title: Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial.
abstract: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question.
  
  
  
  The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0-24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %.
  
  
  
  Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems.
  
  
  
  This trial was registered with clinicaltrials.gov (registration number: NCT01408914 ) on 2 August 2011.
authors: Harvard Medical School, Boston, MA, 02118, USA.
authors: Meredith
authors: M
authors: Milstein
authors: Partners In Health, Boston, MA, 02215, USA.|Socios En Salud, Sucursal-Peru, Lima, Peru.
authors: Leonid
authors: L
authors: Lecca
authors: University of Florida, Gainesville, FL, USA.
authors: Charles
authors: C
authors: Peloquin
authors: St. Georges University, London, UK.
authors: Denis
authors: D
authors: Mitchison
authors: Partners In Health, Boston, MA, 02215, USA.|Brigham and Women's Hospital, Boston, MA, USA.
authors: Kwonjune
authors: K
authors: Seung
authors: Harvard School of Public Health, Boston, MA, USA.
authors: Marcello
authors: M
authors: Pagano
authors: St. Georges University, London, UK.
authors: David
authors: D
authors: Coleman
authors: Harvard Medical School, Boston, MA, 02118, USA.
authors: Elna
authors: E
authors: Osso
authors: Harvard Medical School, Boston, MA, 02118, USA.
authors: Julia
authors: J
authors: Coit
authors: Hospital Nacional Hipólito Unanue, El Augustino, Lima, Peru.
authors: Dante Elmo
authors: DE
authors: Vargas Vasquez
authors: Hospital Nacional Sergio E. Bernales, Comas, Lima, Peru.
authors: Epifanio
authors: E
authors: Sanchez Garavito
authors: Partners In Health, Boston, MA, 02215, USA.|Socios En Salud, Sucursal-Peru, Lima, Peru.
authors: Roger
authors: R
authors: Calderon
authors: Partners In Health, Boston, MA, 02215, USA.|Socios En Salud, Sucursal-Peru, Lima, Peru.
authors: Carmen
authors: C
authors: Contreras
authors: University of Liverpool, Liverpool, UK.
authors: Geraint
authors: G
authors: Davies
authors: Harvard Medical School, Boston, MA, 02118, USA. Carole_Mitnick@hms.harvard.edu.|Partners In Health, Boston, MA, 02215, USA. Carole_Mitnick@hms.harvard.edu.
authors: Carole D
authors: CD
authors: Mitnick
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin
keywords: Pharmacokinetics; Randomized trial; Rifampi(ci)n; Treatment shortening; Tuberculosis