Clinical trial NCT01589497: Essentiality of INH in TB Therapy
Official title: Essentiality of Isoniazid in Tuberculosis Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-05-02
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Tuberculosis (TB) disease is caused by bacteria that have infected the lung. TB bacteria are very small living agents that are spread by coughing and can be killed by taking TB drugs. To kill these TB bacteria TB patients have to take a combination of four drugs for 2 months and then two drugs for a further 4 months. During the first 2 months patients take rifampicin, isoniazid, ethambutol, and pyrazinamide. After that patients take only isoniazid and rifampicin for a further 4 months, making a total of 6 months therapy.

In A5307 the investigators wanted to test a new combination of drugs to see if the investigators could treat TB faster in the future.

Studies in animals have suggested that one of the four drugs, isoniazid, only works for a few days and may not be needed after the first two doses of TB treatment to kill the TB bacteria. After that its effects wear off to the point that it may even interfere with the other drugs. The investigators wanted to see if stopping isoniazid early, or using moxifloxacin, a different drug, instead could treat TB faster. This study was the first time that this type of regimen without isoniazid had been tested in humans. If the investigators could show that isoniazid stops working after a few days, the investigators could then try to see if they could possibly make a better tuberculosis treatment in the future.

Detailed description: This was a Phase IIa open label, randomized clinical trial comparing the early bactericidal activity (EBA) of four anti-tuberculosis regimens. Participants with acid fast bacilli (AFB) smear-positive pulmonary tuberculosis were hospitalized from screening through Day 15 of the study, during which time, sputum, blood, and urine were collected. Participants returned to the clinic on Day 28 for the final visit. The study duration was 29 days.

The purpose of the study was to estimate the primary outcome within each study arm and the study was not designed for between arm comparisons.

Eligibility criteria: 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.

Primary outcomes:
measure: Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14
timeFrame: Pre-entry, Day 0 and Day 14
Secondary outcomes:
measure: Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14
timeFrame: Pre-entry, Day 0 and Day 14
measure: Daily Change in log10 Transformed Colony-forming Unit (CFU) Counts Per mL Sputum From Baseline (Study Treatment Initiation) to Day 2
timeFrame: Pre-entry, Day 0 and Day 2
measure: Daily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 14
timeFrame: Day 2 and day 14
measure: Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2
timeFrame: Pre-entry, Day 0 and Day 2
measure: Daily Change in Time to Positivity (TTP) From Day 2 to Day 14
timeFrame: Day 2 and Day 14
measure: Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14
timeFrame: Pre-entry, Day 0 and Day 14
measure: Correlation Between Time to Positivity (TTP) and log10 Transformed Colony-forming Unit (CFU) Counts Per mL
timeFrame: Pre-entry, Day 0, Day 1, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11 and Day 14
measure: Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-24hour) for Rifampicin (RIF)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14
measure: Rifampicin PK Parameter Clearance (CL/F)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14
measure: Rifampicin PK Parameter Maximum Plasma Concentration (Cmax)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14
measure: Rifampicin PK Parameter Last Concentration (CLast)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Rifampicin dosing at Day 1 and Day 14
measure: AUC0-24hour for Isoniazid (INH) at Day 1
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1
measure: Isoniazid PK Parameter CL/F at Day 1
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1
measure: Isoniazid PK Parameter Cmax at Day 1
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1
measure: Isoniazid PK Parameter CLast at Day 1
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 1
measure: AUC0-24hour for Isoniazid at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14
measure: Isoniazid PK Parameter CL/F at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14
measure: Isoniazid PK Parameter Cmax at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14
measure: Isoniazid PK Parameter CLast at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Isoniazid dosing at Day 14
measure: AUC0-24hour for Pyrazinamide (PZA)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14
measure: Pyrazinamide PK Parameter CL/F
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14
measure: Pyrazinamide PK Parameter Cmax
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14
measure: Pyrazinamide PK Parameter CLast
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Pyrazinamide dosing at Day 1 and Day 14
measure: AUC0-24hour for Ethambutol (EMB)
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14
measure: Ethambutol PK Parameter CL/F
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14
measure: Ethambutol PK Parameter Cmax
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14
measure: Ethambutol PK Parameter CLast
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Ethambutol dosing at Day 1 and Day 14
measure: AUC0-24hour for Moxifloxacin (Mox) at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14
measure: Moxifloxacin PK Parameter CL/F at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14
measure: Moxifloxacin PK Parameter Cmax at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14
measure: Moxifloxacin PK Parameter CLast at Day 14
timeFrame: -0.5 hour (pre-dose), 1, 2, 3, 5, 7, 10, 12 and 24 hours after Moxifloxacin dosing at Day 14
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute (UCTLI) CRS (31792)
state: Western Cape
city: Bellville
country: South Africa
facility: TASK Applied Science CRS (31718)
Study officials:
affiliation: Johns Hopkins Center for TB Research
name: William Bishai, MD, PhD
role: STUDY_CHAIR
affiliation: TASK Applied Science CRS
name: Andreas Diacon, MD, PhD
role: STUDY_CHAIR
References:
citation: 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).
citation: 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.