A Randomised Trial to Evaluate Toxicity and Efficacy of 1200mg and 1800mg Rifampicin for Pulmonary Tuberculosis
A Randomised Trial to Evaluate Toxicity and Efficacy of 1200mg and 1800mg Rifampicin for Pulmonary Tuberculosis
In this trial, the investigators are assessing whether giving an increased dose of rifampicin
 to patients receiving the standard treatment for tuberculosis is safe and, when given for 4
 months only, will also result in greater and faster killing of the tubercle bacillus in the
 lungs and result in relapse rates similar to those found in the World Health Organisation
 (WHO) recommended standard 6 month regimen.
Type of design An open-label 3-arm trial to compare a standard 6-month control regimen with
 two 4-month treatment regimens for the treatment of tuberculosis (TB).

 Disease/patients studied The trial will include 654 patients newly diagnosed with pulmonary
 TB with sputum positive or negative for TB on microscopy but with a positive result on a
 GeneXpert Test with organisms fully sensitive to rifampicin

 The treatment regimens - Control and Experimental

 Patients enrolled in the trial will be randomly allocated to receive one of the following
 three chemotherapy treatment regimens:

 1. Control regimen (R10): The standard regimen of isoniazid, pyrazinamide and ethambutol
 plus 10 mg/kg rifampicin for the initial 8 weeks, followed by isoniazid and rifampicin
 (at the same dose size) for an additional 4 months (2HRZE/4HR)A.

 2. Study regimen 1(SR1): 2 months of daily ethambutol, isoniazid, rifampicin, and
 pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of
 either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70
 and more kg) of rifampicin will be given throughout the four months (2EHR
 1200Z/2HR1200)B.

 3. Study regimen 2(SR2): 2 months of daily ethambutol, isoniazid, rifampicin, and
 pyrazinamide followed by 2 months of daily isoniazid and rifampicin. A supplement of
 either 450 mg (weight bands 35-39kg and 40-54kg) or 600mg (weight band 55-69kg and 70
 and more kg) of rifampicin will be given throughout the four months
 (2EHR1800Z/2HR1800)C.

 1.1 Outcome measures Primary outcome measure

 1. Since the objective of the trial is to reduce treatment duration by increasing the dose
 of rifampicin, the primary outcome measure is the combined rate of failure at the end of
 treatment and relapse during the subsequent 12 months in smear positive patients.

 2. The occurrence of grade 3 or 4 adverse events at any time during chemotherapy.
Inclusion Criteria:

 1. GeneXpert sputum positive, rifampicin susceptible, newly diagnosed pulmonary
 tuberculosis will be included even if they are microscopy negative.

 2. No previous anti-tuberculosis chemotherapy.

 3. Patients ≥ 18 years

 4. Consent to participation in the trial and to HIV testing

 5. Provide informed consent.

 6. Patient has a stable home address within easy reach of the treatment facility and
 likely to remain there for the next 18 months.

 7. Pre-menopausal women must be using a barrier form of contraception or be surgically
 sterilised or have an Intrauterine Contraceptive Device (IUCD) in place for the
 duration of the treatment phase

 Exclusion Criteria:

 1. Patients with rifampicin resistance identified by GeneXpert or by direct
 susceptibility testing (late exclusions).

 2. Has any condition that may prove fatal during the study period.

 3. Has TB meningitis.

 4. Has pre-existing non-tuberculous disease likely to prejudice the response to, or
 assessment of, treatment e.g. insulin-dependent diabetes, liver or kidney disease,
 blood disorders, peripheral neuritis, and severe thrombocytopenia, rash, increase of
 bilirubin and other diseases that are likely to be contraindicated with rifampicin

 5. Is female and known to be pregnant, or breast feeding.

 6. Is suffering from a condition likely to lead to uncooperative behaviour such as
 psychiatric illness or alcoholism.

 7. Has contraindications to any medications in the study regimens

 8. Is HIV positive

 9. Haemoglobin <7g/l

 10. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 5 times the upper
 limit of normal (ULN) for that laboratory

 11. Creatinine clearance (CrCl) of < 30mls/min. Calculated as CrCl (mL/min) = N x [140-age
 (years)] x weight (kg) Serum creatinine (micromol/L) Where N = 1.23 males, 1.04
 females

 12. Has glucose in urine

 13. Weight < 35kg