title: Drug versus placebo randomized controlled trials in neonates: A review of ClinicalTrials.gov registry.
abstract: BACKGROUND
  Despite specific initiatives and identified needs, most neonatal drugs are still used off-label, with variable dosage administrations and schedules. In high risk preterm and term neonates, drug evaluation is challenging and randomized controlled trials (RCT) are difficult to conduct and even more is the use of a placebo, required in the absence of a reference validated drug to be used as comparator.
  
  
  METHODS
  We analyzed the complete ClinicalTrials.gov registry 1) to describe neonatal RCT involving a placebo, 2) to report on the medical context and ethical aspects of placebo use.
  
  
  RESULTS
  Placebo versus drug RCT (n = 146), either prevention trials (n = 57, 39%) or therapeutic interventions (n = 89, 61%), represent more than a third of neonatal trials registered in the National Institute of Health clinical trial database (USA) since 1999. They mainly concerned preterm infants, evaluating complications of prematurity. Most trials were conducted in the USA, were single centered, and funded by non-profit organizations. For the three top drug trials evaluating steroids (n = 13, 9.6%), erythropoietin (EPO, n = 10, 6.8%) and nitric oxide (NO, n = 9, 6.2%), the objectives of the trial and follow-up were analyzed in more details.
  
  
  CONCLUSIONS
  Although a matter of debate, the use of placebo should be promoted in neonates to evaluate a potential new treatment, in the absence of reference drug. Analysis of the trials evaluating steroids showed that long-term follow-up of exposed patients, although required by international guidelines, is frequently missing and should be planned to collect additional information and optimize drug evaluation in these high-risk patients.
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hopital Robert Debré, Paris, France.|Clinical Investigation Center INSERM CIC1426, Hopital Robert Debré, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Desselas
authors.affiliation: Department of Public Health, Laboratory for Mother and Child Health, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pansieri
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hopital Robert Debré, Paris, France.|Clinical Investigation Center INSERM CIC1426, Hopital Robert Debré, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Leroux
authors.affiliation: Department of Public Health, Laboratory for Mother and Child Health, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bonati
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Hopital Robert Debré, Paris, France.|Clinical Investigation Center INSERM CIC1426, Hopital Robert Debré, Paris, France.|Université Paris 7 Diderot, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000280:Administration, Inhalation; D004358:Drug Therapy / Q000379:methods*; D004921:Erythropoietin / Q000627:therapeutic use; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012042:Registries / Q000706:statistics & numerical data*; D013256:Steroids / Q000627:therapeutic use
chemical_list: C554270:EPO protein, human; D010919:Placebos; D013256:Steroids; D004921:Erythropoietin; D009569:Nitric Oxide