These were two nearly identical randomized, placebo-controlled, double-blind, two-arm, parallel-group, multicenter, pivotal phase 2 studies. Both studies were conducted at 2 study sites in the United States: Study 1 (NCT03549117) was conducted from October 2010 through January 2011 in Cincinnati, OH, and Verona, NJ, and Study 2 (NCT03549130) from November 2010 through February 2011 in Paramus, NJ, and Indianapolis, IN. The studies were performed in full concordance with good clinical practice (ICH 1996) and the Declaration of Helsinki and were approved by an institutional review board. All subjects gave written informed consent.
The study designs included a screening phase, a 7-day baseline qualification phase, and a 14-day treatment phase. Clinic visits were scheduled at baseline, day 7, and day 14. Subjects were randomly assigned to receive either an asymmetric butterfly nasal dilator strip (BRNS) or an asymmetric butterfly placebo strip. Treatment allocation was conducted by dispensing staff using a randomization schedule provided by the sponsor. Aside from the dispensing staff, all study personnel at both the research centres and sponsor who could influence study outcomes were blinded to the treatment allocation.
BRNS or placebo strips were applied by the subjects to the outside of the nose, across the bridge from alar crease to alar crease, every night during the treatment phase. The strips were used for approximately 8 h per night but no more than 12 h per night.
Subjects were healthy adults who had a leptorrhine nose with a nasal tip protrusion index ≥ 45 and chronic nocturnal nasal congestion for at least the past year, while reporting trouble with sleep. They were also required to have recorded a score of ≤ 70 on the 100-point visual analogue scale (VAS) Nasal Openness Qualifying Question on at least 4 of 7 nights during the baseline qualification period prior to the baseline visit; on this scale, 0 corresponds to extremely blocked and 100 corresponds to extremely open. This instrument was administered at bedtime while the subject was in the supine position.
Exclusion criteria included allergy or intolerance to study materials (or to closely related materials such as adhesive bandages or latex), a history of skin cancer, the presence of a chronic skin condition, eczema of the face or nose, evidence of visible open sores, a diagnosis of sleep apnoea or any other major sleep disorder, a non-typical sleep schedule (e.g., shift work), regular/habitual consumption of more than five cups or glasses per day of xanthine-containing beverages (i.e., tea, coffee, cola), or current use of any product or medication that has any effect on nasal congestion or sleep within specified times of study entry (e.g., antihistamines, stimulants, antidepressants), severe nasal obstruction caused by a structural abnormality, or pregnancy or nursing.
Efficacy was assessed in the clinic using the subjective, validated Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ) , which assesses specific problems in people with allergic rhinoconjunctivitis who experience symptoms predominantly at night, which in turn have an impact on how they feel and their ability to function the next day. The NRQLQ includes 16 items in 4 domains (i.e., composite variables): “Sleep Problems”, “Sleep Time Problems”, “Symptoms on Waking in the Morning”, and “Practical Problems”. Each NRQLQ item was scored using a scale ranging from 0 = not troubled to 6 = extremely troubled. The changes in score for each question and domain on the NRQLQ from baseline to the visits at days 7 and 14 were evaluated. The proportion of subjects showing improvement on each question and domain was also measured.
At-home measurements included questions that were answered by the subject and recorded in a daily diary. These questions related to the perception of nasal breathing and congestion. Subjects were instructed to record their responses while in the supine position before and after application of the strip at bedtime and before removal of the strip in the morning in Study 1, and before application of the strip at bedtime only in Study 2. In Study 1, the change from baseline to the visits at days 7 and 14 and the percentage of subjects showing improvement in the morning and evening ratings at days 1, 3, 7, and 14 were evaluated. In Study 2, mean daily scores were summarized for days 1 through 14. The incidence of adverse events, including severity and relationship to treatment (based on the investigator’s assessment), was evaluated throughout both studies.
The co-primary efficacy endpoints in these two studies were the mean change from baseline in the “Sleep Problems” domain of the NRQLQ and the “Feel Tired and Unrefreshed” item on the “Symptoms on Waking in the Morning” (during the first hour after waking) domain of the NRQLQ. The criteria for success for these endpoints required that the mean total score on the “Sleep Problems” domain of the NRQLQ was statistically significant and clinically relevant versus placebo, and there was a statistically significant difference versus placebo on the “Feel Tired and Unrefreshed” item on the “Symptoms on Waking in the Morning” domain.
In Study 1, secondary efficacy endpoints included the daily diary items, “How Easy It Is to Breathe Through Your Nose” and “How Open Your Nose Felt” after applying the strip at night. In order for these secondary endpoints to be met, there must have been a statistically significant difference in the change from baseline and an increase in the percentage of subjects showing improvement on these items in the BRNS group compared with the placebo group. There were no prespecified secondary endpoints for Study 2.
Sample size calculations were based on the results of a previous study (ClinicalTrials.gov identifier NCT01122849). To provide 80% power to detect a significant difference between BRNS and placebo (alpha = 0.05), it was estimated that a sample size of 57 subjects per arm would be required for an expected treatment difference of 2.30 units with a standard deviation of 4.31 units on the “Sleep Problems” domain of the NRQLQ on day 7, and a sample size of 64 subjects per arm would be required for an expected treatment difference of 0.62 units, with a standard deviation of 1.24 units on the “Feel Tired or Unrefreshed” item in the “Symptoms on Waking in the Morning” domain of the NRQLQ on day 7. In order to meet both of these primary endpoints, a sufficient number of subjects was enrolled to achieve a target sample size of 64 subjects per arm.
All subjects who were randomized, received study treatment, and had at least one follow-up visit were included in the safety population. Efficacy analyses were performed on the intent-to-treat population, which included subjects who were randomized and had at least one post-baseline efficacy assessment.
For the co-primary efficacy analyses (both studies), analysis of covariance (ANCOVA) was used to compare BRNS and placebo on subjective measures of congestion and sleep quality at days 7 and 14. In both studies, the model included treatment and site as factors and baseline score as a covariate; in Study 2, the model also included the following as covariates: baseline score, age, level of congestion symptoms at baseline, Berlin Questionnaire (risk of sleep apnoea) score, and Epworth Sleepiness Scale score. The adjusted mean changes from baseline and 95% confidence intervals were provided. Chi square tests were used to compare the proportion of subjects showing improvements in selected items on the NRQLQ, with all tests performed at the 5% significance level.
In Study 1, ANCOVA was used to analyze changes in the degree of perception of nasal breathing and nasal congestion recorded for the daily diary items. A secondary analysis was also conducted using age, level of congestion symptoms at baseline, Berlin Questionnaire score, and Epworth Sleepiness Scale score as covariates. Analyses were carried out for days 1, 3, 7, and 14; summary statistics were presented for other days. Chi square tests were used to compare the proportion of subjects showing improvements in selected diary items.
Separate analyses were performed in a number of subgroup categories, including age group (18−24 years, 25−54 years, and ≥ 55 years), Berlin Questionnaire score [≥ 2 (subjects at risk for sleep apnoea) and < 2 (not at risk)], and Epworth Sleepiness Scale score (≤ 10 and > 10). Subgroup analyses were conducted for daily diary items in Study 1, and for NRQLQ domains in Study 2.