Participants
This randomized, double-blind, crossover, active- and placebo-controlled clinical
trial was conducted at the Center for Man in Aviation, RNLAF (Soesterberg, the
Netherlands) and adhered to the principles of the Declaration of Helsinki, the
International Council on Harmonization, and the Good Clinical Practice
guidelines. The protocol was approved by the Medical Ethical Committee Brabant
(reference: NL62145.028.17/P1749) and the Surgeon General of the Ministry of
Defence. The study was registered in the Dutch Trial Register (No. NTR6922) and
EU Clinical Trials Register (No. 2017-002288-16).Healthy employees of the RNLAF aged between 18 and 60 years were eligible for
inclusion. Eligible participants were fit to fly according to the RNLAF Military
Aviation Regulations or European Aviation Regulations (European Aviation Safety
Authority [After being informed, both verbally and in writing, about the aims, consequences,
and constraints of the study, all participants gave written consent. This
informed consent was voluntary and could be retracted at any time without any
consequences. According to (inter)national privacy regulations, no study data
were included in the medical files of the participants.This study included 32 subjects, two of whom only completed two of the three test
days due to operational reasons. Both subjects missed the caffeine
administration; per protocol their test results were included in the analysis.
The subjects were aged between 25 and 59 years (mean: 35 years; standard
deviation: 10 years). Five (16%) of the 32 subjects were female and 21 (66%) of
all subjects were pilots. On the test days, the median waking time of the
subjects was 07:00 AM, meaning that at medication administration, the subjects
had a median period of wakefulness of 17 h (range: 15.5–20.0 h, (interquartile
range) IQR: 16.5–18.0 h).