ethambutol; 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.
Active Comparator: RHZE-RMZE Participants were administered RHZE Day 1 to Day 2 and rifampin-moxifloxacin-pyrazinamide-ethambutol (RMZE) from Day 3 to Day 14.	Drug: Rifampicin; 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.; Drug: Isoniazid; Participants were administered three 100 mg tablets or one 300 mg tablet once daily.; Drug: Pyrazinamide; 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.; Drug: Ethambutol; 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.; Drug: Moxifloxacin; Participants were administered one 400 mg tablet orally once a day.; Other Names: Avelon
Active Comparator: RZE-RZE Participants were administered only RZE from Day 1 through Day 14.	Drug: Rifampicin; 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.; Drug: Pyrazinamide; 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.; Drug: Ethambutol; 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.

Outcome Measures

Primary Outcome Measures

1. Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14 [Pre-entry, Day 0 and 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.

Secondary Outcome Measures

1. Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14 [Pre-entry, Day 0 and 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.

2. Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2 [Pre-entry, Day 0 and 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.

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

4. Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2 [Pre-entry, Day 0 and 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.

5. Daily Change in Time to Positivity (TTP) From Day 2 to Day 14 [Day 2 and Day 14]

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

6. Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14 [Pre-entry, Day 0 and Day 14]

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

7. Correlation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mL [Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14]

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

8. 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 14]

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

9. 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 14]

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

10. 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 14]

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

11. 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 14]

    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.

12. 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 1]

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

13. 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 1]

    Isoniazid PK parameter CL/F obtained Day 1

14. 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 1]

    Isoniazid PK parameter Cmax obtained Day 1

15. 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 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.

16. 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 14]

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

17. 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 14]

    Isoniazid PK parameter CL/F obtained Day 14

18. 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 14]

    Isoniazid PK parameter Cmax obtained Day 14

19. 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 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.

20. 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 14]

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

21. 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 14]

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

22. 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 14]

    Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14

23. 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 14]

    Pyrazinamide PK parameter CLast obtained Day 1 and Day 14

24. 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 14]

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

25. 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 14]

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

26. 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 14]

    Ethambutol PK parameter Cmax obtained Day 1 and Day 14

27. 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 14]

    Ethambutol PK parameter CLast obtained Day 1 and Day 14

28. 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 14]

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

29. 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 14]

    Moxifloxacin PK parameter CL/F obtained Day 14

30. 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 14]

    Moxifloxacin PK parameter Cmax obtained Day 14

31. 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 14]

    Moxifloxacin PK parameter CLast obtained Day 14

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Cape Town Lung Institute (UCTLI) CRS (31792)	Cape Town	Western Cape	South Africa	7705
2	TASK Applied Science CRS (31718)	Bellville		South Africa	7531

Sponsors and Collaborators

• AIDS Clinical Trials Group
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: William Bishai, MD, PhD, Johns Hopkins Center for TB Research
• Study Chair: Andreas Diacon, MD, PhD, TASK Applied Science CRS

Study Documents (Full-Text)

None provided.

More Information

Publications

• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009).

• Responsible Party: AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01589497
• Other Study ID Numbers: ACTG A5307; 1U01AI068636
• First Posted: May 2, 2012
• Last Update Posted: Apr 6, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Tuberculosis; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol

Study Results

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 Detail	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.

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14. Rifampicin: Participants with body weight </= 50kg were administered one 450 mg tablet orally once daily; with body weight >50kg were administered one 600 mg tablet orally once daily. Isoniazid: Participants were administered three 100 mg tablets or one 300 mg tablet once daily. Pyrazinamide: Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 500 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily. Ethambutol: Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 400 mg tablets orally once daily.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14. Rifampicin: Participants with body weight </= 50kg were administered one 450 mg tablet orally once daily; with body weight >50kg were administered one 600 mg tablet orally once daily. Isoniazid: Participants were administered three 100 mg tablets or one 300 mg tablet once daily. Pyrazinamide: Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily; with body weight of 56-75 kg were administered three 500 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily. Ethambutol: Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 400 mg tablets orally once	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14. Rifampicin: Participants with body weight </= 50kg were administered one 450 mg tablet orally once daily; with body weight >50kg were administered one 600 mg tablet orally once daily. Isoniazid: Participants were administered three 100 mg tablets or one 300 mg tablet once daily. Pyrazinamide: Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 500 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily. Ethambutol: Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 400 mg tablets orally once daily. Moxifloxacin: one 400 mg tablet orally once a day.	Participants were administered only RZE from Day 1 through Day 14. Rifampicin: Participants with body weight </= 50kg were administered one 450 mg tablet orally once daily; with body weight >50kg were administered one 600 mg tablet orally once daily. Pyrazinamide: Participants with a body weight of 40-55 kg were administered two 500 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 500 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 500 mg tablets orally once daily. Ethambutol: Participants with a body weight of 40-55 kg were administered two 400 mg tablets orally once daily; with a body weight of 56-75 kg were administered three 400 mg tablets orally once daily; with a body weight of 76-90 kg were administered four 400 mg tablets orally once daily.
Period Title: Overall Study
STARTED	18	17	16	18
COMPLETED	17	16	15	17
NOT COMPLETED	1	1	1	1

Baseline Characteristics

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE	Total
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.	Total of all reporting groups
Overall Participants	18	17	16	18	69
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	28.5	31	33.5	32	31
Age, Customized (Count of Participants)
<20	2 11.1%	0 0%	1 6.3%	1 5.6%	4 5.8%
20-29	7 38.9%	4 23.5%	6 37.5%	5 27.8%	22 31.9%
30-39	5 27.8%	11 64.7%	2 12.5%	5 27.8%	23 33.3%
40-49	2 11.1%	1 5.9%	4 25%	6 33.3%	13 18.8%
50-59	2 11.1%	1 5.9%	3 18.8%	1 5.6%	7 10.1%
Sex: Female, Male (Count of Participants)
Female	5 27.8%	1 5.9%	3 18.8%	3 16.7%	12 17.4%
Male	13 72.2%	16 94.1%	13 81.3%	15 83.3%	57 82.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 5.9%	0 0%	0 0%	1 1.4%
Not Hispanic or Latino	18 100%	15 88.2%	16 100%	18 100%	67 97.1%
Unknown or Not Reported	0 0%	1 5.9%	0 0%	0 0%	1 1.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	18 100%	17 100%	16 100%	18 100%	69 100%
White	0 0%	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Karnofsky score (scores on a scale) [Median (Full Range) ]
Median (Full Range) [scores on a scale]	90	90	90	90	90
BMI (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	18.5	19.4	19.8	18.7	18.9
HIV status (participants) [Number]
HIV negative	16 88.9%	16 94.1%	15 93.8%	18 100%	65 94.2%
HIV positive	2 11.1%	1 5.9%	1 6.3%	0 0%	4 5.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	12	11	10	15
Median (Inter-Quartile Range) [log10 CFU/ mL]	0.134	0.096	0.136	0.119

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	16
Median (Inter-Quartile Range) [hours]	-12	-12	-13	-11

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	12	13	12	12
Median (Inter-Quartile Range) [log10 CFU/ mL]	0.255	0.385	0.111	0.034

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	10	11	11	11
Median (Inter-Quartile Range) [log10 CFU/ mL]	0.143	0.093	0.123	0.104

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	16
Median (Inter-Quartile Range) [hours]	-31	-30	-29	-25

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
Median (Inter-Quartile Range) [hours]	-9	-9	-12	-9

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Standard Processing Method	Decontaminated Processing Method
Arm/Group Description	The standard sputum processing method	The decontaminated sputum processing method
Measure Participants	63	63
Pre-entry	5.80	5.89
Day 0	5.68	5.58
Day 14	4.01	3.74

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Overall
Arm/Group Description	Qualified samples from overall participants
Measure Participants	63
Number [correlation coefficient]	-0.75

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
RIF AUC0-24hour at Day 1	37358.8	42062.6	51434.1	39294.0
RIF AUC0-24hour at Day 14	31361.4	27161.7	26751.2	30521.0

10. Secondary Outcome

Title	Rifampicin PK Parameter Clearance (CL/F)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
RIF CL/F Day 1	14.0	12.5	10.5	14.3
RIF CL/F Day 14	18.0	22.1	21.5	17.0

11. Secondary Outcome

Title	Rifampicin PK Parameter Maximum Plasma Concentration (Cmax)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
RIF Cmax at Day 1	5565	6060	8660	4880
RIF Cmax at Day 14	7145	6960	7370	8350

12. Secondary Outcome

Title	Rifampicin PK Parameter Last Concentration (CLast)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
RIF CLast at Day 1	74.5	20	133	20
RIF CLast at Day 14	20	20	20	20

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	16	15	15
Median (Inter-Quartile Range) [h*ng/mL]	10725.8	7970.6	7165.1

14. Secondary Outcome

Title	Isoniazid PK Parameter CL/F at Day 1
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	16	15	15
Median (Inter-Quartile Range) [L/hour]	28.0	37.6	41.9

15. Secondary Outcome

Title	Isoniazid PK Parameter Cmax at Day 1
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	16	15	15
Median (Inter-Quartile Range) [ng/mL]	3165	2920	2760

16. Secondary Outcome

Title	Isoniazid PK Parameter CLast at Day 1
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	16	15	15
Median (Inter-Quartile Range) [ng/mL]	50	50	50

17. Secondary Outcome

Title	AUC0-24hour for Isoniazid at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.
Measure Participants	16
Median (Inter-Quartile Range) [h*ng/mL]	9797.2

18. Secondary Outcome

Title	Isoniazid PK Parameter CL/F at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.
Measure Participants	16
Median (Inter-Quartile Range) [L/hour]	30.6

19. Secondary Outcome

Title	Isoniazid PK Parameter Cmax at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.
Measure Participants	16
Median (Inter-Quartile Range) [ng/mL]	3130

20. Secondary Outcome

Title	Isoniazid PK Parameter CLast at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RHZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.
Measure Participants	16
Median (Inter-Quartile Range) [ng/mL]	50

21. Secondary Outcome

Title	AUC0-24hour for Pyrazinamide (PZA)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
PZA AUC0-24hour at Day 1	301214.5	255283.0	292078.2	272853.9
PZA AUC0-24hour at Day 14	249879.1	201389.7	280071.0	252276.8

22. Secondary Outcome

Title	Pyrazinamide PK Parameter CL/F
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
PZA CL/F Day 1	4.1	4.8	4.7	4.2
PZA CL/F Day 14	4.5	5.4	4.7	4.7

23. Secondary Outcome

Title	Pyrazinamide PK Parameter Cmax
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
PZA Cmax at Day 1	27650	27000	28800	25800
PZA Cmax at Day 14	29300	27000	29300	28000

24. Secondary Outcome

Title	Pyrazinamide PK Parameter CLast
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
PZA CLast at Day 1	3370	2850	3130	2710
PZA CLast at Day 14	1955.0	1280	1790	1770

25. Secondary Outcome

Title	AUC0-24hour for Ethambutol (EMB)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
EMB AUC0-24hour at Day 1	11918.8	11145.8	11322.4	10716.8
EMB AUC0-24hour at Day 14	16414.9	16675.9	15181.2	16574.6

26. Secondary Outcome

Title	Ethambutol PK Parameter CL/F
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
EMB CL/F Day 1	93.6	85.4	83.8	76.5
EMB CL/F Day 14	57.9	63.5	56.8	60.1

27. Secondary Outcome

Title	Ethambutol PK Parameter Cmax
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
EMB Cmax at Day 1	2650	2040	2470	2220
EMB Cmax at Day 14	2980	3090	2780	2920

28. Secondary Outcome

Title	Ethambutol PK Parameter CLast
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RHZE	RHZE-RZE	RHZE-RMZE	RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.	Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.	Participants were administered only RZE from Day 1 through Day 14.
Measure Participants	16	15	15	17
EMB CLast at Day 1	86.5	85	40	86
EMB CLast at Day 14	205.0	176	164	159

29. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RMZE
Arm/Group Description	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	15
Median (Inter-Quartile Range) [h*ng/mL]	22498.4

30. Secondary Outcome

Title	Moxifloxacin PK Parameter CL/F at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RMZE
Arm/Group Description	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	15
Median (Inter-Quartile Range) [L/hour]	17.8

31. Secondary Outcome

Title	Moxifloxacin PK Parameter Cmax at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RHZE-RMZE
Arm/Group Description	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	15
Median (Inter-Quartile Range) [ng/mL]	3010

32. Secondary Outcome

Title	Moxifloxacin PK Parameter CLast at Day 14
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	RHZE-RMZE
Arm/Group Description	Participants will be administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.
Measure Participants	15
Median (Inter-Quartile Range) [ng/mL]	178

Adverse Events

Time Frame	From treatment dispensation to study discontinuation. The duration of the study was 29 days.
Adverse Event Reporting Description	The protocol required reporting of all new diagnoses and new signs and symptoms and laboratory abnormalities of >=Grade 2. The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs. Expedited adverse event reporting followed Version 2.0 of the DAIDS Expedited Adverse Event Manual.
Arm/Group Title	RHZE-RHZE		RHZE-RZE		RHZE-RMZE		RZE-RZE
Arm/Group Description	Participants were administered RHZE from Day 1 to Day 14.		Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14.		Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14.		Participants were administered only RZE from Day 1 through Day 14.
All Cause Mortality
	RHZE-RHZE		RHZE-RZE		RHZE-RMZE		RZE-RZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Serious Adverse Events
	RHZE-RHZE		RHZE-RZE		RHZE-RMZE		RZE-RZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		1/17 (5.9%)		1/16 (6.3%)		0/18 (0%)
Infections and infestations
Pneumonia bacterial	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Nervous system disorders
Loss of consciousness	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		0/18 (0%)
Vascular disorders
Deep vein thrombosis	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	RHZE-RHZE		RHZE-RZE		RHZE-RMZE		RZE-RZE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		5/17 (29.4%)		3/16 (18.8%)		5/18 (27.8%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		0/18 (0%)
Cardiac disorders
Tachycardia	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Gastrointestinal disorders
Constipation	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Toothache	1/18 (5.6%)		1/17 (5.9%)		0/16 (0%)		0/18 (0%)
General disorders
Chest pain	2/18 (11.1%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Hepatobiliary disorders
Hepatotoxicity	2/18 (11.1%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Investigations
Alanine aminotransferase increased	2/18 (11.1%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Aspartate aminotransferase increased	2/18 (11.1%)		0/17 (0%)		0/16 (0%)		0/18 (0%)
Haemoglobin decreased	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Joint stiffness	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Pain in extremity	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Nervous system disorders
Headache	2/18 (11.1%)		2/17 (11.8%)		2/16 (12.5%)		0/18 (0%)
Lethargy	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Neuropathy peripheral	0/18 (0%)		0/17 (0%)		0/16 (0%)		2/18 (11.1%)
Paraesthesia	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Tachypnoea	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Pruritus generalised	0/18 (0%)		1/17 (5.9%)		0/16 (0%)		1/18 (5.6%)
Rash	0/18 (0%)		0/17 (0%)		0/16 (0%)		1/18 (5.6%)
Rash erythematous	0/18 (0%)		0/17 (0%)		1/16 (6.3%)		0/18 (0%)
Rash pruritic	1/18 (5.6%)		0/17 (0%)		0/16 (0%)		0/18 (0%)

Limitations/Caveats

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Principal Investigators are NOT employed by the organization sponsoring the study.

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