The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1
and Protocol S1
The study was conducted in compliance with the Helsinki Declaration and was approved by the Institutional Review Boards at Group Health and the Centers for Disease Control and Prevention.
Study design and population
We conducted a randomized, observer and participant blinded, placebo controlled trial of acetaminophen prophylaxis among children less than 10 months of age enrolled in Group Health Cooperative, a managed care organization in Washington State. Children were eligible for enrollment if they were expected to receive two or more injected vaccines at an upcoming well child visit occurring after six weeks and before 10 months of age. Children less than four months of age who had a birth weight of <2500 grams or gestational age of <36 weeks were excluded from enrollment but children four through nine months of age could be enrolled regardless of birth weight or gestational age.
Recruitment, enrollment, and randomization
Children potentially eligible for study participation were identified from the Group Health data systems and parents were mailed a letter providing information on the study and inviting them to contact the study team if they were interested in more information. If the child was confirmed to be eligible by phone interview with the parents and by medical record review, a consent form was mailed to the parents for them to sign and return.
After the parents returned the signed consent form, the child was randomized with equal probability to receive acetaminophen or placebo. The randomization sequence was generated by the study biostatistician and provided to the study pharmacy. To ensure balanced allocation, the randomization schedule was generated with a variable block size of between six and twelve. Neither the study biostatistician nor the study pharmacist was involved with the enrollment of participants.
At a time proximate to the scheduled well child vaccination visit, the parents were mailed an enrollment package that included the bottle of study medication, two 3.0 mL medication syringes graduated in 0.5 mL intervals, a digital thermometer, the study diary, and the study medication dosing instructions.
Study drug, dosage, and timing
The liquid placebo and the acetaminophen suspension were flavored to mask differences in taste and packaged by the study pharmacy in identical containers identified only by study id number. The acetaminophen suspension was formulated to provide 160 mg of acetaminophen per 5 mL dose volume. The parents were instructed to use the dosage table provided in the enrollment package to identify the recommended dose volume based on the child's weight, which would provide between 10 mg and 15 mg of acetaminophen per kilogram. Parents and study staff members involved in recruitment, enrollment, and follow up were blinded to study assignment.
Parents were encouraged to take the bottle of study medication to the vaccination visit, and to give the first dose at that visit and within an hour before or after the vaccinations. If the parent was unable to give the first dose within an hour of vaccination, they were asked to give the first dose as close as possible to the vaccination, and within the allowable window of four hours before through up to 24 hours after the vaccinations.
Following the initial dose, parents were instructed to give subsequent doses no earlier than, but as close to, four hours following the previous dose as possible. A maximum of five doses of study medication should be given, and the last dose must be given no later than 24 hours after the study vaccination regardless of the total number of doses administered. If all doses were given exactly on schedule, doses would be given at 0, 4, 8, 12, and 16 hours after vaccination.
Parents completed a study diary and recorded the child's weight (measured at the vaccination visit), the time that vaccinations were administered, and the timing and volume of each dose of study medication administered. If they discontinued the study medication, they were asked to record the reason(s).
Parents were asked to take the child's rectal temperature just prior to administration of the second, third, fourth, and fifth doses of study medication and to take a final rectal temperature approximately 24 hours after vaccination, or four hours after the final dose of study medication, whichever was later. At each study medication dosage time, and at the time of the final temperature assessment, parents were also asked to record the child's level of fussiness.
Parents were also asked to record the relative amount of sleep that each parent and the child had on the night following the vaccinations and were asked to report whether they were scheduled to work on the day of or the day following the child's vaccination visit and, if so, whether either parent missed work to care for the child due to fever, fussiness, or possible vaccine reaction. Parents were to record any use of medical services for fever or other acute symptoms following the vaccination visit through the next day. To judge the adequacy of the blinding procedure, parents were also asked to indicate their guess as to whether their child received acetaminophen or placebo.
Vaccinations given at the vaccination visit were identified from Group Health immunization records.
Provisions for unblinding
The parents were instructed that if they or a health care provider believed the child needed acetaminophen treatment for any reason, the parent or health care provider could call study staff at any time to request unblinding of the randomization assignment. Study staff could unblind a child's assignment by opening an individual, sealed envelope labeled with the child's study number. After unblinding, study staff referred the parent to the consulting nurse or the child's physician for further clinical management, if needed, of the febrile illness or other symptoms that led to the request for unblinding.
Primary and secondary outcomes
The primary outcome was a rectal temperature ≥38°C within 32 hours of vaccination. This time interval was chosen because it corresponds to 8 hours after the latest possible administration of the last dose of study medication (to be given no later than 24 hours after vaccination) and thus encompasses the maximum window of expected activity of the study medication.
Secondary outcomes and their definitions are as follows. All outcomes were specified a priori
Rectal temperature ≥39°C within 32 hours of vaccination.
Medical utilization. Telephone calls to the consulting nurse or the child's physician that were made due to concerns regarding an acute illness, fever, or possible vaccine reaction and outpatient, urgent care, and emergency room visits that were for evaluation of an acute illness, fever, or a possible vaccine reaction, within 32 hours of vaccination.
Parent time lost from work. Parents were asked to report whether they were scheduled to work on the day of the vaccination visit, but following that visit, or the next day and, if so, whether they had to miss work to care for their infant because of fever, fussiness, or possible vaccine reaction on those days.
Time lost from sleep. Parents were asked about their sleep and the child's sleep on the night following the vaccinations. They were asked to report whether they and the infant slept much less than usual, less than usual, about the usual amount, more than usual, or much more than usual on that night.
Infant fussiness. Parents were asked to record level of fussiness (compared with the child's usual) within 32 hours of vaccination, using the categories much less than usual, less than usual, about usual, more than usual, and much more than usual.
Unblinding of study drug assignment. The need for unblinding, including the timing of and the precipitating reason, was assessed.