title: Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial.
abstract: BACKGROUND
  Tuberculous meningitis is the most severe form of tuberculosis. Mortality for untreated tuberculous meningitis is 100%. Despite the introduction of antibiotic treatment for tuberculosis the mortality rate for tuberculous meningitis remains high; approximately 25% for HIV-negative and 67% for HIV positive patients with most deaths occurring within one month of starting therapy. The high mortality rate in tuberculous meningitis reflects the severity of the condition but also the poor antibacterial activity of current treatment regimes and relatively poor penetration of these drugs into the central nervous system. Improving the antitubercular activity in the central nervous system of current therapy may help improve outcomes. Increasing the dose of rifampicin, a key drug with known poor cerebrospinal fluid penetration may lead to higher drug levels at the site of infection and may improve survival. Of the second generation fluoroquinolones, levofloxacin may have the optimal pharmacological features including cerebrospinal fluid penetration, with a ratio of Area Under the Curve (AUC) in cerebrospinal fluid to AUC in plasma of >75% and strong bactericidal activity against Mycobacterium tuberculosis. We propose a randomized controlled trial to assess the efficacy of an intensified anti-tubercular treatment regimen in tuberculous meningitis patients, comparing current standard tuberculous meningitis treatment regimens with standard treatment intensified with high-dose rifampicin and additional levofloxacin.
  
  
  METHODS
  A randomized, double blind, placebo-controlled trial with two parallel arms, comparing standard Vietnamese national guideline treatment for tuberculous meningitis with standard treatment plus an increased dose of rifampicin (to 15 mg/kg/day total) and additional levofloxacin. The study will include 750 patients (375 per treatment group) including a minimum of 350 HIV-positive patients. The calculation assumes an overall mortality of 40% vs. 30% in the two arms, respectively (corresponding to a target hazard ratio of 0.7), a power of 80% and a two-sided significance level of 5%. Randomization ratio is 1:1. The primary endpoint is overall survival, i.e. time from randomization to death during a follow-up period of 9 months. Secondary endpoints are: neurological disability at 9 months, time to new neurological event or death, time to new or recurrent AIDS-defining illness or death (in HIV-positive patients only), severe adverse events, and rate of treatment interruption for adverse events.
  
  
  CONCLUSIONS
  Currently very few options are available for the treatment of TBM and the mortality rate remains unacceptably high with severe disabilities seen in many of the survivors. This trial is based on the hypothesis that current anti-mycobacterial treatment schedules for TBM are not potent enough and that outcomes will be improved by increasing the CSF penetrating power of this regimen by optimising dosage and using additional drugs with better CSF penetration.
  
  
  BACKGROUND
  International Standard Randomised Controlled Trial Number ISRCTN61649292.
authors.affiliation: Hospital for Tropical Diseases Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme 190 Ben Ham Tu, District 5, Ho Chi Minh City, Vietnam. dheemskerk@oucru.org
authors.forename: Dorothee
authors.initials: D
authors.lastname: Heemskerk
authors.forename: Jeremy
authors.initials: J
authors.lastname: Day
authors.forename: Tran Thi Hong
authors.initials: TT
authors.lastname: Chau
authors.forename: Nguyen Huy
authors.initials: NH
authors.lastname: Dung
authors.forename: Nguyen Thi Bich
authors.initials: NT
authors.lastname: Yen
authors.forename: Nguyen Duc
authors.initials: ND
authors.lastname: Bang
authors.forename: Laura
authors.initials: L
authors.lastname: Merson
authors.forename: Piero
authors.initials: P
authors.lastname: Olliaro
authors.forename: Thomas
authors.initials: T
authors.lastname: Pouplin
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004185:Disability Evaluation; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000150:complications / Q000401:mortality; D006801:Humans; D064704:Levofloxacin; D009460:Neurologic Examination; D015242:Ofloxacin / Q000008:administration & dosage* / Q000009:adverse effects; D012107:Research Design; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D014744:Vietnam / Q000453:epidemiology
chemical_list: D000995:Antitubercular Agents; D064704:Levofloxacin; D015242:Ofloxacin; D012293:Rifampin