E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bilateral Nasal Polyposis |
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E.1.1.1 | Medical condition in easily understood language |
Bilateral Nasal Polyposis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Ear, nose and throat diseases [C09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028754 |
E.1.2 | Term | Nasal polyp |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to compare the efficacy of
intranasal administration of 100, 200, and 400 μg of fluticasone
propionate twice a day delivered by the OptiNose device with placebo in
subjects with bilateral nasal polyposis. Two co-primary endpoints will be used in the study: reduction of nasal congestion/obstruction symptoms
at the end of Week 4 of the double-blind treatment phase measured by
the 7-day average instantaneous AM diary symptom scores, and
reduction in total polyp grade (sum of scores from both nasal cavities)
over the 16 weeks of the double-blind treatment phase as determined by a nasal polyp grading scale score measured by nasoendoscopy. |
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E.2.2 | Secondary objectives of the trial |
To compare the effect of intranasal administration of fluticasone
propionate twice a day during the double-blind treatment phase (DBTP) of the study with placebo on:
• Change in polyp grade
• Change in nasal congestion/obstruction symptoms, sense of smell, rhinorrhea symptoms, and facial pain or pressure symptoms
• Change in subject symptoms and functioning
• Change in nasal patency
• Change in monthly use of rescue medication
• In subjects with comorbid asthma, change:
- in asthma symptoms
- in forced expiratory volume in 1 second (FEV-1)
• Change in patient-reported outcomes
• Improvement in sleep quality
• Assessment of health economic measures related to bilateral nasal
polyposis
• Subject assessment of current/most recent nasal spray and of the study drug
• Subject assessment of Patient Global Impression of Change (PGIC) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Men or women aged 18 years and older
• Must have bilateral nasal polyposis with a grade of 1 to 3 in each of the nasal cavities as determined by a nasal polyp grading scale score measured by nasoendoscopy at Visit 1 (Screening)
• Must have at least moderate symptoms (as defined in the protocol) of nasal congestion/obstruction as reported by the subject, on average, for the 7 day
period preceding Visit 1 (Screening)
• At Visit 2, Day 1 (Baseline), 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 chronic obstructive pulmonary
disease (COPD) must be stable with no exacerbations (eg, no emergency room visits, hospitalizations, or oral or parenteral steroid use) within the
3 months before Visit 1 (Screening). 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 Visit 1 (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 Visit 1 (Screening)
• Must be able to cease treatment with oral and nasal decongestants and antihistamines at Visit 1 (Screening)
• Must be able to use the OptiNose device correctly; all subjects will be required to demonstrate correct use of the practice placebo device at Visit 1 (Screening) |
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E.4 | Principal exclusion criteria |
• 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 Visit 1 (Screening)
• Have evidence of significant mucosal injury, ulceration or erosion (eg, exposed cartilage, perforation) on Visit 1 (Screening) nasal examination/nasoendoscopy
• 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 Visit 1 (Screening)
• History of any surgical procedure that prevents the ability toaccurately grade polyps
• Have symptoms of seasonal allergic rhinitis at Visit 1 (Screening) or Visit 2, Day 1 (Baseline) and/or, based on time of year, would anticipate onset of symptoms within 4 weeks of randomization
• Purulent nasal infection, acute sinusitis, or upper respiratory tract infection within 2 weeks before Visit 1 (Screening). Potential subjects presenting with any of these infections may be rescreened 4 weeks after symptom resolution
• Planned sinonasal surgery during the period of the study
• 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
• Current diagnosis of the presence (in either eye) of a cataract of Grade 1 or greater as defined on the Eye Examination Worksheet (see Attachment 2) OR, less than a Grade 1 cataract with associated visual impairment |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Mean change from baseline to the end of Week 4 of the double-blind treatment phase in average instantaneous AM nasal congestion/obstruction scores; scores are the averaged instantaneous AM scores over the 7 days before Visit 2, Day 1 (Baseline) and over the 7 days before the Week 4 visit from the subject diary
• Mean change from baseline over the 16 weeks of the double-blind treatment phase in total polyp grade (sum of scores from both nasal cavities) as determined by a nasal polyp grading scale score measured by nasoendoscopy |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Mean change from baseline to the end of Week 4 of the double-blind treatment phase in average instantaneous AM nasal congestion/obstruction scores; scores are the averaged instantaneous AM scores over the 7 days before Visit 2, Day 1 (Baseline) and over the 7 days before the Week 4 visit from the subject diary
• Mean change from baseline over the 16 weeks of the double-blind treatment phase in total polyp grade (sum of scores from both nasal cavities) as determined by a nasal polyp grading scale score measured by nasoendoscopy |
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E.5.2 | Secondary end point(s) |
• Mean change from baseline to Week 4, 8, 12, 16, end of double-blind treatment phase, and Week 24/end of open-label extension phase in polyp grade (total and worst nostril) as determined by a nasal polyp grading scale score measured by nasoendoscopy
• Mean change from baseline to Week 4, 8, 12, 16, and the end of the double-blind treatment phase:
• in average instantaneous and reflective AM scores and in average
instantaneous and reflective PM scores, averages are based on scores recorded in the diary for the 7 days before each time point for:
- nasal congestion/obstruction score
- sense of smell score
- rhinorrhea score
- facial pain or pressure score
Note: For the nasal congestion/obstruction score, the instantaneous AM score for the end of Week 4 of the double-blind treatment phase time point is also part of the co-primary endpoint.
• in the Sinonasal Outcome Test - 22 (SNOT-22) total score (also calculated at Week 24/end of open-label extension phase)
• in the SNOT-22 nasal symptom-related items score; items 1, 2, 3, 5, 6, 21, and 22 (also calculated at Week 24/end of open-label extension phase)
• in peak nasal inspiratory flow (PNIF)
• For subjects with comorbid asthma:
• in Asthma Control Test (ACT) total score
• in FEV-1
• Average monthly use of rescue medication (loratadine or another country-available, non-sedating antihistamine) after the Week 4 visit during the double-blind treatment phase
• The proportions of subjects who have reductions in the AM and PM, instantaneous and reflective, average nasal congestion/obstruction
symptom scores by 0.5 or more points from baseline to the end of the double blind treatment phase
• The proportion of subjects who have a reduction in the total polyp grade score (sum of scores from both nasal cavities) by 1 or more points
from baseline to the end of the double-blind treatment phase
• Mean change from baseline to the end of the double-blind treatment
phase for:
• Rhinosinusitis Disability Index (RSDI) total score
• 36-Item Short Form Health Survey version 2 (SF-36v2) scores (also calculated at Week 24/end of open-label extension phase)
• Mean change from baseline to Week 4, 8, 12, 16, and the end of the double-blind treatment phase in the Medical Outcomes Study Sleep Scale
– Revised (MOS Sleep-R) scores
• Comparison of health economic measures during the double-blind treatment and open-label extension phases related to bilateral nasal polyposis (eg, criteria for surgical intervention for nasal polyps is met [independent of actual surgery performed], missed work or school days/lost productivity)
• Subject evaluation of current/most recent nasal spray at screening and subject evaluation of study drug during double-blind treatment and open-label extension phases will be summarized
• Patient Global Impression of Change (PGIC) scores at Week 4, 16, and 24 will be summarized
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For timepoints please refer to protocol, Section 9.2.2 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
8-Week Open-Label Extension Phase |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
European Union |
South Africa |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 15 |