Efficacy and Safety Study of Intranasal Administration of 100, 200, and 400 μg of Fluticasone Propionate Using a Novel Bi-directional Device

A 16-Week Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study Evaluating the Efficacy and Safety of Intranasal Administration of 100, 200, and 400 μg of Fluticasone Propionate Twice a Day (Bid) Using a Novel Bi-directional Device in Subjects With Bilateral Nasal Polyposis Followed by an 8-week, Open-label Extension Phase to Assess Safety

The primary objective of this study was to compare the efficacy of intranasal administration of 100, 200, and 400 μg twice daily (bid) of fluticasone propionate, delivered by the Optinose device, with matching placebo in subjects with bilateral nasal polyposis and nasal congestion.

Study Overview

• Status: Completed
• Conditions: Bilateral Nasal Polyposis
• Intervention / Treatment: Drug: Fluticasone propionate

Detailed Description

This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to assess the efficacy and safety of intranasal administration of 3 doses of fluticasone propionate (100, 200, and 400 μg bid), delivered by the Optinose device, in subjects with bilateral nasal polyposis and nasal congestion.

This study consisted of 3 phases. After signing informed consent, subjects who met eligibility criteria at Visit 1 (screening) visit entered the study.

1. Pretreatment phase (single-blind, placebo, run-in): 7 to 14 days duration, to determine disease status eligibility and to ensure the subject was able to comply with study procedures prior to randomization and enrolment in the double-blind treatment phase
2. Double-blind treatment phase: 16 weeks duration with 6 scheduled visits starting with Visit 2 (Day 1) when eligible subjects were randomized by balance allocation to 1 of 4 treatment groups and ending at Visit 7 (Week 16)
3. Open-label extension phase: 8 weeks duration with 1 scheduled visit (Visit 8 [Week 24]), during which all subjects received fluticasone propionate 400 mcg BID delivered by the Optinose device

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Stockton, California, United States, 95207
      • Bensch Clinical Research LLC
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Colorado Allergy & Asthma Centers, PC
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Advanced ENT and Allergy
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Institute for Asthma and Allergy
  • New Jersey
    • Ocean City, New Jersey, United States, 07712
      • Atlantic Research Center, LLC
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Allergy and Asthma Research Group
    • Lake Oswego, Oregon, United States, 98225
      • Baker Allergy, Asthma and Dermatology Research Center, LLC
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18020
      • Valley Clinical Research Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont
  • Washington
    • Bellingham, Washington, United States, 98225
      • Bellingham Asthma, Allergy, and Immunology Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women aged 18 years and older

• Women must

  • be practicing an effective method of birth control (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method [eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel], or male partner sterilization) before entry and throughout the study, or
  • be surgically sterile (have had a hysterectomy or bilateral oophorectomy, or tubal ligation at least 1 year before screening) or otherwise be incapable of pregnancy, or
  • be postmenopausal (spontaneous amenorrhea for at least 1 year).
• Women of child-bearing potential must have a negative serum beta-human chorionic gonadotropin (B-hCG) or urine pregnancy test (depending on local regulations) at the screening visit
• Must have bilateral nasal polyposis with a grade of 1 to 3 in each of the nasal cavities as determined by the Lildholdt scale score measured by nasoendoscopy at both screening and baseline visits
• Must have at least moderate symptoms of nasal congestion/obstruction as reported by the subject for the 7 day period preceding the screening visit
• At the baseline visit (Day 1), must have a morning score of at least 2 (moderate) on nasal congestion/obstruction recorded on the subject diary for at least 5 of the last 7 days of the 7 to up to 14 day run-in period
• Must demonstrate an ability to correctly complete the daily diary during the run-in period to be eligible for randomization
• Subjects with comorbid asthma or COPD must be stable with no exacerbations (eg, no emergency room visits, hospitalizations, or oral or parenteral steroid use) within the 3 months before the screening visit. Inhaled corticosteroid use must be limited to stable doses of no more than 1,000 μg/day of beclomethasone (or equivalent) for at least 3 months before screening with plans to continue use throughout the study.
• Must be able to cease treatment with intranasal medications including, but not limited to, intranasal steroids, intranasal sodium cromolyn, nasal atropine, nasal ipratropium bromide, inhaled corticosteroids (except permitted doses listed above for comorbid asthma and COPD) at the screening visit
• Must be able to cease treatment with oral and nasal decongestants and antihistamines at the screening visit
• Must be able to use the OptiNose device correctly; all subjects will be required to demonstrate correct use of the placebo device at screening, Visit 1.
• Must be capable, in the opinion of the investigator, of providing informed consent to participate in the study. Subjects must sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

• Women who are pregnant or lactating
• Have complete or near-complete obstruction of the nasal cavities
• Inability to achieve bilateral nasal airflow for any reason including nasal septum deviation
• Inability to have each nasal cavity examined for any reason including nasal septum deviation
• Nasal septum perforation
• Has had more than 1 episode of epistaxis with frank bleeding in the month before the screening visit
• Have evidence of significant baseline mucosal injury, ulceration or erosion (eg, exposed cartilage, perforation) on baseline nasal examination/nasal endoscopy
• History of more than 5 sinonasal surgeries for either nasal polyps or nasal/sinus inflammation (lifetime)
• History of sinus or nasal surgery within 6 months before the screening visit
• History of any surgical procedure that prevents the ability to accurately grade polyps
• Have symptoms of seasonal allergic rhinitis at screening or baseline and/or, based on time of year, would anticipate onset of symptoms within 4 weeks of randomization
• Current, ongoing rhinitis medicamentosa (rebound rhinitis)
• Have significant oral structural abnormalities, eg, a cleft palate
• Diagnosis of cystic fibrosis
• History of Churg-Strauss syndrome or dyskinetic ciliary syndromes
• Purulent nasal infection, acute sinusitis, or upper respiratory tract infection within 2 weeks before the screening visit. Potential subjects presenting with any of these infections may be rescreened 4 weeks after symptom resolution Note: Subjects who are taking prophylactic antibiotics will be allowed to enter the study as long as they intend to continue the antibiotics for the duration of the study.
• Planned sinonasal surgery during the period of the study
• Allergy, hypersensitivity, or contraindication to corticosteroids or steroids
• Allergy or hypersensitivity to any excipients in study drug
• Exposure to any glucocorticoid treatment with potential for systemic effects (eg, oral, parenteral, intra-articular, or epidural steroids, high dose topical steroids) within 1 month before the screening visit; except as noted in inclusion criteria for subjects with comorbid asthma or COPD
• Have nasal candidiasis
• Have taken a potent CYP3A4 inhibitor within 14 days before the screening visit.
• History or current diagnosis of any form of glaucoma or ocular hypertension (ie, >21 mmHg)
• History of intraocular pressure elevation on any form of steroid therapy
• History or current diagnosis of the presence (in either eye) of a cataract
• Any serious or unstable concurrent disease, psychiatric disorder, or any significant condition that, in the opinion of the investigator could confound the results of the study or could interfere with the subject's participation or compliance in the study
• A recent (within 1 year of the screening visit) clinically significant history of drug or alcohol use, abuse, or dependence that, in the opinion of the investigator could interfere with the subject's participation or compliance in the study
• Positive urine drug screen at screening visit for drugs of abuse, with the exception of prescribed medications for legitimate medical conditions
• Have participated in an investigational drug clinical trial within 30 days of the screening visit
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: OPN-375 100 mcg; Double-Blind Treatment Phase: OPN-375 100 mcg BID x 16 weeks; Open-Label Extension Phase: OPN-375 400 mcg BID x 8 weeks	Drug: Fluticasone propionate; Delivered via Optinose Exhalation Delivery System; Other Names: OPN-375
Active Comparator: OPN-375 200 mcg; Double-Blind Treatment Phase: OPN-375 200 mcg BID x 16 weeks; Open-Label Extension Phase: OPN-375 400 mcg BID x 8 weeks	Drug: Fluticasone propionate; Delivered via Optinose Exhalation Delivery System; Other Names: OPN-375
Active Comparator: OPN-375 400 mcg; Double-Blind Treatment Phase: OPN-375 400 mcg BID x 16 weeks; Open-Label Extension Phase: OPN-375 400 mcg BID x 8 weeks	Drug: Fluticasone propionate; Delivered via Optinose Exhalation Delivery System; Other Names: OPN-375
Placebo Comparator: Placebo; Double-Blind Treatment Phase: Matched Placebo BID x 16 weeks; Open-Label Extension Phase: OPN-375 400 mcg BID x 8 weeks	Drug: Fluticasone propionate; Delivered via Optinose Exhalation Delivery System; Other Names: OPN-375

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 7-day Average Instantaneous Morning Diary Congestion/Obstruction Symptoms	Subjects reported nasal symptoms using the electronic diary twice daily immediately before dosing. 0: None; Mild, symptoms clearly present, but minimal awareness, and easily tolerated; Moderate, definite awareness of symptoms that is bothersome but tolerable; Severe, symptoms that are hard to tolerate, cause interference with activities or daily living During the single-blind run-in phase and during the 16-week, double-blind treatment phase, an electronic diary was provided to each subject. Subjects reported both instantaneous (evaluation of symptom severity immediately preceding the time of scoring) and reflective (evaluation of symptoms severity over the previous 12 hours) scores for nasal congestion/obstruction symptoms.	Baseline, Week 4 of the double-blind treatment phase
Change in Total Polyp Grade	Determined by a nasal polyp grading scale score (sum of scores from both nasal cavities) measured by nasoendoscopy	Baseline, Week 16 of the double-blind treatment phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MOS Sleep-R Score	The MOS Sleep-R is a brief, self-administered, validated questionnaire designed to measure key aspects of sleep, such as disturbance, adequacy, somnolence, and quantity. The 12-item version with a 4-week recall was used in this study. The score range for the 12-item version is 0 to 100, lower scores indicating better sleep and higher scores indicating worse sleep. The scale yields a Sleep Problem Index and scores on the following 6 subscales: Sleep Disturbance, Snoring, Shortness of Breath or Headache, Sleep Adequacy, Sleep Somnolence, and Sleep Quantity.	Baseline, Week 16 of the double-blind treatment phase
Rhinosinusitis Disability Index (RSDI) Total Score	The RSDI is a subject-completed instrument that evaluates the self-perceived impact of disease specific head and neck disorders. The RSDI has 30 items in 3 domains: Physical (11 items), Functional (9 items), and Emotional (10 items). The RSDI scale ranges from 0-120, 0 being better quality of life and less impact of CRS on daily function and 120 being worse quality of life and more impact of CRS on daily function.	Baseline, Week 16 of the double-blind treatment phase
Nasal Congestion/Obstruction Score (7-day Instantaneous Morning)	Measured by the 7-day average instantaneous morning diary symptom scores	Week 16 of the double-blind treatment phase
Change in Rhinorrhea Score (7-day Instantaneous Morning)	Change from baseline in rhinorrhea symptoms, as measured by AM and PM diary symptom scores	Baseline, Week 16 of the double-blind treatment phase
Facial Pain or Pressure Score (7-day Instantaneous Morning)	Change from baseline in facial pain/pressure symptoms, as measured by AM and PM diary symptom scores	Week 16 of the double-blind treatment phase
Hyposmia Score (7-day Instantaneous Morning)	Change from baseline in hyposmia symptoms, as measured by AM and PM diary symptom scores	Week 16 of the double-blind treatment phase
Change in Total Nasal Polyp Score	Polyp grading of each nasal cavity was determined by a nasal polyp grading scale score measured by nasoendoscopy. 0: No polyps; Mild polyposis: polyps not reaching below the inferior border of the middle turbinate; Moderate polyposis: polyps reaching below the inferior border of the middle concha, but not the inferior border of the inferior turbinate; Severe polyposis large polyps reaching below the lower inferior border of the inferior turbinate Determined by a nasal polyp grading scale score (sum of scores from both nasal cavities measured by nasoendoscopy)	Baseline, Week 24 of the open-label extension phase
Polyp Grade of 0 in at Least One Nostril	Subjects with a Polyp Grade of 0 (None) in at least one nostril Polyp grading of each nasal cavity was determined by a nasal polyp grading scale score measured by nasoendoscopy. This outcome measured how many patients with a polyp grad of 0 in at least 1 nostril. 0: No polyps; Mild polyposis: polyps not reaching below the inferior border of the middle turbinate; Moderate polyposis: polyps reaching below the inferior border of the middle concha, but not the inferior border of the inferior turbinate; Severe polyposis large polyps reaching below the lower inferior border of the inferior turbinate	Week 16 of the double-blind treatment phase, Week 24 of the open-label extension phase
Sinonasal Outcome Test 22 (SNOT-22) Total Score	SNOT-22 is a subject-completed questionnaire that consists of 22 questions. The questions on the SNOT-22 efficacy evaluation were used to calculate a total score. 22 questions are divided among 4 subscales: Rhinologic (7 questions), Ear/Facial Symptoms (4 questions), Sleep Function (3 questions), and Psychological Issues (6 questions). Each item was rated on the 5-point scale. The total score can range from 0-110, 0 being the best and 110 being the worst. 0: No problem; Very mild problem; Mild or slight problem; Moderate problem; Severe problem; Problem as bad as it can be	Baseline, Week 16 of the double-blind treatment phase, Week 24 of the open-label extension phase
SF-36v2 - Mental Component	The SF-36v2 is a multipurpose, scaled, 36-item, subject-completed validated questionnaire that measures 8 domains of health: limitations in physical activities, limitations in social activities, limitations in usual role activities, bodily pain, general mental health, limitations in usual role activities, vitality, and general health. It yields scale scores for each of the 8 health domains, and 2 summary measures of physical and mental health. Each scale range is from 0-100. A lower score means more disability and a higher score means less disability.	Baseline, Week 16 of the double-blind treatment phase, Week 24 of the open-label extension phase
SF-36v2 - Physical Component	The SF-36v2 is a multipurpose, scaled, 36-item, subject-completed validated questionnaire that measures 8 domains of health: limitations in physical activities, limitations in social activities, limitations in usual role activities, bodily pain, general mental health, limitations in usual role activities, vitality, and general health perceptions. It yields scale scores for each of the 8 health domains, and 2 summary measures of physical and mental health. Each scale range is from 0-100. A lower score means more disability and a higher score means less disability.	Baseline, Week 16 of the double-blind treatment phase, Week 24 of the open-label extension phase
Number of Participants in Each Category of PGIC	Patient Global Impression of Change; subject responses to the question: "Since starting the study drug, how would you rate the change in your symptoms?" Percentage includes patients who scored either "very much improved," "much improved," or "minimally improved."	Week 16 of the double-blind treatment phase, Week 24 of the open-label extension phase
Number of Participants Eligible for Nasal Polyp Surgery	A subject was considered eligible for surgical intervention if the following conditions were met: Subject has had moderate symptoms of congestion from nasal polyposis for ≥ 3 months.; Subject continues to suffer from at least moderate symptoms despite use of topical steroids at conventional doses for ≥ 6 weeks.; Subject continues to suffer from at least moderate symptoms despite use (or previous use) of saline lavage for ≥ 6 weeks.; Subject has endoscopically visualized bilateral nasal polyposis of at least moderate severity (nasal polyp grading score ≥ 2 in at least 1 nostril).	Week 16 of the double-blind treatment phase; Week 24 of the open-label extension phase
Peak Nasal Inspiratory Flow (PNIF)	The PNIF is an assessment of nasal passage obstruction and was measured using an In-Check portable nasal inspiratory flow meter. To measure PNIF, a mask was placed over the nose during inspiration and inspiratory flow was recorded. Each subject inhaled 3 times and each measurement was recorded. The PNIF value used was the greatest of the 3 results at each time point. Change from baseline in Peak Nasal Inspiratory Flow (PNIF)	Week 16 of the double-blind treatment phase; Week 24 of the open-label extension phase

Collaborators and Investigators

• Sponsor: Optinose US Inc.

Publications and helpful links

General Publications

• Ow RA, McGinnis JP 2nd, Sacks HJ, Mehle ME. The Effect of EDS-FLU on Objective and Patient-Reported Subjective Outcomes for Patients with Chronic Rhinosinusitis with Nasal Polyps. Ear Nose Throat J. 2022 Apr 18:1455613221088698. doi: 10.1177/01455613221088698. Online ahead of print.
• Skoner DP, Meltzer EO, Skoner J, Sacks HJ, Lumry WR. Evaluation of the ocular safety associated with the exhalation delivery system with fluticasone. Allergy Asthma Proc. 2022 Jan 9;43(1):70-77. doi: 10.2500/aap.2022.43.210096. Epub 2021 Nov 9.
• Leopold DA, Elkayam D, Messina JC, Kosik-Gonzalez C, Djupesland PG, Mahmoud RA. NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis. J Allergy Clin Immunol. 2019 Jan;143(1):126-134.e5. doi: 10.1016/j.jaci.2018.06.010. Epub 2018 Jun 19.

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2013
• Primary Completion (Actual): May 11, 2015
• Study Completion (Actual): July 3, 2015

Study Registration Dates

• First Submitted: June 13, 2012
• First Submitted That Met QC Criteria: June 18, 2012
• First Posted (Estimate): June 21, 2012

Study Record Updates

• Last Update Posted (Actual): December 5, 2018
• Last Update Submitted That Met QC Criteria: December 4, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Nose Diseases; Polyps; Nasal Polyps; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Fluticasone; Xhance
• Other Study ID Numbers: OPN-FLU-NP-3102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: randomization codes sent to PIs