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

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 OPN-375
(100, 200, and 400 µg bid) 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) entered the study.

1. Pretreatment phase (single-blind, placebo, run-in): 7 to up 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 (baseline) 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]).

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