title: An adaptive, phase II, dose-finding clinical trial design to evaluate L-carnitine in the treatment of septic shock based on efficacy and predictive probability of subsequent phase III success.
abstract: OBJECTIVE
  Sepsis is the tenth leading cause of death in the United States. Despite extensive research, mortality rates for sepsis have not substantially improved in the last several decades. We describe an innovative phase II clinical trial design for evaluating the addition of L-carnitine to the treatment of vasopressor-dependent septic shock.
  
  
  METHODS
  The design incorporates a variety of features to increase efficiency, including a normal dynamic linear dose-response model, adaptive randomization, and early stopping for futility or success based on the probability that a future phase III trial using a 28-day mortality outcome would be successful.
  
  
  METHODS
  Trial design and computer simulation of a trial to be conducted in the emergency department and ICU.
  
  
  METHODS
  Proposed to study intravenous L-carnitine.
  
  
  METHODS
  The proposed trial uses an early endpoint, the 48-hour change in Sequential Organ Failure Assessment score, to drive adaptive randomization and dose selection.
  
  
  RESULTS
  We use existing data to model the expected relationship between the Sequential Organ Failure Assessment change and the 28-day mortality to determine the trial's operating characteristics using Monte Carlo simulation.
  
  
  CONCLUSIONS
  The resulting trial efficiently identifies the best dose of L-carnitine and provides clear guidance regarding whether to continue development into phase III.
authors.affiliation: Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Kert
authors.initials: K
authors.lastname: Viele
authors.forename: Kristine
authors.initials: K
authors.lastname: Broglio
authors.forename: Scott M
authors.initials: SM
authors.lastname: Berry
authors.forename: Alan E
authors.initials: AE
authors.lastname: Jones
mesh_terms: D061605:Administration, Intravenous; D002331:Carnitine / Q000008:administration & dosage* / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D006305:Health Status Indicators; D006801:Humans; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality; D014803:Vitamin B Complex / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D014803:Vitamin B Complex; D002331:Carnitine