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| ID | Type | Description | Link |
|---|---|---|---|
| 1U01AI068636 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RHZE-RHZE | Active Comparator | Participants were administered rifampin-isoniazid-pyrazinamide-ethambutol (RHZE) from Day 1 to Day 14. |
|
| RHZE-RZE | Active Comparator | Participants were administered RHZE from Day 1 to Day 2, then rifampin-pyrazinamide-ethambutol (RZE) from Day 3 to Day 14. |
|
| RHZE-RMZE | Active Comparator | Participants were administered RHZE Day 1 to Day 2 and rifampin-moxifloxacin-pyrazinamide-ethambutol (RMZE) from Day 3 to Day 14. |
|
| RZE-RZE | Active Comparator | Participants were administered only RZE from Day 1 through Day 14. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifampicin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Pre-entry, Day 0 and Day 14 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Pre-entry, Day 0 and Day 14 |
| Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2 |
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Inclusion Criteria:
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:
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.
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| Name | Affiliation | Role |
|---|---|---|
| William Bishai, MD, PhD | Johns Hopkins Center for TB Research | Study Chair |
| Andreas Diacon, MD, PhD | TASK Applied Science CRS | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Cape Town Lung Institute (UCTLI) CRS (31792) | Cape Town | Western Cape | 7705 | South Africa | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | 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). | ||
| 33834177 | Derived | Diacon A, Miyahara S, Dawson R, Sun X, Hogg E, Donahue K, Urbanowski M, De Jager V, Fletcher CV, Hafner R, Swindells S, Bishai W. Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial. Lancet Microbe. 2020 Jun;1(2):e84-e92. doi: 10.1016/s2666-5247(20)30011-2. Epub 2020 Jun 8. |
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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.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | RHZE-RHZE | 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. |
| FG001 | RHZE-RZE | 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 |
| FG002 | RHZE-RMZE | 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. |
| FG003 | RZE-RZE | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Intent to treat: All enrolled 69 participants were included in the baseline characteristics.
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| ID | Title | Description |
|---|---|---|
| BG000 | RHZE-RHZE | Participants were administered RHZE from Day 1 to Day 14. |
| BG001 | RHZE-RZE | Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | log10 CFU/ mL | Pre-entry, Day 0 and Day 14 |
|
From treatment dispensation to study discontinuation. The duration of the study was 29 days.
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | RHZE-RHZE | Participants were administered RHZE from Day 1 to Day 14. | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia bacterial | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Iron deficiency anaemia | Blood and lymphatic system disorders | MedDRA 19.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| ACTG Clinicaltrials.gov Coordinator | ACTG Network Coordinating Center, Social & Scientific Systems, Inc. | (301) 628-3313 | ACTGCT.Gov@s-3.com |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D012293 | Rifampin |
| D007538 | Isoniazid |
| D011718 | Pyrazinamide |
| D004977 | Ethambutol |
| D000077266 | Moxifloxacin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Isoniazid | Drug | Participants were administered three 100 mg tablets or one 300 mg tablet once daily. |
|
| Pyrazinamide | Drug | 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. |
|
| Ethambutol | Drug | 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. |
|
| Moxifloxacin | Drug | Participants were administered one 400 mg tablet orally once a day. |
|
|
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. |
| Pre-entry, Day 0 and Day 2 |
| 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. | Day 2 and day 14 |
| 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. | Pre-entry, Day 0 and Day 2 |
| 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. | Day 2 and Day 14 |
| 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. | Pre-entry, Day 0 and Day 14 |
| 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 | Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14 |
| 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 | -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) | Rifampicin PK parameter Clearance (CL/F) obtained Day 1 and Day 14 | -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 Maximum Plasma Concentration (Cmax) | Rifampicin PK parameter Parameter Maximum Plasma Concentration (Cmax) obtained Day 1 and Day 14 | -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 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. | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14 |
| AUC0-24hour for Isoniazid (INH) at Day 1 | PK AUCs of Isoniazid (INH) from 0 to 24 hours obtained 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 at Day 1 | Isoniazid PK parameter CL/F obtained 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 at Day 1 | Isoniazid PK parameter Cmax obtained 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 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. | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1 |
| AUC0-24hour for Isoniazid at Day 14 | PK AUCs of Isoniazid from 0 to 24 hours obtained 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 at Day 14 | Isoniazid PK parameter CL/F obtained 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 at Day 14 | Isoniazid PK parameter Cmax obtained 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 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. | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14 |
| AUC0-24hour for Pyrazinamide (PZA) | PK AUCs of Pyrazinamide (PZA) from 0 to 24 hours obtained at Day 1 and Day 14 | -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 | Pyrazinamide PK parameter CL/F obtained Day 1 and Day 14 | -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 | Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14 | -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 | Pyrazinamide PK parameter CLast obtained Day 1 and Day 14 | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14 |
| AUC0-24hour for Ethambutol (EMB) | PK AUCs of Ethambutol (EMB) from 0 to 24 hours obtained at Day 1 and Day 14 | -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 | Ethambutol PK parameter CL/F obtained Day 1 and Day 14 | -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 | Ethambutol PK parameter Cmax obtained Day 1 and Day 14 | -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 | Ethambutol PK parameter CLast obtained Day 1 and Day 14 | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14 |
| AUC0-24hour for Moxifloxacin (Mox) at Day 14 | PK AUCs of Moxiflozacin (Mox) from 0 to 24 hours obtained 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 at Day 14 | Moxifloxacin PK parameter CL/F obtained 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 at Day 14 | Moxifloxacin PK parameter Cmax obtained 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 at Day 14 | Moxifloxacin PK parameter CLast obtained Day 14 | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14 |
| TASK Applied Science CRS (31718) |
| Bellville |
| 7531 |
| South Africa |
| Death |
|
| Pre-entry overnight sputum< 10ML |
|
| BG002 | RHZE-RMZE | Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14. |
| BG003 | RZE-RZE | Participants were administered only RZE from Day 1 through Day 14. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Karnofsky score | The karnofsky score was determined according to karnofsky performance scale. The scale ranged from 0 to 100, by 10. A higher value represents a better outcome. | Median | Full Range | scores on a scale |
|
| BMI | Median | Inter-Quartile Range | kg/m^2 |
|
| HIV status | Number | participants |
|
| RHZE-RZE |
Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14. |
| OG002 | RHZE-RMZE | Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14. |
| OG003 | RZE-RZE | Participants were administered only RZE from Day 1 through Day 14. |
|
|
| 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | hours | Pre-entry, Day 0 and Day 14 |
|
|
|
| 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | log10 CFU/ mL | Pre-entry, Day 0 and Day 2 |
|
|
|
| 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | log10 CFU/ mL | Day 2 and day 14 |
|
|
|
| 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | hours | Pre-entry, Day 0 and Day 2 |
|
|
|
| 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. | Participants with qualified sputum samples who had results available at all time points specified in the time-frame | Posted | Median | Inter-Quartile Range | hours | Day 2 and Day 14 |
|
|
|
| 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. | Participants with qualified sputum samples who had results available at least one time point specified in the time-frame | Posted | Median | Inter-Quartile Range | log10 CFU/ mL | Pre-entry, Day 0 and Day 14 |
|
|
|
| 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 | Participants with qualified sputum samples who had results available at least one time point specified in the time-frame | Posted | Number | correlation coefficient | Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14 |
|
|
|
| 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 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14 |
|
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| Secondary | Rifampicin PK Parameter Clearance (CL/F) | Rifampicin PK parameter Clearance (CL/F) obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14 |
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| Secondary | Rifampicin PK Parameter Maximum Plasma Concentration (Cmax) | Rifampicin PK parameter Parameter Maximum Plasma Concentration (Cmax) obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14 |
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| 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. | 63 with qualified samples were included in the primary and secondary analyses including PK analysis | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14 |
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| Secondary | AUC0-24hour for Isoniazid (INH) at Day 1 | PK AUCs of Isoniazid (INH) from 0 to 24 hours obtained at Day 1 | 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. | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1 |
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| Secondary | Isoniazid PK Parameter CL/F at Day 1 | Isoniazid PK parameter CL/F obtained Day 1 | 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. | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1 |
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| Secondary | Isoniazid PK Parameter Cmax at Day 1 | Isoniazid PK parameter Cmax obtained Day 1 | 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. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1 |
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| 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. | 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. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1 |
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| Secondary | AUC0-24hour for Isoniazid at Day 14 | PK AUCs of Isoniazid from 0 to 24 hours obtained at Day 14 | 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. | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14 |
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| Secondary | Isoniazid PK Parameter CL/F at Day 14 | Isoniazid PK parameter CL/F obtained Day 14 | 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. | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14 |
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| Secondary | Isoniazid PK Parameter Cmax at Day 14 | Isoniazid PK parameter Cmax obtained Day 14 | 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. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14 |
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| 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. | 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. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14 |
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| Secondary | AUC0-24hour for Pyrazinamide (PZA) | PK AUCs of Pyrazinamide (PZA) from 0 to 24 hours obtained at Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14 |
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| Secondary | Pyrazinamide PK Parameter CL/F | Pyrazinamide PK parameter CL/F obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14 |
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| Secondary | Pyrazinamide PK Parameter Cmax | Pyrazinamide PK parameter Cmax obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14 |
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| Secondary | Pyrazinamide PK Parameter CLast | Pyrazinamide PK parameter CLast obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14 |
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| Secondary | AUC0-24hour for Ethambutol (EMB) | PK AUCs of Ethambutol (EMB) from 0 to 24 hours obtained at Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14 |
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| Secondary | Ethambutol PK Parameter CL/F | Ethambutol PK parameter CL/F obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14 |
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| Secondary | Ethambutol PK Parameter Cmax | Ethambutol PK parameter Cmax obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14 |
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| Secondary | Ethambutol PK Parameter CLast | Ethambutol PK parameter CLast obtained Day 1 and Day 14 | 63 with qualified samples were included in the primary and secondary analyses including PK analysis. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14 |
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| Secondary | AUC0-24hour for Moxifloxacin (Mox) at Day 14 | PK AUCs of Moxiflozacin (Mox) from 0 to 24 hours obtained at Day 14 | 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 | Posted | Median | Inter-Quartile Range | h*ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14 |
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| Secondary | Moxifloxacin PK Parameter CL/F at Day 14 | Moxifloxacin PK parameter CL/F obtained Day 14 | 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 | Posted | Median | Inter-Quartile Range | L/hour | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14 |
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| Secondary | Moxifloxacin PK Parameter Cmax at Day 14 | Moxifloxacin PK parameter Cmax obtained Day 14 | 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 | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14 |
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| Secondary | Moxifloxacin PK Parameter CLast at Day 14 | Moxifloxacin PK parameter CLast obtained Day 14 | 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. | Posted | Median | Inter-Quartile Range | ng/mL | -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14 |
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| 18 |
| 1 |
| 18 |
| 6 |
| 18 |
| EG001 | RHZE-RZE | Participants were administered RHZE from Day 1 to Day 2, then RZE from Day 3 to Day 14. | 0 | 17 | 1 | 17 | 5 | 17 |
| EG002 | RHZE-RMZE | Participants were administered RHZE Day 1 to Day 2 and RMZE from Day 3 to Day 14. | 0 | 16 | 1 | 16 | 3 | 16 |
| EG003 | RZE-RZE | Participants were administered only RZE from Day 1 through Day 14. | 0 | 18 | 0 | 18 | 5 | 18 |
| Loss of consciousness | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Deep vein thrombosis | Vascular disorders | MedDRA 19.0 | Systematic Assessment |
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| Tachycardia | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Toothache | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Chest pain | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Hepatotoxicity | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Alanine aminotransferase increased | Investigations | MedDRA 19.0 | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA 19.0 | Systematic Assessment |
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| Haemoglobin decreased | Investigations | MedDRA 19.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Lethargy | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Neuropathy peripheral | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Tachypnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA 19.0 | Systematic Assessment |
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In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D011719 | Pyrazines |
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| Day 0 |
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| Day 14 |
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| RIF AUC0-24hour at Day 14 |
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| RIF CL/F Day 14 |
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| RIF Cmax at Day 14 |
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| RIF CLast at Day 14 |
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| PZA AUC0-24hour at Day 14 |
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| PZA CL/F Day 14 |
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| PZA Cmax at Day 14 |
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| PZA CLast at Day 14 |
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| EMB AUC0-24hour at Day 14 |
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| EMB CL/F Day 14 |
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| EMB Cmax at Day 14 |
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| EMB CLast at Day 14 |
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