Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.

Background-Aspirin (ASA) often is used to prevent thrombosis in infants with congenital heart disease after placement of a systemic-to-pulmonary artery shunt, but its effect on outcomes is unknown. Methods and Results-The present multicenter study prospectively collected data on 1-year postoperative rates of death, shunt thrombosis, or hospitalization age Ͻ4 months for bidirectional Glenn/hemi-Fontan surgery in 1004 infants. The use and dose of ASA were recorded. Kaplan-Meier event rates were calculated for each event and the composite outcome, and a Cox regression model was constructed for time to event. Model terms were ASA use and type of surgery, with adjustment for age at surgery. Diagnoses were hypoplastic left heart syndrome (nϭ346), tricuspid atresia (nϭ103), tetralogy of Fallot (nϭ127), pulmonary atresia (nϭ177), heterotaxy syndrome (nϭ38), and other (nϭ213

IMPORTANCE Invasive candidiasis in premature infants causes mortality and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole is unknown. OBJECTIVE To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes—defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18–22-months corrected age. RESULTS Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio 0.73 [95% CI 0.43–1.23]; P=.24; treatment difference −5% [95% CI, −13%–3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%] vs the placebo group (9% [95% CI, 5%–14%]; P=.02; treatment difference −6% [95% CI, −11%–−1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole 31% [95% CI, 21–41%] vs placebo, 27% [95% CI, 18–37%]; P=.60; treatment difference 4% [95% CI, −10–17%]). CONCLUSIONS AND RELEVANCE Among infants with a birth weight of less 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely-low-birth-weight infants. TRIAL REGISTRATION ClinicalTrials.gov number NCT00734539

We thank Caruthers and Dorsch for their interest in the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. 1 The variability in inhibition of ADP-induced platelet aggregation by clopidogrel reported for pediatric patients in PICOLO (Figure 2 of our article 1 ) is similar to the well-described variability in inhibition of ADP-induced platelet aggregation by clopidogrel observed in adult patients. 2 Caruthers and Dorsch's main concern is that because clopidogrel undergoes metabolism through CYP3A4, lower CYP3A4 activity in neonates may explain the variability in our results. This theory assumes that lower CYP3A4 activity in neonates compared with infants would result in lower levels of the circulating metabolite of clopidogrel and, therefore, less inhibition of ADP-induced platelet aggregation. Their theory is of interest, as neonates tended to have higher, though statistically nonsignificant, inhibition of maximum extent of platelet aggregation at all doses evaluated, even though the mean aggregation response of each group before clopidogrel exposure was almost identical (Ϸ40%). Thus, these data would contradict the supposition that significantly less active metabolite was being generated in the neonate cohort. As with adults, it has been postulated that variability of clopidogrel responsiveness may be due to differences in CYP3A4 activity and polymorphisms of the P2Y12 receptor, as well as baseline reactivity or pathophysiological status of individual patients.Caruthers and Dorsch go on to state that "Clinical experience with clopidogrel has shown a need for higher doses to achieve 30% to 50% inhibition of 5 mol/L ADP-induced platelet aggregation in the early years of life." However, only prospective, multicenter, randomized, placebo-controlled trials such as the PICOLO trial 1 can provide definitive conclusions in this regard.Caruthers and Dorsch conclude by stating that, "It also seems reasonable to start with a dose based on this subset data and then check periodic platelet aggregation based on simple point-of-care tests to confirm the 30% to 50% inhibition." However, there is no established or validated relationship between any simple point-ofcare tests and platelet aggregometry. 3,4 Furthermore, studies in neither children nor adults have demonstrated benefit by guiding the dose of clopidogrel based on the results of platelet function testing. DisclosuresDrs Bokesch, Graham, Takahashi, and Sanders served on the steering committee and received honoraria from Sanofi-aventis. All authors indicate that their institutions have received research grants from Bristol-Myers Squibb and Sanofi-aventis.

NCT00621192.