Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02079792 |
| Other study ID # |
HeadPositionMAD2014 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
March 4, 2014 |
| Last updated |
April 13, 2016 |
| Start date |
June 2014 |
| Est. completion date |
August 2015 |
Study information
| Verified date |
April 2016 |
| Source |
St. Paul's Hospital, Canada |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Canada: Health Canada |
| Study type |
Interventional
|
Clinical Trial Summary
Chronic Rhinosinusitis (CRS) is a common disorder of the nose characterized by stuffy nose,
discoloured nasal discharge, sinus congestion or pressure and decreased sense of smell,
present for over twelve weeks. Anti-inflammatory steroid medication is often used to treat
sinus inflammation in CRS. These steroids are sometimes delivered using a spray device that
creates a mist to deliver steroid medication deep into the nose. However, the distribution
and efficacy of sprayed medication can be affected by the position of the patient's head.
This study aims to determine which of two head positions is best for delivering steroid to
the sinuses.
Description:
1. PURPOSE
The purpose of this study is to determine if the Lying Head Back or Head Down and
Forward head position for administering topical atomized nasal medication results in
greater distribution and efficacy of budesonide administered via the mucosal
atomization device in chronic rhinosinusitis patients who have had previous sinus
surgery.
2. HYPOTHESIS
The investigators hypothesize that endoscopic sinonasal mucosal scores will be lower
(improved) in patients oriented in the LHB than the HDF position while applying
medication after 12 weeks of treatment.
3. JUSTIFICATION:
Topical medications administered by nebulizers are frequently utilized for patients
suffering from refractory CRS. Nebulizers are useful as they atomize medication to
increase contact with surrounding mucosa. This technique is most useful for widespread
inflammation of the olfactory cleft, ethmoid, sphenoid and frontal sinuses where
increased inflammation may obstruct drainage pathways. Obstructed sinus ostia may
prevent mucosal clearance, impair ciliary function and subsequently contribute to
infection. Topical medication, such as steroid therapy is a safe and effective method
to locally reduce inflammation. The success of atomized nasal medications is dependent
on multiple factors such as gravity, obstructive features of sinonasal anatomy and
patient interpretation of the preferred delivery method. Several delivery methods for
topical nasal therapies have previously been evaluated to determine the optimal head
position for administration. However, a review of the literature suggests that the
optimal method of administering atomized nasal steroids to the paranasal sinuses in
human subjects has yet to be determined. It has been previously suggested that
successful distribution of intranasal steroid sprays requires topical agents to contact
and remain on desired mucosa to prevent disease reoccurrence. In a prospective
single-cohort study, healthy subjects were recruited to evaluate the distribution and
clearance rate of fluorescein-labeled nasal spray distributed using a squeeze bottle,
nasal gel or nasal spray device. The investigators found there was no significant
difference in clearance rate between the delivery methods.
This trial provides the preliminary evidence to support further investigation on the
rate of distribution from intranasal steroid administration in CRS patients. The
findings cannot be generalized to a wider CRS population, as patients enrolled were
healthy with no history of CRS or sinus surgery. Similarly, the investigators did not
report the head position utilized to administer the treatment. Therefore, there remains
no formal consensus for the optimal head position for CRS patients suffering from
recurrent symptoms for the distribution and clearance rate of intranasal steroid
medication.
Clinician experience at the St. Paul's Sinus Centre (SPSC) has recommended that
patients should orient themselves in the Lying Head Back (LHB) position to effectively
treat edematous mucosa of the ethmoid roof and frontal sinus recess. These instructions
are based on evidence collected in a previous cadaveric trial completed at our centre
(in press). Our team evaluated the effect of head position on the distribution of
fluorescent nasal spray within the paranasal sinuses of cadaver specimens. The
investigators utilized two commonly instructed head positions, the Lying Head Back
(LHB) or Mygind position and the Head Down and Forward (HDF) or Moffat's position. In
this trial the investigators oriented cadaver specimens in either study position and
evaluated the presence of fluorescent nasal spray across eleven clinically relevant
anatomical areas. the investigators concluded that the LHB position had significantly
greater frequency of distribution (OR = 1.85, 95% CI: 3.0, 6.9, p< 0.001) to all
evaluated areas than the HDF position. This trial was limited by a number of factors,
which include a small sample size (n=20). Similarly, cadaveric specimens cannot be
generalized to humans, as moist and ciliated mucosa, and nasal polyps are not
represented. Therefore, it remains controversial the optimal head position for the
deposition of intranasal medication.
4. OBJECTIVES:
Primary Objective
The primary objective of this clinical trial is to compare endoscopic sinonasal mucosal
inflammation between patients oriented in the LHB and HDF position after 12 weeks of
treatment. Subject sinus cavities will be assessed by a validated endoscopic mucosal
staging system first at baseline, then at 6 and 12 weeks of treatment. Total scores
will be compared between the treatment groups. The Lund-Kennedy (LKES) and
Philpott-Javer (PJES) endoscopic staging systems will be utilized to quantify the
severity of sinonasal disease. The Principal Investigator will complete all endoscopic
evaluations and will be blind to treatment allocation.
Secondary Objectives:
The secondary objectives of this trial will be to compare LKES and PJES scores to
compare sensitivity to change during the treatment period and degree of correlation
between total scores and change in scores between the scoring systems. Inter-rater and
intra-rater reliability will be calculated and compared for each scoring system. The
purpose of this secondary outcome is to validate the PJES with the "gold standard" and
widely used LKES, in terms of overall score and sensitivity to treatment.
5. RESEARCH METHOD:
Study Design:
Parallel, single-blind, randomized controlled trial of subjects previously randomized
to LHB or HDF treatment arms (from Part 1) in order compare endoscopic sinonasal
mucosal scores after 12 weeks of treatment.
Patients who meet the inclusion and exclusion criteria will be recruited for the study
at the clinic. After study patients voluntarily consent to participate in the study,
data collection will begin.
Randomization
Treatment Arm #1: Administering topical fluorescent-labeled nasal spray in the LHB
position.
Treatment Arm #2: Administering topical fluorescent-labeled nasal spray in the HDF
position.
Adult patients suffering from refractory CRS symptoms post-FESS will be randomized to
either Treatment Arm #1 or #2 in equal ratio. The sequence will be computer generated
by the trial statistician. The sequence will be ordered random-permuted blocks to
ensure allocation remains concealed. The sequence will be maintained in a computer
located in the St. Paul's Sinus Centre (SPSC) with strict passwords necessary for
access. Non-transparent sealed envelopes with treatment assignments will be kept in a
secure environment and accessible only to study personnel at the SPSC. When study
personnel are notified of a potential candidate, inclusion and exclusion criteria will
be evaluated. When consent has been provided the next consecutive envelope will be
taken and treatment group assigned. After treatment is assigned, the patient will
preserve the envelope to ensure the Principal Investigator remains blinded to their
treatment allocation.
Blinding:
Part 1:
As patients will be required to orient themselves in the appropriate study positions,
blinding will not be feasible for subjects. However, the Principal Investigator and two
additional senior Rhinologists evaluating endoscopic images for mucosal disease
severity will be blinded to each subject's allocated head position.
Patients will be randomized to a head position group, either the Lying Head Back (LHB)
or Head Down and Forward (HDF) position. Patients will remain in the allocated group
and administer their medication in their respective head position for 12 weeks. As
above, patients will not be blind to which position they have been randomized. However,
the Principal Investigator and two additional senior Rhinologists will be blind to
which position the subject had been oriented throughout the treatment period (12
weeks). Images of each sinus cavity will be captured at baseline and after 12 weeks and
evaluated using the LKES and PJES scoring systems. Total scores and change in scores
will be compared. The randomization sequence will not be broken until the final
analysis is complete.
Conduct of Study:
Baseline and Intervention:
Adult CRS patients having previously received FESS, who meet the inclusion/exclusion
criteria and provide consent will be randomized to either the LHB or HDF positions to
administer a budesonide topical nasal corticosteroid spray to their sinus cavities.
Baseline characteristics will be collected from patient charts as outlined above. Each
subject in both study groups will receive a sterile 3ml syringe fixed with a Mucosal
Atomization Device (MAD) tip (Wolf-Tory Medical, Salt Lake City, UT). This device is
advantageous as its produces a fine mist, increasing the surface area for absorption
within the paranasal sinuses.4 Budesonide is a well-tolerated, glucocorticoid steroid
that is primarily used for treatment in asthma and nasal polyposis.20 At SPSC, it is
standard practice to prescribe budesonide to treat postoperative sinonasal inflammation
utilizing the MAD. From discussion with senior Rhinologists at SPSC, patients are
typically instructed to administer treatment twice a day for 6-12 weeks. However,
dosage and frequency may be modified to suit individual circumstances.
For the purpose of this trial, patients will be instructed to load each syringe with
2cc of the budesonide (1mg in 2cc saline) solution to be distributed to the right and
left sides of the nose. A designated research assistant will collect baseline data and
describe and demonstrate the allocated study position in a separate room from the
Principal Investigator. To ensure that positioning has been correctly communicated,
subjects will then orient themselves in the appropriate position with guidance from
research staff if required. Subjects randomized to the LHB position will be instructed
to lay supine on the clinical table, with their head hanging over the edge of the bed
as far as possible without discomfort (Figure 1). Subjects randomized to the HDF
position will be instructed to kneel down, placing the top of their head on the ground
and forehead close to the knees with the nostrils facing upwards (Figure 2). Once
positioned, subjects will insert the MAD-syringe at a 45-degree angle into the nasal
valve, direct the tip to the lateral epicanthus of the ipsilateral orbit and depress
the syringe plunger completely. Subjects will remain positioned for 60 seconds. At this
time a designated research associate will be measure the angle of the subjects head in
relation to the horizontal plane, using an analog protractor. As all subjects may not
be able to orient themselves in a single standardized angle, the investigators will
note the angle most comfortable to determine a range of possible orientations.
Subjects will be instructed to administer budesonide 1mg/2cc nebules daily for 6 weeks
using the MAD syringe, in the head position allocated to which they were randomized at
the baseline visit. After this time, subjects will return to SPSC for endoscopic
examination of their sinus cavities. Bilateral nasal endoscopy will be performed using
a 2.3mm Karl Storz rigid nasal endoscope. The Principal Investigator capturing images
of the sinus cavities will be blind to which head position group the subject was
randomized. Each sinus cavity will be assessed independently with images captured and
stored on a password-protected, centrally located computer. Once endoscopic images are
captured for patients returning after 12 weeks of treatment, three independent senior
Rhinologists will score each sinus cavity according to the LKES and PJES criteria.18,19
This will be completed twice, with a 1-week break between assessments. Responses will
be tabulated on separate, password-protected spreadsheets with each Rhinologist
receiving a study code to prevent identification. A blind statistician will summarize
the data and compare the total and change in endoscopic scores between the treatment
groups. Secondary analysis will be completed to determine the extent of correlation and
sensitivity between the LKES and PJES responses. Inter and intra-rater reliability will
also be computed to determine the extent of agreement between the scoring systems.
Data collection:
The following data will be collected at the initial clinic visit:
- Baseline characteristics will be collected including age (years), sex (male or
female), number of cigarettes per day (count), height (centimeters), weight
(kilograms), handedness (right or left), number of prior sinus surgeries (count),
preoperative disease severity (Lund-Mackay CT Score).
The following data will be collected at the 6 and 12 week follow-up visits:
- PJ Endoscopic scores
- LK Endoscopic scores
- SNOT-22 scores
6. STATISTICAL ANALYSIS:
Sample size determination:
From our recent trial evaluating the LHB and HDF positions in human cadavers, the incidence
of total spray distribution was 76% and 41% in the LHB and HDF positions. Incorporating
these findings, the investigatorsperformed a sample size calculation using a Type I error
(alpha) of 5%, Type II error (beta) of 20% and an effect size of 73%. The effect size was
calculated using the incidence proportions from our centre's previous trial in cadaver
specimens, which was identified as clinically relevant and practically achievable. A
two-proportion calculation was used to compare the average distribution of all anatomical
sites between the head position groups. The calculation revealed a necessary sample size of
30 patients per group. Based on clinical experience of the Principal Investigator it is
estimated that 60% of patients requiring sinus surgery (n=400/year) will be eligible for
enrollment (n=280/year). Accounting for 70% enrollment of eligible subjects (n=196/year),
the investigators estimate that 16 patients can be recruited every month. Adjusting for a
dropout rate of 20%, the investigators will increase our total sample size (n=60) by 6
patients. the investigators estimated that our desired sample size adjusting for
loss-to-follow-up (n = 66) will be achieved in 4 months (Figure 3). Patients will be
recruited in equal ratio to the experimental and control groups (33 in each arm).
Baseline characteristics analysis:
Baseline characteristics of the two groups will be reported. Descriptive statistics will be
reported included mean, median, standard deviation and range. These will be reported for
age, height, weight, number of prior surgeries and preoperative disease severity. The
proportion of males and females, right and left handed subjects and frequency of blood clots
and adhesions present prior to the intervention will also be described.
End of Study Analysis:
Subject sinus cavities will be assessed using the LKES and PJES scales. Measurements will be
made at baseline and 5 weeks after treatment. The LKES assesses each sinus (ethmoid,
maxillary, sphenoid, frontal) for the presence of polyps (0=absent, 1=present in middle
meatus only, 2=beyond middle meatus); presence of edema, scarring or crusting (each
evaluated as 0=absent, 1=mild, 2=severe) and presence of discharge (0=absent, 1=clear and
thin, 2=thick or purulent). A total, bilateral score is calculated for all sinuses
evaluated. The PJES is a similar scoring system that evaluates each sinus cavity
individually to yield a total bilateral score out of a total of 80. Additional points are
awarded for the presence allergic mucin or purulent discharge. Two endoscopic scores will be
recorded for each subject, using both scales for baseline and 5 weeks post treatment. The
difference in baseline and 5 week results will be calculated for each subject and summed
together to yield an average change for the LHB and HDF groups. Outcome data will be
summarized by mean, median, standard deviation and interquartile range. The Students t-test
will be used to test if the changes in endoscopic scores are significantly different between
the treatment groups. Pearson's (R) correlation will be calculated to determine the extent
of linear association between the LKES and PJES results. From a previous study evaluating
the association between endoscopic scoring systems, an a priori decision has been made to
categorize R < 0.49 as a weak correlation, 0.50 < R < 0.69 as a moderate correlation and R >
0.70 as a strong correlation. Linear correlation will be calculated in terms of absolute
score and change in score between the study time points.
To determine the extent of clinical agreement between the senior Rhinologists evaluating
each subject, intra and inter-rater kappa scores will be calculated. It has been determined
a priori that scores < 0 will be assigned no agreement, 0.01 - 0.20 poor agreement,
0.21-0.40 slight agreement, 0.41-0.60 fair agreement, 0.61-0.80 good agreement, 0.81-0.92
very good agreement and 0.93-1.00 excellent agreement.
