OPN-FLU-CS-3205
Research type
Research Study
Full title
A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of OPN 375 Twice a Day (BID) in Subjects with Chronic Sinusitis With or Without the Presence of Nasal Polyps
IRAS ID
263849
Contact name
Nirmal Kumar
Contact email
Sponsor organisation
Optinose US Inc.
Eudract number
2019-000368-12
Clinicaltrials.gov Identifier
Duration of Study in the UK
1 years, 4 months, 23 days
Research summary
Summary of Research
OptiNose has developed OPN-375 (proprietary name XHANCE®) as an intranasal drug delivery system with the intention to improve the performance of fluticasone propionate in the treatment of nasal inflammatory diseases by facilitating deposition of the topical steroid in regions affected by local inflammation. Delivery of drug using an Exhalation Delivery System (EDS) is intended to improve reproducibility of nasal delivery, particularly deposition of the topical steroid to the middle meatus where the sinuses ventilate and drain (ostiomeatal complex). OPN-375 is also intended to address user preference associated with reduced drip-out (posterior and anterior) and taste, and to improve tolerability and efficiency by significantly reducing loss of drug to nontarget sites such as the gastrointestinal (GI) tract and lungs.
Fluticasone propionate is an androstane glucocorticoid with high lipophilicity, high selectivity and affinity for the glucocorticoid receptor, low oral and nasal systemic absorption, and rapid metabolic clearance. It is approved in many countries for use in the treatment of dermatosis (topical), rhinitis (intranasal), and asthma and chronic obstructive pulmonary disease (COPD) (inhaled) and is one of the most well studied and characterized glucocorticoids in clinical use today.Summary of Results
This was a 24-week, randomised, double-blind, placebo-controlled, parallel-group, multicenter study designed to assess the efficacy and safety of intranasal administration of OPN-375 (186 and 372 μg twice daily) in subjects with chronic sinusitis with or without the presence of nasal polyps. The study was carried out by Optinose, US, Inc.
Patients with chronic sinusitis currently have limited medical options for treatment, and no medication is approved in the United States or European Union for the treatment of chronic sinusitis. While some symptoms may be reduced, patients are often left with symptoms due to the suboptimal delivery method of current treatments. Standard nasal spray pumps suffer from a number of drawbacks and are considered suboptimal for reliable drug delivery to target sites beyond the nasal valve. OPN-375, with its breath assisted mechanism of delivery, provides specific benefits over current nasal drug delivery systems including increased reliability of delivery of topical medication to the anatomical sites, which are central to the pathology of chronic sinusitis.
332 subjects participated in the study (from 91 study sites in Bulgaria, Georgia, Sweden, the United Kingdom, the Russian Deferation, Poland, Canada and the United States of America,) and were randomised into one of the three treatment groups. The three treatments were the placebo, a fake drug that looks like the real study drug and the study drug 0PN-375 at two different doses, 186 and 372 μg administered twice daily. The study period took place between 19th February 2020 to 19th January 2022.
Study Subjects: Of the 332 subjects who were randomised and received at least 1 dose of study drug (SAS), 299 (90.1%) completed 24 weeks of double-blind study treatment. A total of 33 (9.9%) subjects discontinued study treatment: 16 (14.3%) placebo recipients and 17 (7.7%) OPN-375 recipients (9 [8.1%] subjects in the 186 µg group and 8 [7.3%] subjects in the 372 µg group). The most common reasons given for discontinuation of OPN-375 (both dose levels combined) and placebo were lack of efficacy (LOE) and AEs. The 332 SAS subjects were also in the ITT Analysis Set and 327 were in the FAS. The mean age of the 332 subjects was 49.1 years (mean ages across the 3 study groups were similar and ranged from 48.4 to 49.6 years). Overall, 191 (57.5%) subjects were male, 141 (42.5%) were female. The population was predominantly White (90.1%). There was a similar distribution of age, gender, race, and ethnicity among subjects in each treatment group. The 3 treatment groups were similar with respect to the proportion of subjects who were reported to have NP and the proportion who had a previous sinus surgery, both of which were variables for which randomization was stratified. Overall, 304 (91.6%) subjects reported using at least 1 standard nasal steroid spray for chronic sinusitis at study entry.
The study met both of its co-primary endpoints and the results were robust with the sensitivity analyses conducted. Specifically, the differences between OPN-375 and placebo were statistically significant (P < 0.05) for the symptom-based outcome (instantaneous AM CSS score at Week 4) on the primary and all 4 supplementary estimands and for observed data (no imputation). For the primary estimand, P < 0.001 for both dose groups with minimal (only 5) observations missing precluded reaching a tipping point; therefore, tipping point analyses was not done. For the sinus opacification outcome (APOV score at Week 24/ET), statistical significance was observed for both doses compared with placebo on the primary and 3 of 4 supplementary estimands with the high dose of OPN-375 and on the primary and 2 of 4 supplementary estimands with the low dose of OPN-375. While the treatment differences on 2 additional supplementary estimands did not reach nominal statistical significance, the results were numerically consistent with the results of the other 2 supplementary estimands. Tipping point analyses were done, and the tipping points were 0.5 and 1.6 times the within-group standard deviation (SD) for the low and high dose groups, respectively. The difference between active and placebo treatment as measured by APOV was also statistically significant when analyzed using ranked values (non-parametrically) and with observed data (no imputation). For the CSS co-primary endpoint, results for the subjects with NP, subjects without NP, and subjects with and without prior sinus surgery were similar to those for the total FAS population and reached nominal statistical significance compared to placebo in both OPN-375 dose groups with similar magnitude of effect. For the imaging co-primary endpoint, Week 24/ET changes from baseline in APOV for subjects with NP and subjects with prior sinus surgery were similar to those for the FAS and reached nominal statistical significance. For the subjects without NP and subjects without prior sinus surgery, the results were directionally the same as for the FAS overall but of insufficient magnitude for nominal statistical significance to be achieved. The magnitude of change from baseline for the 372 µg OPN-375 group was similar for subjects without NP and the FAS overall. However, the magnitude of benefit experienced by subjects without NP on placebo was much greater than the benefit of placebo for any other subgroup.Clinical benefit on symptoms was observed through Week 12, the end of data collection via daily symptom reporting diaries. For the FAS overall population, the AM instantaneous scores for all individual symptoms and the CSS generally decreased/improved numerically compared to baseline in all 3 treatment groups at Weeks 4, 8, and 12, indicating that the effect observed with the CSS was not being driven by a single symptom. Results for mean PM instantaneous, mean AM reflective, and mean PM reflective scores for all individual symptoms and the CSS for the FAS overall and subgroups based on NP and prior sinus surgery were similar to those for AM instantaneous scores demonstrating that the duration of symptomatic benefit lasted the 12-hour dosing interval.
Treatment with OPN-375 at doses of 1 and 2 sprays per nostril BID (186 and 372 µg BID) resulted in statistically significant greater improvements than placebo treatment on the co-primary measures of combined symptoms (change from baseline to Week 4 in 7-day average instantaneous AM CSS) and objective sinus inflammation (change from baseline to Week 24/ET in APOV of the maxillary and ethmoid sinuses). Supportive results from a broad range of secondary endpoints demonstrated clinically meaningful improvements with OPN-375 treatment in nasal symptoms of the disease as well as additional objective (e.g., CT-based, sense of smell) and subjective (e.g., multiple subject-reported symptom and disease burden, general and disease-specific quality of life) outcome measures, and surgical eligibility. Particularly important was the finding of markedly reduced incidence of acute disease exacerbations with active treatment. Treatment with OPN-375 was well tolerated and showed no unusual or unexpected events in the context of prior knowledge and experience with OPN-375, expectations for other combination products delivering fluticasone, and expectations for an intranasal topically acting corticosteroid. The incidences of treatment-emergent adverse events TEAEs in the active treatment groups were similar to those observed in the placebo group and reported with other INS when studied in similar populations (e.g., subjects with NP) for similar durations. Most TEAEs were mild or moderate, transient, and resolved with continued exposure to study medication. No deaths or life-threatening events were reported. The most frequently reported TEAE in OPN-375 recipients versus placebo recipients was a nosebleed and no such event was severe or serious.
REC name
South Central - Berkshire B Research Ethics Committee
REC reference
19/SC/0347
Date of REC Opinion
1 Oct 2019
REC opinion
Further Information Favourable Opinion