title: A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis.
abstract: Randomised Phase IIB clinical trial.
  
  
  
  To assess whether increasing the dose of rifampicin (RMP) from 10 mg/kg to 15 or 20 mg/kg results in an increase in grade 3 or 4 hepatic adverse events and/or serious adverse events (SAE).
  
  
  
  Three hundred human immunodeficiency virus negative patients with newly diagnosed microscopy-positive pulmonary tuberculosis (TB) were randomly assigned to one of three regimens: 1) the control regimen (R10), comprising daily ethambutol (EMB), isoniazid (INH), RMP and pyrazinamide for 8 weeks, followed by INH and RMP daily for 18 weeks; 2) Study Regimen 1 (R15), as above, with the RMP dose increased to 15 mg/kg body weight daily for the first 16 weeks; and 3) Study Regimen 2 (R20), as above, with RMP increased to 20 mg/kg. Serum alanine transferase (ALT) levels were measured at regular intervals.
  
  
  
  There were seven grade 3 increases in ALT levels, 1/100 (1%) among R10 arm patients, 2/100 (2%) in the R15 arm and 4/100 (4%) in the R20 arm (trend test P = 0.15). One (R15) patient developed jaundice, requiring treatment modification. There were no grade 4 ALT increases. There was a non-significant increase in culture negativity at 8 weeks with increasing RMP dosage: 75% (69/92) in R10, 82.5% (66/80) in R15 and 83.1% (76/91) R20 patients (P = 0.16).
  
  
  
  No significant increase in adverse events occurred when the RMP dose was increased from 10 mg/kg to 15 mg/kg or 20 mg/kg.
authors.affiliation: St George's, University of London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Jindani
authors.affiliation: St George's, University of London, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Borgulya
authors.affiliation: Centros Broncopulmonares, Cruz Roja, Santa Cruz, Bolivia.
authors.forename: I Westermann
authors.initials: IW
authors.lastname: de Patiño
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gonzales
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: de Fernandes
authors.affiliation: German Nepal Tuberculosis Project, Kathmandu, Nepal.
authors.forename: B
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Epicentre, Mbarara, Uganda.
authors.forename: D
authors.initials: D
authors.lastname: Atwine
authors.affiliation: Epicentre, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Bonnet
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: M
authors.initials: M
authors.lastname: Burgos
authors.affiliation: St George's, University of London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Dubash
authors.affiliation: St George's, University of London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Patel
authors.affiliation: St George's, University of London, London, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Checkley
authors.affiliation: St George's, University of London, London, UK.
authors.forename: T S
authors.initials: TS
authors.lastname: Harrison
authors.affiliation: St George's, University of London, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Mitchison
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004977:Ethambutol / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin