| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009137 |
| E.1.2 | Term | Chronic sinusitis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 twice-daily doses of 186 and 372 μg of OPN-375 (fluticasone propionate) with placebo in subjects with chronic rhinosinusitis (CRS) using the following co-primary endpoints:
• change from baseline in symptoms as measured by a composite score of nasal symptoms (CSNS): congestion, facial pain or pressure sensation, and nasal discharge (anterior and/or posterior) at the end of Week 4
and
• change from baseline to Week 24 in the average percent of the opacified volume (APOV) in the ethmoid and maxillary sinuses |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of this study are to compare the efficacy twice-daily doses of 186 and 372 μg of OPN-375 with placebo on:
• change from baseline to Week 24 in subject symptoms and functioning, as measured by Sinonasal Outcome Test - 22 (SNOT-22) total score
• change from baseline to Week 24 in the 36-Item Short Form Health Survey version 2 (SF-36v2) mental composite score (MCS)
• change from baseline to Week 24 in the SF-36v2 physical composite score (PCS)
• frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of symptoms that requires escalation of treatment
Safety Objective:
• to evaluate the safety of OPN-375 by monitoring adverse events (AEs) throughout the study; results of nasal examination, vital signs measurements (ie, blood pressure, pulse), and weight; and monitoring concomitant medication usage |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A substudy will be conducted (at select sites in the United States) to evaluate clinical biomarkers to characterize the microbiome and cytokine profiles in a subset of subjects at selected study centers as detailed in an attachment to the protocol
The objectives of this substudy are as follows:
- to characterize the local microenvironment of the sinonasal cavity of subjects before and after treatment with OPN375 or placebo - to evaluate if inflammatory characteristics of the microenvironment predict response to treatment with OPN 375
- to evaluate changes in plasma eosinophil counts in subjects treatedwith OPN 375 or placebo
Clinical biomarker endpoints are as follows:
- change from Visit 2/Baseline/Day 1 to Visit 3/Week 4 and Visit 6/Week 24/ET in- sinonasal microbiome measures of diversity, presence of commensal organisms, and presence of pathogenic organisms using 16S rRNA gene sequencing
- cytokine concentrations as follows:
* IFNa, TNFa, IL1b, IL4, IL5, IL6, IL8, IL10, IL13, IL17a, IL22, IL25,IL33, TSLP,ECP
* GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10,IL-12p70, IL-13, IL-17A, MCP1, MIP1a, MIP1b, TNFa
- change from Visit 1/Screening to Visit 6/Week 24/ET in plasmaeosinophilcounts |
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| E.3 | Principal inclusion criteria |
1. men or women aged 18 years and older at baseline visit
2. women of child bearing potential must be abstinent, or if sexually active,
a. 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
b. be surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), or
c. be postmenopausal (amenorrhea for at least 1 year)
3. women of child-bearing potential must have a negative urine pregnancy test at Visit 1 (Screening)
4. must have a history of CRS and be currently experiencing 2 or more of the following symptoms, 1 of which has to be either nasal congestion or nasal discharge (anterior and/or posterior nasal discharge) for equal to or greater than 12 weeks:
• nasal congestion
• nasal discharge (anterior and/or posterior nasal discharge)
• facial pain or pressure
• reduction or loss of smell
5. endoscopic evidence of nasal mucosal disease, with edema or purulent discharge; or polyps/polypoid tissue <Grade 1 in middle meatus, bilaterally, or presence of bilateral disease on a prior CT scan performed within 14 days of Visit 1
6. must have confirmatory evidence via a computed tomography(CT) scan of bilateral sinus disease (have at least 1 sinus on each side of nose with a Lund-Mackay score of ≥1)
7. baseline CT scan must show a combined ≥25% opacification of the ethmoid sinuses and ≥25% opacification of at least 1 maxillary sinus
8. must have at least moderate symptoms (as defined in protocol) of nasal congestion as reported by the subject, on average, for the 7-day period preceding Visit 1 (Screening) run-in
9. must have an average morning score of at least 1.5 for congestion on the Nasal Symptom Scale (as defined in protocol) recorded on the subject diary over a 7-day period during the first 14 days of the single-blind run-in period
10. must demonstrate an ability to correctly complete the daily diary during the run-in period to be eligible for randomization
11. Subjects with comorbid asthma or chronic obstructive pulmonary disorder (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.
12. Subjects with aspirin-exacerbated respiratory disease, who have undergone aspirin desensitization and are receiving daily aspirin therapy, must be receiving therapy for at least 6 months prior to Visit 1.
13. must be able to cease treatment with intranasal steroids, inhaled corticosteroids (except permitted doses listed above for asthma and COPD) at the screening visit
14. must be able to cease treatment with oral and nasal decongestants and antihistamines at Visit 1 (Screening)
15. must be able to use the exhalation delivery system correctly; all subjects will be required to demonstrate correct use with the practice exhalation delivery system (EDS) at Visit 1 (Screening).
16. 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. |
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| E.4 | Principal exclusion criteria |
1. women who are pregnant or lactating
2. inability to have each nasal cavity examined for any reason, including nasal septum deviation
3. inability to achieve bilateral nasal airflow
4. is currently taking XHANCE®
5. have previously used XHANCE for more than 1 month and did not achieve an adequate symptomatic response
6. the nasal/sinus anatomy prevents the accurate assessment of sinus volume via CT scan
7. history of sinus or nasal surgery within 6 months before Visit 1 or has not healed from a prior sinus or nasal surgery
8. have current evidence of odontogenic sinusitis, sinus mucocele (the affected sinus is completely opacified and either the margins are expanded and/or thinned OR there are areas of complete bone resorption resulting in bony defect and extension of the “mass” into adjacent tissues), evidence of allergic fungal sinusitis, or evidence of complicated sinus disease (including, but not limited to, extension of inflammation outside of the sinuses and nasal cavity)
9. have a paranasal sinus or nasal tumor
10. have polyp grade ≥1 (polyp that is free on 5 sides and has a stalk) on either side of the nose as determined by the nasoendoscopy at screening
11. have a nasal septum perforation
12. have had more than 1 episode of epistaxis with frank bleeding in the month before Visit 1 (Screening)
13. have evidence of significant mucosal injury, ulceration (eg, exposed cartilage) on Visit 1 (Screening) nasal examination/nasoendoscopy
14. have current, ongoing rhinitis medicamentosa (rebound rhinitis)
15. have significant oral structural abnormalities (eg, a cleft palate)
16. have a diagnosis of cystic fibrosis
17. history of eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) or dyskinetic ciliary syndromes
18. symptom resolution or last dose of antibiotics for purulent nasal infection, acute sinusitis, or upper respiratory tract infection influenza,
or SARS-CoV-2 (COVID-19) has not occurred before Visit 1 or was less than 4 weeks before the CT scan. Potential subjects presenting with any of these infections may be rescreened 4 weeks after symptom resolution.
19. planned sinonasal surgery during the period of the study
20. allergy, hypersensitivity, or contraindication to corticosteroids or steroids
21. has used oral steroids in the past for treatment of CRS and did not experience any relief of symptoms
22. has a steroid eluting sinus stent still in place within 30 days of Visit 1
23. allergy or hypersensitivity to any excipients in study drug
24. exposure to any glucocorticoid treatment with potential for systemic effects (eg, oral, parenteral, intraarticular, or epidural steroids, high dose topical steroids) within 1 month before Visit 1 (Screening); except as noted in inclusion criteria for subjects with comorbid asthma or COPD
25. have nasal candidiasis
26. history or current diagnosis of any form of glaucoma or ocular hypertension (intraocular pressure [IOP] at screening of >21 mm Hg)
27. history of IOP elevation on any form of steroid therapy
28. history or current diagnosis of the presence (in either eye) of cataract unless both natural intraocular lenses have been removed
29. history of immunodeficiency
30. 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
31. have a positive drug screen or a recent (within 1 year of Visit 1 [Screening]) history of drug or alcohol abuse, or dependence that, in the opinion of the investigator could interfere with the subject's participation or compliance in the study
32. have participated in an investigational drug clinical trial within 30 days of Visit 1 (Screening)
33. have received mepolizumab (Nucala®), reslizumab (Cinquair®), dupilumab (Dupixent®), omalizumab (Xolair®), or benralizumab (Fasenra™) within 6 months of Visit 1 (Screening)
34. is using strong cytochrome P450 3A4 (CYP3A4) inhibitor (eg, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, voriconazole, cobicistat)
35. is an employee 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, or is a family member of the employee or the investigator
36. Patients who report unexplained worsening of vision within the past 3 months (e.g. difficulty reading or seeing traffic signs from a distance.)
A diagnosis of presbyopia established by an eye doctor is not exclusionary. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Endpoints:
- change from baseline to the end of Week 4 in average total instantaneous morning (AM) scores (evaluation of symptom severity immediately preceding the time of scoring) of:
• nasal congestion
• nasal discharge (anterior and/or posterior)
• facial pain/pressure sensation
The baseline CSNS is the average of the total instantaneous AM scores over the last 7 days of the single-blind run-in period, and at the end of Week 4, scores are averaged over 7 days before Week 4.
- change from baseline to Week 24 in the APOV in the ethmoid and maxillary sinuses |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to schedule of study procedures and evaluations |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints:
• change from baseline to Week 24 in subject symptoms and functioning as measured by SNOT-22 total score
• change from baseline to Week 24 on the MCS of the SF-36v2
• change from baseline to Week 24 on the PCS of the SF-36v2
• frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of symptoms that requires escalation of treatment
Safety Endpoints:
• monitoring adverse events (AEs) throughout the study; results of nasal examinations, vital signs measurements (ie, blood pressure, pulse), and weight; and monitoring concomitant medication
usage |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to schedule of study procedures and evaluations |
|
| 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 | No |
| 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 | 3 |
| 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Australia |
| Czech Republic |
| Georgia |
| New Zealand |
| Poland |
| Romania |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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