Essentiality of INH in TB Therapy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Essentiality of Isoniazid in Tuberculosis Therapy

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Rifampicin
* Drug: Isoniazid
* Drug: Pyrazinamide
* Drug: Ethambutol
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 |