Essentiality of INH in TB Therapy
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: Rifampicin; Isoniazid; Pyrazinamide; Ethambutol; Moxifloxacin
Intervention description: 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.; Participants were administered three 100 mg tablets or one 300 mg tablet once daily.; 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.; 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.; Participants were administered one 400 mg tablet orally once a day.
Intervention MeSH terms: Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 69.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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.