Study design and procedures
This was a randomized, placebo- and active-controlled, parallel-group, exploratory phase 2 study conducted at Valley Clinical Research Center, Bethlehem, PA, and TKL Research, Paramus, NJ from October 13, 2009 to February 4, 2010 (ClinicalTrials.gov identifier: NCT01122849). Subjects were randomly assigned to receive 1 of 3 treatments: a BRNS clear strip, an asymmetric butterfly prototype, or an asymmetric butterfly placebo prototype that lacked the springs in the active prototype. Investigators and subjects were blinded as to whether the butterfly-shaped strips were the active or placebo strips. The currently marketed BRNS clear strip was compared with the butterfly placebo because subject awareness of the shape of the strip was not expected to influence efficacy while the subject was asleep. Each strip was applied to the outside of the nose, across the bridge from alar crease to alar crease, according to dispensing instructions that were provided. Subjects used their assigned strip at home every night, for approximately 8 h but no more than 12 h per night, for 2 weeks.
The GSK Consumer Healthcare Biostatistics Department generated the randomization schedule. All subjects were assigned numbers at randomization in consecutive ascending numerical order at one site and consecutive descending numerical order at the second site.
Subjects scored their perceptions of nasal breathing and congestion in a daily diary at home, while lying in a supine position, both before and after applying the strip at bedtime and before and after removing the strip upon waking. Nasal breathing was scored using a 100-mm visual analog scale (VAS) ranging from 0 = extremely difficult to breathe through my nose to 100 = extremely easy to breathe through my nose. Nasal stuffiness was rated on a categorical scale of 0 = no symptoms, 1 = mild symptoms (symptoms clearly present, but minimal awareness and easily tolerated), 2 = moderate symptoms (definite awareness of symptoms that are bothersome but tolerable), and 3 = severe symptoms (symptoms that are hard to tolerate, cause interference with activities or daily living) and on a 100-mm VAS ranging from 0 = nose is extremely blocked to 100 = nose is extremely clear. After applying the nasal strip, subjects rated how breathing felt on an 11-point categorical scale where − 5 = much worse, 0 = same, and 5 = much better; they used the same scale to rate how breathing felt after strip removal.
Subjects visited the study site at baseline, day 7, and day 14 to complete three validated questionnaires: the Pittsburgh Insomnia Rating Scale (PIRS) [18, 19], the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ) [20], and the Congestion Quantifier Seven-Item Test (CQ7) [21].
Ethical considerations
This study was reviewed and approved by an Institutional Review Board (Allendale Investigational Review Board, Old Lyme, CT, USA) and conducted in accordance with Declaration of Helsinki requirements. All subjects provided written informed consent at screening.
Study population
Subjects were recruited from the general population via advertising or referral. To participate, they had to be ≥ 18 years of age and in good general health, have leptorrhine noses with nocturnal nasal congestion on all or nearly all nights for at least the last year, and report trouble sleeping. A leptorrhine nose was defined as ≥ 45 on the nasal tip protrusion index, which is the ratio of the protrusion of the nose from the face relative to the width of the nose (measured as the length of the columella divided by the width of the alar cartilage) × 100. This inclusion criterion was used because nasal resistance is likely to be greater in leptorrhine noses [22].
Exclusion criteria included allergy or intolerance to the study materials or adhesive bandages, sleep apnea or other major sleep disorder, upper respiratory tract infection, severe deviated septum, nasal polyps, structural abnormality, and treatment for sleep-disordered breathing. Potential subjects with skin conditions that could preclude use of the device (e.g., skin cancer, chronic skin condition, eczema, open sores, sunburn, or irritation on face/nose) were excluded, as were those with a nontypical sleep schedule (e.g., shift work) or plans to travel across time zones during the study period. Current use of prescription or nonprescription medications that affect sleep or nasal congestion was prohibited, as was use of any intranasally administered medications. Those with current alcohol abuse (regular consumption of > 3 drinks/day), recent history (within last 2 years) of substance or alcohol abuse, positive urine drug screen for drugs of abuse, or regular consumption of > 5 cups per day of caffeinated beverages were excluded. Additional exclusion criteria included severe, unstable disease states, pain syndromes, or any medical/surgical condition that would increase the risk of harm to study participants or interfere with data interpretation. Female subjects of childbearing potential had to be practicing a reliable method of contraception, and must not be pregnant or lactating. Individuals who had participated in another study or received an investigational drug within 30 days of the qualification phase, and employees of the sponsor or study site and their immediate family members, were not eligible to participate.
Those who met the eligibility criteria and provided informed consent had to complete a 1-week, at-home, baseline qualification phase. Subjects who scored nasal openness ≤ 70 on a 100-point VAS, where 0 = extremely blocked and 100 = extremely open, on ≥ 4 of 7 nights before bedtime qualified for randomization into the 2-week in-home treatment phase of the study. All corticosteroids (irrespective of route of administration); intranasal cromolyn; intranasal, oral, and ocular antihistamines; other nasal dilators; topical and oral decongestants; intranasal, oral, and inhaled anticholinergics; long-acting beta agonists; and oral antileukotrienes were discontinued and washed out prior to the qualification phase. Subjects were instructed to abstain from consuming alcohol within 8 h of bedtime, maintain consistent sleep and exercise routines, and discontinue use of any lubricating sprays/rinses and throat strips before the baseline qualification phase.
Efficacy outcomes
Efficacy was evaluated based on changes from baseline for each question and domain on the PIRS, NRQLQ, and CQ7 at weeks 1 and 2, as well as the number and proportion of subjects showing improvement. Efficacy was also evaluated based on changes in VAS ratings of nasal breathing and congestion over weeks 1 and 2. The relationship between the change in these VAS ratings and the change in PIRS, NRQLQ, and CQ7 ratings was explored.
Safety
Adverse events (AEs) and serious AEs were monitored throughout the study. AEs were graded for severity, and relationship to treatment was assessed by the investigator. Incidents consisting of device malfunction or deterioration or inadequacy of the labeling/instructions for use that could potentially lead to the death or serious deterioration in health of the user or other persons were also monitored.
Statistical analyses
No power analysis was performed for this exploratory study. We anticipated that screening 90 subjects would allow for enrollment and completion of the study by 60 subjects (20 in each treatment group), with few dropouts.
There were two analysis populations. The safety population consisted of all subjects who were randomized and received any treatment. The intent-to-treat (ITT) population included all randomized subjects who had at least one post-baseline efficacy assessment.
Composite variables were derived as the sum of the item scores within each composite variable. Analysis of covariance (ANCOVA) was used to compare changes from baseline to days 7 and 14, with baseline and site as covariates.
Statistical comparisons were made for four questions from PIRS pertaining to waking after sleep onset, unrefreshing sleep, sleep quality, and satisfaction with sleep; four composite variables on NRQLQ (sleep problems, sleep time problems, symptoms on waking in the morning, and practical problems); and a composite of all seven questions of CQ7. Pairwise multiple comparisons were used to compare the three treatments. Within-treatment improvement from baseline was tested using least square (LS) means compared with zero from the same ANCOVA model described above. All tests were performed at the 5% significance level, and 95% confidence intervals (CIs) were determined.
An additional ad hoc analysis was conducted to analyze three composite variables on the PIRS, explore responses of patients at risk for sleep apnea (defined as meeting at least two of the following three criteria on the Berlin Questionnaire: score ≥ 2 on sum of questions 1–5, score ≥ 2 on sum of questions 6–9; and response of 1 on question 10 or body mass index > 30 kg/m2), and determine the incidence of subjects showing any improvement after treatment in their subjective perception of response on the PIRS, NRQLQ, and perception of nasal patency from the daily diary questions. The three composite variables on the PIRS consisted of daytime distress (questions 1‒12), nighttime sleep parameters (questions 13‒16), and quality of life (questions 17‒20). Number and percentage of subjects showing improvement after 7 and 14 days were calculated for sleep quality compared with most people (PIRS question 17), satisfaction with sleep (PIRS question 18), PIRS nighttime sleep parameters and quality-of-life domains, and NRQLQ sleep problems and symptoms on waking domains. Number and percentage of subjects showing any improvement in daily diary ratings on the first night were also calculated. Changes from baseline to days 7 and 14 were analyzed using ANCOVA with treatment as a fixed effect and site and baseline as covariates. Other statistical analyses used in the ad hoc analysis were the same as described for the primary analysis above.
The same ANCOVA model from the primary analysis was also used to compare changes in the degree of perception of nasal breathing and nasal congestion on the daily diary ratings on days 1, 3, 7, and 14. For the two VAS ratings and the 4-point categorical rating of nasal stuffiness, ratings after the strip was applied were compared with ratings before strip application at bedtime, and ratings while wearing the strip were compared with ratings after strip removal upon awakening. Since the 11-point categorical rating of how breathing felt after the strip was applied was performed only during treatment, there was no comparison with before or after use for this outcome.
No imputations were made for missing data or dropouts.
