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Essentiality of INH in TB Therapy

This study has been completed.
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01589497
First received: April 30, 2012
Last updated: March 24, 2017
Last verified: March 2017
  Purpose

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 Intervention Phase
Tuberculosis Drug: Rifampicin Drug: Isoniazid Drug: Pyrazinamide Drug: Ethambutol Drug: Moxifloxacin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Essentiality of Isoniazid in Tuberculosis Therapy

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Daily Decrease in log10 Transformed Colony-forming Unit (CFU) Counts Per ml Sputum From Baseline (Study Treatment Initiation) to Day 14 [ Time Frame: 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:
  • Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 14 [ Time Frame: 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.


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


  • Daily Change in log10 Colony-forming Unit (CFU) Counts Per mL Sputum From Day 2 to Day 14 [ Time Frame: 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.


  • Daily Change in Time to Positivity (TTP) From Baseline (Study Treatment Initiation) to Day 2 [ Time Frame: 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.


  • Daily Change in Time to Positivity (TTP) From Day 2 to Day 14 [ Time Frame: 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.


  • Log10 Transformed Colony-forming Unit (CFU) Count Per mL From Sputum Samples at Baseline and Day 14 [ Time Frame: Pre-entry, Day 0 and Day 14 ]
    The log10 CFU count per mL from sputum samples processed by standard method or decontaminated method.

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

  • AUC, CL/F, Cmax, and C24 for Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol at Day 1 and 14 and for Moxifloxacin at Day 14 [ Time Frame: Day 1 and Day 14 ]
    pharmacokinetic parameters, AUC, CL/F, Cmax, and C24 will be examined for rifampicin, isoniazid, pyrazinamide, and ethambutol at day 1 and 14 and for moxifloxacin at day 14. The lab has started testing the samples, and the results should be available by January 2018.


Enrollment: 69
Study Start Date: June 2015
Study Completion Date: February 2016
Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01589497

Locations
South Africa
University of Cape Town Lung Institute (UCTLI) CRS (31792)
Capetown, Western Cape, South Africa, 7705
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
  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     History of Changes
Other Study ID Numbers: ACTG A5307
1U01AI068636 ( US NIH Grant/Contract Award Number )
Study First Received: April 30, 2012
Results First Received: January 24, 2017
Last Updated: March 24, 2017

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Rifampin
Isoniazid
Ethambutol
Moxifloxacin
Pyrazinamide
Norgestimate, ethinyl estradiol drug combination
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Topoisomerase II Inhibitors

ClinicalTrials.gov processed this record on June 23, 2017