Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02638506 |
| Other study ID # |
INF2016-1028 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 2016 |
| Est. completion date |
August 18, 2020 |
Study information
| Verified date |
September 2020 |
| Source |
St. Justine's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background : Headaches are a common presentation for children consulting to the Emergency
Department (ED). However, only few studies have evaluated the rapid pain improvement provided
by medications in the acute management of headaches in the pediatric population.
Objective : To evaluate pain reduction provided by intranasal fentanyl (INF) compared to
placebo in addition to ibuprofen for children presenting to a pediatric ED with moderate to
severe headaches.
Methods : A single-center, double-blind, randomized, placebo controlled clinical trial will
be conducted in an urban, university-affiliated, tertiary care pediatric hospital ED. All
children eight to 18 years old who will present to the ED with headaches as a main chief
complaint and with pain of ≥ 36 mm out of 100 on Visual Analog Scale (VAS) will be recruited.
Study participants will be randomly allocated to receive INF 1.5 mcg/kg (maximum dose of 100
mcg) or similar volume of a placebo solution via an atomizer. Co-administration of oral
ibuprofen 10 mg/kg (maximum dose of 600 mg) will also be provided to the two groups if not
received in the previous 4 hours. The primary outcome will be the mean pain rating reduction
at 15 minutes. The secondary outcomes will be mean pain reduction at 30 and 60 minutes,
patient's and parental satisfaction levels, percent of being pain free, sedation score,
immediate and within 72 hours adverse events, additional ED analgesics and other medications,
length of ED stay, disposition outcomes, hospital admission rate and ED revisit rate within
72 hours. The primary analysis will use an intention-to-treat approach to compare mean pain
score reduction between the two groups using a Student's T-test. The sample size of 60
participants per arm was calculated to have a power of 80% to identify a difference of 10 mm
in the VAS.
Expected results : Our study might demonstrate that INF provides additional pain relief for
children presenting to an ED with headaches. Providing INF could relieve their symptoms more
quickly, potentially improve patient's and family's satisfaction, possibly reduce the length
of their ED stay and consequently, have a significant impact on patient quality of care and
cost-effectiveness.
Description:
The primary objective of the present study would be to determine the additive value on
analgesic effectiveness of INF in children aged eight to 18 years with acute moderate to
severe headaches. We would also aim to gather information on the safety and acceptability of
INF for headaches. We believe that providing INF for moderate to severe headaches will
decrease pain levels in children aged 8 to 18 years old.
We will perform a prospective, double-blind, randomized placebo-controlled clinical trial.
The study setting will be a single center, urban, university-based, tertiary care pediatric
university-affiliated hospital ED with an annual census of 75,000 patient visits. The study
should be conducted between 2015-2018.
Study population : Inclusion criteria will consist of children aged eight to 18 years who
present to the pediatric ED with a chief complaint of headaches, regardless of the type, with
a moderate or severe pain score. Pain was considered at least moderate if superior or equal
to 36 mm on the VAS as demonstrated by Hirschfeld et. Al. This level have been chosen because
it has been recognized that adequate sensitivity in analgesia trials for acute pain can only
be obtained if patients experience at least moderate pain before administration of any
treatment.
Intervention: All patients will receive a 1.5 mcg⁄kg dose of fentanyl or an equivalent volume
of similar looking placebo. This will be administered intranasally via a mucosal atomiser
device (MAD) using 50 mcg/mL solution with a 2 mL syringe. Prior studies have shown that this
dose is as effective as IV or IM morphine and provides a bioavailability which is 71% of the
IV dose. The minimum dose prescribed will be 20 mcg, to ensure delivery of 15 mcg of fentanyl
to a 10 kg child, allowing for the MAD dead space of 0.1 mL (5 mcg of fentanyl). For
analgesic dose-volumes equal to and less than 0.5 mL, the entire dose will be administered in
one nostril; doses above 0.5 mL will be divided equally and administered to both nostrils.
Concentrated medications in a small volume (0.2-0.3 mL per nostril) are ideal, whereas
volumes in excess of 1 mL per nostril are not reliably absorbed as a result of mucosal
surface saturation and runoff from the nasal cavity. The maximum dose administered will be
100 mcg due to volume constraints. The placebo solution will consist of normal saline that
would be delivered via the proposed atomiser. The value administered will be adjusted to the
patients weight as for the active study medication. No additional dose of either study
medication would be provided. A MAD have been chosen because it is suggested to increase the
mucosal coverage and absorption of the medication by atomizing particles and decreasing the
amount of medication lost due to swallowing.
Oral ibuprofen (10 mg/kg) (maximum dose of 600 mg) will also be administered within the first
15 minutes of intranasal administration of the study medication unless it had been given in
the previous 4 hours. It has been chosen over acetaminophen because a direct comparison has
shown that complete pain relief after two hours is achieved twice as frequently with
ibuprofen.
The randomization process will occur at the local pharmacy and randomization allotment will
be known only by a pharmacist who is not involved in the study. Therefore, all providers
involved in the patient's care and patients will be blinded to group assignment until data
analysis completion. The participant will be randomly assigned to one of the two groups as
follows : 1) INF 1.5 mcg/kg and 2) placebo solution, given via an atomizer (MAD device: MAD
Nasal, U.S. Patent #6,112,743, Wolfe-Tory Medical, Inc., 79 West 4500 South, Salt Lake City,
Utah 84107).
The study medications will be provided to the ED by the local pharmacy. For each randomized
patient, a consecutive study medication package will be opened in the ED. Each study package
will contain a study medication (either generic fentanyl bottle or saline bottle), a syringe
and an atomizer for delivery. An on-site nurse will withdraw the study medication from the
specific bottle provided in the package and will deliver the study medication to the patient.
The study research assistant will remain blinded. At the pharmacy, the patient's
identification will be coded so that only a user having the access code will be able to
identify participants.
Procedure : Every patient will be weighed in triage. Enrollment will be limited to times when
a research assistant is available. A research assistant will recruit the patients after a
pediatric ED physician has assessed them and once the symptoms of headaches are clearly
established. The pain associated with headaches will be assessed by using the VAS, which has
been validated for the use in children aged eight years and older across a variety of
clinical settings and has an excellent interrater-reliability and validity in analgesia
research.
Once eligibility and exclusion criteria will be confirmed, caregivers will be given written
and verbal study information. Written consent for enrolment will be gained from both the
accompanying parent and the child, when appropriate. The research assistant will use timers
to coordinate all the events. At baseline, before any intervention, the VAS score, baseline
vital signs and sedation score (UMSS) will be recorded by the research assistant. For the
assessment of the VAS score, the children will be asked to mark on a standardized data
collection booklet, the level of their pain on a 100-mm non hatched VAS scale with at one end
"no pain" and at the other "worst pain ever" with the following, verbatim: "Show me on the
line the level of your pain: here is no pain; there is the worst possible pain." The patient
will then cross a line to indicate his or her level of pain. All measurements will be
recorded to the closest 1 mm.
At time zero, the solution contained in a syringe will be administered by the on-site nurse
to the anterior aspect of the participant's nasal cavity over few seconds. The dose (or half
of it, if necessary) will be administered into one of the patient's nostrils with the MAD.
The second half of the dose, if needed, will be administered in the contralateral nostril
using the same MAD. Younger children will have the medication administered while sitting in
the lap of a parent, with their heads reclined and necks hyperextended. Older children will
receive the medication while lying in a semi recumbent position on the gurney. No additional
dose would be provided. The research assistant will remain blinded to which medication the
patient has received.
At the fifteenth, thirtieth and sixtieth minute post-intervention, the research assistant
will obtain a pain score via the VAS from the patient and ask for the change in their pain.
They will be asked to give a verbal rating of their pain as 'a lot less', 'a little less',
'the same', 'a little more' or 'a lot more' compared to the initial baseline, at time zero
and reassess level of pain on the VAS as used previously. Children will not be permitted to
refer to previous scales markings and will remain blinded to their prior scores. The sedation
score will also be recorded using the University of Michigan Sedation Scale (UMSS) which
overall validity was demonstrated and declared as a simple, valid and reliable tool that
facilitates rapid and frequent assessment and documentation of depth of sedation in children.
The vital signs will also be taken at these intervals.
A detailed demographic and clinical data will also be collected after the study medication
administration. A standardized questionnaire of the patient's present and past headaches,
will be completed by the research assistant during their stay in the pediatric ED. The
questionnaire will include questions on duration, location, description of pain, associated
symptoms of the present headache and past medical history.
No other meds, IV fluids, IV procedures or other painful procedures will be done during the
study period unless the patient's condition changes or deteriorates. If any of these
procedure is needed during the study period, the patient will be withdrawn from the study and
will be treated according of his state of health.
At the sixtieth minute of the study, marking the end of the study, patients who had assented
to the study and parents will be asked to rate their satisfaction on the efficacy of the
study medication on a Likert scale ('strongly disagree' 'disagree', 'neither agree nor
disagree', 'agree', or 'strongly agree'). This satisfaction scale will be given to patients
and parents after the last pain score was obtained. The study would be then completed, and
further care will be at the discretion of the attending pediatric ED medical staff.
A follow-up call by a research assistant will be done at 72 hours after discharge to assess
headache recurrence, late medication side effects, and a return to another medical facility.
All children hospitalized will also be reached.
A chart review will be done by a member of the research team to collect final pediatric ED
diagnosis as well as any additional investigations (e.g. CT scan, consultation with a
neurologist, blood tests, TSH, etc.).
Data will be collected using pediatric ED medical records of recruited patients and the
sociodemographic questionnaire completed by a research assistant. The results of all other
variables: VAS, UMSS and satisfaction score will be collected in real time by the research
assistant during the pediatric ED stay.
A data collection form will be used, and these forms will be later cross-referenced with the
patient's clinical records by a member of the research team to verify correct documentation
and eligibility.
Sample size and statistics :
This is the first study evaluating pain related to all types of headaches in children.
Accordingly, no previous study perfectly matches our design to infer sample size. However,
two previous studies evaluated an intervention provided to decrease acute pain secondary to
migraine in children using the VAS. These studies reported a standard deviation of 18.5 and
20 mm. Powell et al found the minimum clinically significant difference (MCSD) in VAS pain
score for children aged 8 to 15 years (on a 100-mm VAS scale) to be 10 mm (95% confidence
interval 7 to 12 mm). In studies of populations, differences of less than this amount, even
if statistically significant, are unlikely to be of clinical significance. Previous research
in adults has found the same MCSD in VAS pain scores and did not differ in adults with age,
sex, or cause of pain. Based on these data, using an alpha value of 0,05 and a power of 80%,
it was estimated that we need, 57 patients per group. Accounting to a maximal 5% drop-off
rate, we inflated this number to 60 participants per group.
All data will be entered in an excel database (Microsoft Inc., Richmond, WA) and will be
analyzed with SPSS v21 (IBM Inc). The primary study analysis will be a Student's T-test to
compare the mean differences in scores between the intervention group and the placebo group.
An intention-to-treat approach will be used. Also, secondary analyses will be performed using
a Student's T-test for continuous variables and a Pearson Chi-square test for categorical
variables. The 95% confidence intervals will be measured for each result.
