Kelly K Storm, Robert B Flint, Wes Onland, Sylvia A Obermann-Borst, Jarinda A Poppe, Debbie H Nuytemans, Willem P de Boode, Katherine Carkeek, Vincent Cassart, Luc Cornette, Peter H Dijk, Marieke Ac Hemels, Matthias C Hütten, Dorottya Kelen, Ellen Hm de Kort, André A Kroon, Julie Lefevere, Katleen Plaskie, Sarah Verbeeck, Michiel Voeten, Olivia Williams, Inge A Zonnenberg, Arjan B Te Pas, Irwin Km Reiss, Anton H van Kaam, Karel Allegaert, Anne Smits, G Jeroen Hutten, Sinno Hp Simons, DOXA-trial Consortium
Restricting open-label access to an off-label investigational drug can substantially increase parental consent and patient enrolment in neonatal RCTs. To promote both ethical recruitment and optimal enrolment, future trials should explicitly discuss equipoise in each contributing unit and align local clinical practices with the trial design prior to initiation.
OBJECTIVE: To assess how restricting open-label access to an off-label drug influences consent and trial enrolment in neonatal medicine.
DESIGN: Multicentre, quasinatural experiment.
SETTING: Seventeen neonatal intensive care units in the Netherlands and Belgium participating in the DOXA-trial, a double-blind, randomised, placebo-controlled study of doxapram in extremely preterm infants.
PATIENTS: Infants born before 29 weeks' gestation whose parents were approached for DOXA-trial participation.
INTERVENTIONS: Ten centres discontinued open-label doxapram outside the DOXA-trial (intervention centres), while seven continued its use (control centres).
MAIN OUTCOME MEASURES: Parental consent rates (proportion of parents who provided written informed consent among those approached) and patient enrolment rates (proportion of infants randomised among those whose parents were approached), compared 12 months before and after the policy change in intervention centres and before and after a corresponding reference point in control centres. The reference point in control centres was defined as the mean discontinuation date across intervention centres RESULTS: Overall consent rates increased from 27.8% to 37.1% after the intervention or reference point (+9.3, 95% CI 3.3 to 15.4, p=0.003). In intervention centres, the consent rates rose from 27.1% to 42.9% (+15.8, 95% CI 8.6 to 23.0, p<0.001) and enrolment rates rose proportionally from 9.9% to 16.6% (+6.7, 95% CI 1.5 to 11.9, p=0.011), whereas in control centres, consent and enrolment rates remained unchanged.
CONCLUSION: Restricting open-label access to an off-label investigational drug can substantially increase parental consent and patient enrolment in neonatal RCTs. To promote both ethical recruitment and optimal enrolment, future trials should explicitly discuss equipoise in each contributing unit and align local clinical practices with the trial design prior to initiation.