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Clinical Trial Results:
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.

Summary
EudraCT number	2011-004887-31
Trial protocol	GB
Global end of trial date	03 Jul 2015

Results information
Results version number	v1(current)
This version publication date	02 Jan 2021
First version publication date	02 Jan 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

OPN-FLU-NP-3102

ISRCTN number

US NCT number

NCT01624662

WHO universal trial number (UTN)

Sponsor organisation name

OptiNose US, Inc

Sponsor organisation address

1020 Stony Hill Road, Suite 300, Yardley, United States, PA 19067

Public contact

Jennifer Carothers, Vice President Global Clinical Operations & Outsourcing, OptiNose US, Inc, +1 267 364-3500, jennifer.carothers@optinose.com

Scientific contact

Jennifer Carothers, Vice President Global Clinical Operations & Outsourcing, OptiNose US, Inc, +1 267 364-3500, jennifer.carothers@optinose.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Mar 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 May 2015

Global end of trial reached?

Yes

Global end of trial date

03 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to compare the efficacy of intranasal administration of 100, 200, and 400 µg twice daily (bid) of OPN-375 with matching placebo in subjects with bilateral nasal polyposis and nasal congestion. Two co-primary endpoints were used in the study: 1) 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 morning diary symptom scores (ADS7-IA); and 2) reduction in total polyp grade (sum of scores from both nasal cavities) at Week 16 of the double-blind treatment phase as determined by a nasal polyp grading scale score measured by nasoendoscopy.

Protection of trial subjects

This clinical study was conducted in compliance with the protocol, ethical principles that have their origin in the Declaration of Helsinki in its revised edition, the guidelines of International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) (CPMP/ICH/135/95), European Union (EU) Clinical Trials Directive 2001/20/EC, EU Commission Directive 2005/28/EC, applicable US FDA Regulations, and with local laws and regulations in any country of conduct.

Background therapy

Allowed concomitant medications: - Acetaminophen and NSAIDs were permitted for analgesia; ASA was permitted for cardiovascular prophylaxis. ASA and NSAIDs were not allowed for subjects with a documented sensitivity to these medications. - Antibiotic medications were permitted (except for those prohibited) for bacterial infections that developed during the study. Subjects, who were taking prophylactic antibiotics, were allowed to enter the study as long as they intended to continue the antibiotics for the duration of the study. - Intranasal saline spray was permitted with the exception that it could not be used within 2 hours before or after study drug administration. - Saline lavage was permitted only for those subjects regularly using it before study entry; subjects could not initiate use during the study, and could not change usage during the study. Saline lavage was not performed within 2 hours before or after study drug administration. - Stable doses of leukotriene receptor antagonists, beta-blockers, and neuroleptics. - Low to medium strength topical corticosteroids for dermatologic purposes. - Other concomitant medications were allowed, if not specifically listed as prohibited. Subjects with comorbid asthma or COPD at study entry, inhaled corticosteroid use was limited to stable doses of no more than 1000 µg/day of beclomethasone (or equivalent). Subjects had to be on a stable dose for least 3 months prior to Visit 1 with plans to continue use throughout the study. Use of rescue medication was not allowed during the single-blind run-in or before the Week 4 visit of the double-blind treatment phase. Subjects were allowed to use OTC loratadine 10 mg per day or another country-available, nonsedating antihistamine (eg, cetirizine, levocetirizine, desloratadine) at the label-recommended usual dose per day as rescue medication following the Week 4 visit in the double-blind treatment phase and throughout the open-label extension phase of the study.

Evidence for comparator

Actual start date of recruitment

30 Oct 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Romania: 55

Country: Number of subjects enrolled

South Africa: 44

Country: Number of subjects enrolled

Ukraine: 54

Country: Number of subjects enrolled

Poland: 131

Country: Number of subjects enrolled

United States: 39

Worldwide total number of subjects

323

EEA total number of subjects

186

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

300

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 456 subjects were screened, 434 subjects entered the single-blind run-in phase, and a total of 323 subjects were subsequently enrolled and randomized (ITT Population) at 38 centers into the double-blind phase.

Screening details

Assessments included nasoendoscopy-related (nasal examination, nasoendoscopy, and surgical intervention assessment) procedures, ocular examinations, clinical laboratory tests, physical examination, and confirmation of ability to use the OptiNose drug delivery system. Subjects also completed a medical evaluation questionnaire.

Number of subjects started

434 ^[1]

Number of subjects completed

323

Reason: Number of subjects

Physician decision: 111

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: During the pretreatment phase subjects administered morning and evening doses of placebo and completed a daily diary immediately prior to morning and evening doses. This consisted of recording both instantaneous (evaluation of symptom severity immediately preceding the time of scoring) and reflective (evaluation of symptom severity over the previous 12 hours) scores for nasal symptoms. At the end of the pretreatment phase, eligible subjects entered into the double-blind treatment phase.

Period 1 title

Double-blind Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

During the double-blind treatment phase of the study, subjects, the investigator and study center personnel at each center, and the sponsor or its designated personnel directly involved in the clinical study, remained blinded to study treatment. The investigator was not provided with the randomization code.

Are arms mutually exclusive

Yes

EDS-Placebo

Arm description

Matched placebo BID x 16 weeks

Arm type

Placebo

Investigational medicinal product name

EDS-Placebo

Investigational medicinal product code

Other name

EDS-Placebo

Pharmaceutical forms

Nasal spray, suspension

Routes of administration

Intranasal use

Dosage and administration details

EDS-Placebo: Matched placebo BID x 16 weeks 100: OPN-375 100 mcg BID x 16 weeks 200: OPN-375 200 mcg BID x 16 weeks 400: OPN-375 400 mcg BID x 16 weeks

OPN-375 100 mcg

Arm description

OPN-375 100 mcg BID x 16 weeks

Arm type

Experimental

Investigational medicinal product name

OPTINOSE FLUTICASONE PROPIONATE

Investigational medicinal product code

OPN-375

Other name

Pharmaceutical forms

Nasal spray, suspension

Routes of administration

Intranasal use

Dosage and administration details

EDS-Placebo: Matched placebo BID x 16 weeks 100: OPN-375 100 mcg BID x 16 weeks 200: OPN-375 200 mcg BID x 16 weeks 400: OPN-375 400 mcg BID x 16 weeks

OPN-375 200 mcg

Arm description

OPN-375 200 mcg BID x 16 weeks.

Arm type

Experimental

Investigational medicinal product name

OPTINOSE FLUTICASONE PROPIONATE

Investigational medicinal product code

OPN-375

Other name

Pharmaceutical forms

Nasal spray, suspension

Routes of administration

Intranasal use

Dosage and administration details

EDS-Placebo: Matched placebo BID x 16 weeks 100: OPN-375 100 mcg BID x 16 weeks 200: OPN-375 200 mcg BID x 16 weeks 400: OPN-375 400 mcg BID x 16 weeks

OPN-375 400 mcg

Arm description

OPN-375 400 mcg BID x 16 weeks

Arm type

Experimental

Investigational medicinal product name

OPTINOSE FLUTICASONE PROPIONATE

Investigational medicinal product code

OPN-375

Other name

Pharmaceutical forms

Nasal spray, suspension

Routes of administration

Intranasal use

Dosage and administration details

EDS-Placebo: Matched placebo BID x 16 weeks 100: OPN-375 100 mcg BID x 16 weeks 200: OPN-375 200 mcg BID x 16 weeks 400: OPN-375 400 mcg BID x 16 weeks

Number of subjects in period 1	EDS-Placebo	OPN-375 100 mcg	OPN-375 200 mcg	OPN-375 400 mcg
Started	80	81	80	82
Completed	70	78	76	82
Not completed	10	3	4	0
Consent withdrawn by subject	3	-	3	-
Adverse event, non-fatal	2	1	1	-
Protocol violation	-	1	-	-
Lack of efficacy	5	1	-	-

Period 2 title

Open-label Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

During the open-label treatment extension phase, all individuals involved in the study were aware that the treatment was open-label OPN-375 400 µg bid, but remained unaware of which treatment had been received during the prior 16 weeks.

OPN-375 400 mcg

Arm description

At the Week 16 visit, subjects received 2 study drug kits. One kit was used during Weeks 17 to 20 and the other kit was used during Weeks 21 to 24. During the open-label extension phase, all subjects received OPN-375 400 µg bid.

Arm type

Experimental

Investigational medicinal product name

OPTINOSE FLUTICASONE PROPIONATE

Investigational medicinal product code

OPN-375

Other name

Pharmaceutical forms

Nasal spray, suspension

Routes of administration

Intranasal use

Dosage and administration details

OPN-375 400 mcg BID x 8 weeks

Number of subjects in period 2 ^[2]	OPN-375 400 mcg
Started	299
Completed	294
Not completed	5
Consent withdrawn by subject	1
Adverse event, non-fatal	3
Lack of efficacy	1

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 17 patients did not start the open label phase for the following reasons: lack of efficacy (6), subject withdrawal (6) adverse events (4) protocol deviations (1)

Baseline characteristics

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Reporting group title

EDS-Placebo

Reporting group description

Matched placebo BID x 16 weeks

Reporting group title

OPN-375 100 mcg

Reporting group description

OPN-375 100 mcg BID x 16 weeks

Reporting group title

OPN-375 200 mcg

Reporting group description

OPN-375 200 mcg BID x 16 weeks.

Reporting group title

OPN-375 400 mcg

Reporting group description

OPN-375 400 mcg BID x 16 weeks

Reporting group values	EDS-Placebo	OPN-375 100 mcg	OPN-375 200 mcg	OPN-375 400 mcg	Total
Number of subjects	80	81	80	82	323
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	73	74	74	79	300
From 65-84 years	7	7	6	3	23
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	46.7 ± 11.95	46.7 ± 13.72	44.8 ± 12.87	45 ± 12.14	-
Gender categorical
Units: Subjects
Female	38	39	34	26	137
Male	42	42	46	56	186
Race/Ethnicity
Units: Subjects
White	76	76	76	76	304
Black / African American	3	3	3	4	13
Asian	0	0	0	0	0
Other	1	2	1	2	6
Use of ICS treatment for polyps in past 10 years
Units: Subjects
Participants with ICS treatment for polyps	73	67	70	70	280
Participants with no ICS treatment for polyps	7	14	10	12	43
Nasal congestion/obstruction score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on scale
arithmetic mean (full range (min-max))					-
Rhinorrhea Score (7-day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on a scale
arithmetic mean (full range (min-max))					-
Facial Pain or Pressure Score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on a scale
arithmetic mean (full range (min-max))					-
Hyposmia Score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: Normal 1: Slightly impaired 2: Moderately impaired 3: Absent
Units: Units ona scale
arithmetic mean (full range (min-max))					-
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 1. Very mild problem 2. Mild or slight problem 3. Moderate problem 4. Severe problem 5. Problem as bad as it can be
Units: Units on a scale
arithmetic mean (full range (min-max))					-
Medical Outcomes Study Sleep Scale Revised (MOS Sleep-R)
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.
Units: Units on a scale
arithmetic mean (full range (min-max))					-
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.
Units: Units on a scale
arithmetic mean (full range (min-max))					-
Short Form (36) Health Survey Version 2 (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.
Units: Units on a scale
arithmetic mean (full range (min-max))					-
Short Form (36) Health Survey Version 2 (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.
Units: Units on a scale
arithmetic mean (full range (min-max))					-
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.
Units: Units on a scale
arithmetic mean (full range (min-max))					-

Subject analysis set title

EDS-Placebo FAS

Subject analysis set type

Full analysis

Subject analysis set description

Full Analysis Set included all subjects who received at least one dose of study drug, and who had baseline assessments of polyp size (nasoendoscopy) and recorded morning nasal congestion/obstruction symptoms.

Subject analysis set title

OPN-375 100 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

OPN-375 200 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

OPN-375 400 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis sets values	EDS-Placebo FAS	OPN-375 100 mcg FAS	OPN-375 200 mcg FAS	OPN-375 400 mcg FAS
Number of subjects	79	80	80	82
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	±	±	±	±
Gender categorical
Units: Subjects
Female
Male
Race/Ethnicity
Units: Subjects
White
Black / African American
Asian
Other
Use of ICS treatment for polyps in past 10 years
Units: Subjects
Participants with ICS treatment for polyps
Participants with no ICS treatment for polyps
Nasal congestion/obstruction score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on scale
arithmetic mean (full range (min-max))	2.29 (1.6 to 3.0)	2.23 (1.6 to 3.0)	2.20 (1.7 to 3.0)	2.25 (1.6 to 3.0)
Rhinorrhea Score (7-day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on a scale
arithmetic mean (full range (min-max))	1.8 (0.0 to 3.0)	1.89 (0.0 to 3.0)	1.86 (0.0 to 3.0)	1.77 (0.0 to 3.0)
Facial Pain or Pressure Score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: None 1. Mild: symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate: definite awareness of symptoms that is bothersome but tolerable 3. Severe: symptoms that are hard to tolerate, cause interference with activities or daily living
Units: Units on a scale
arithmetic mean (full range (min-max))	1.46 (0.0 to 3.0)	1.46 (0.0 to 3.0)	1.48 (0.0 to 3.0)	1.35 (0.0 to 3.0)
Hyposmia Score (-7 day instantaneous morning)
Nasal symptoms were recorded in e-diary each morning for the 7 day period preceding the screening visit, evaluating symptom severity immediately preceding the time of scoring (instantaneous). Nasal Symptom Score 0: Normal 1: Slightly impaired 2: Moderately impaired 3: Absent
Units: Units ona scale
arithmetic mean (full range (min-max))	2.47 (0.0 to 3.0)	2.36 (0.0 to 3.0)	2.54 (0.9 to 3.0)	2.33 (0.0 to 3.0)
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 1. Very mild problem 2. Mild or slight problem 3. Moderate problem 4. Severe problem 5. Problem as bad as it can be
Units: Units on a scale
arithmetic mean (full range (min-max))	52.0 (14 to 94)	48.5 (9 to 97)	48.1 (11 to 92)	47.1 (7 to 103)
Medical Outcomes Study Sleep Scale Revised (MOS Sleep-R)
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.
Units: Units on a scale
arithmetic mean (full range (min-max))	41.7 (5.6 to 86.1)	40.9 (8.3 to 94.4)	43.0 (2.8 to 86.1)	39.1 (0.0 to 77.8)
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.
Units: Units on a scale
arithmetic mean (full range (min-max))	44.9 (4 to 98)	43.9 (7 to 111)	39.7 (2 to 89)	41.5 (0 to 85)
Short Form (36) Health Survey Version 2 (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.
Units: Units on a scale
arithmetic mean (full range (min-max))	43.1 (21.5 to 63.8)	44.4 (12.27 to 61.03)	45.9 (19.63 to 64.81)	47.0 (20.6 to 61.63)
Short Form (36) Health Survey Version 2 (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.
Units: Units on a scale
arithmetic mean (full range (min-max))	45.8 (26.97 to 60.07)	46.1 (28.61 to 58.86)	46.5 (29.56 to 59.43)	46.4 (22.64 to 60.32)
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.
Units: Units on a scale
arithmetic mean (full range (min-max))	119.7 (30 to 370)	123.4 (30 to 370)	107.6 (40 to 350)	122.7 (30 to 370)

End points

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Reporting group title

EDS-Placebo

Reporting group description

Matched placebo BID x 16 weeks

Reporting group title

OPN-375 100 mcg

Reporting group description

OPN-375 100 mcg BID x 16 weeks

Reporting group title

OPN-375 200 mcg

Reporting group description

OPN-375 200 mcg BID x 16 weeks.

Reporting group title

OPN-375 400 mcg

Reporting group description

OPN-375 400 mcg BID x 16 weeks

Reporting group title

OPN-375 400 mcg

Reporting group description

Subject analysis set title

EDS-Placebo FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

OPN-375 100 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

OPN-375 200 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

OPN-375 400 mcg FAS

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Change in 7-day Average Instantaneous Morning Diary Congestion/Obstruction Symptoms

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End point title

Change in 7-day Average Instantaneous Morning Diary Congestion/Obstruction Symptoms

End point description

Assessment was done on Full Analysis Set, that included all subjects who received at least one dose of study drug, and who had baseline assessments of polyp size (nasoendoscopy) and recorded morning nasal congestion/obstruction symptoms. Subjects reported nasal symptoms using the electronic diary twice daily immediately before dosing. 0: None 1. Mild, symptoms clearly present, but minimal awareness, and easily tolerated 2. Moderate, definite awareness of symptoms that is bothersome but tolerable 3. 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.

End point type

Primary

End point timeframe

Baseline, week 4 of the double-blind treatment phase

End point values	EDS-Placebo	OPN-375 100 mcg	OPN-375 200 mcg	OPN-375 400 mcg
Number of subjects analysed	79	80	80	82
Units: Units on a scale
least squares mean (standard error)	-0.24 ± 0.07	-0.59 ± 0.07	-0.68 ± 0.07	-0.62 ± 0.07

Change in instantaneous AM ADS7-IA

Statistical analysis description

Inferential statistics were derived from a generalized linear model (GLM) model with treatment and country factors and baseline ADS7-IA score for nasal congestion/obstruction as a covariate.

Comparison groups

OPN-375 100 mcg v OPN-375 200 mcg v OPN-375 400 mcg v EDS-Placebo

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Generalized Linear Model

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

-0.23

Variability estimate

Standard error of the mean

Primary: Change in Total Polyp Grade

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End point title

Change in Total Polyp Grade

End point description

Assessment was done on Full Analysis Set, that included all subjects who received at least one dose of study drug, and who had baseline assessments of polyp size (nasoendoscopy) and recorded morning nasal congestion/obstruction symptoms. Determined by a nasal polyp grading scale score (sum of scores from both nasal cavities) measured by nasoendoscopy.

End point type

Primary

End point timeframe

Baseline, Week 16 of the double-blind treatment phase

End point values	EDS-Placebo	OPN-375 100 mcg	OPN-375 200 mcg	OPN-375 400 mcg
Number of subjects analysed	79	80	80	82
Units: Units on a Scale
least squares mean (standard error)	-0.61 ± 0.11	-1.31 ± 0.11	-1.22 ± 0.11	-1.41 ± 0.10

Change in total polyp grade

Comparison groups

EDS-Placebo v OPN-375 100 mcg v OPN-375 200 mcg v OPN-375 400 mcg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Confidence interval

Variability estimate

Standard error of the mean

Notes
[1] - Inferential statistics were derived from a mixed effect repeated measures model with visit, treatment, country, and treatment by visit interaction factors and baseline total polyp grade as covariate.

Adverse events

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Timeframe for reporting adverse events

From time of Screening until completion of the end-of open-label extension visit or an early termination visit (either during double-blind or open-label phase). SAEs were reported through 30 days after last dose of study drug administration.

Adverse event reporting additional description

Safety was assessed via typical assessment of spontaneous AE reporting on the part of the subject as well as through vital signs, protocol-defined nasal examination via nasal endoscopy by a specialist and protocol-defined ocular examination, including slit lamp exam, tonometry, and visual acuity, by an ophthalmologist.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

SAS EDC-Placebo

Reporting group description

All safety analyses were performed on the SAS, ie, those subjects in the set of subjects randomly assigned to a treatment group who received 1 or more doses of placebo or active treatment (100 µg, 200 µg, and 400 µg groups) in the double-blind treatment phase of the study. The treatment group classification in the safety analysis set is according to the treatment actually received by the subject.

Reporting group title

SAS OPN-375 100 mcg

Reporting group description

Reporting group title

SAS OPN-375 200 mcg

Reporting group description

Reporting group title

SAS OPN-375 400 mcg

Reporting group description

Reporting group title

OPN-375 400 mcg (Open-label phase)

Reporting group description

A total of 299 subjects continued in the open-label extension phase of the study during which all subjects received OPN-375 400 µg bid.

Serious adverse events	SAS EDC-Placebo	SAS OPN-375 100 mcg	SAS OPN-375 200 mcg	SAS OPN-375 400 mcg	OPN-375 400 mcg (Open-label phase)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 79 (2.53%)	0 / 80 (0.00%)	0 / 80 (0.00%)	1 / 82 (1.22%)	0 / 299 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Nervous system disorders
Vertigo positional
subjects affected / exposed	0 / 79 (0.00%)	0 / 80 (0.00%)	0 / 80 (0.00%)	1 / 82 (1.22%)	0 / 299 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Meningitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 80 (0.00%)	0 / 80 (0.00%)	0 / 82 (0.00%)	0 / 299 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 79 (1.27%)	0 / 80 (0.00%)	0 / 80 (0.00%)	0 / 82 (0.00%)	0 / 299 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	SAS EDC-Placebo	SAS OPN-375 100 mcg	SAS OPN-375 200 mcg	SAS OPN-375 400 mcg	OPN-375 400 mcg (Open-label phase)
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 79 (48.10%)	39 / 80 (48.75%)	39 / 80 (48.75%)	46 / 82 (56.10%)	60 / 299 (20.07%)
Investigations
Intraocular pressure increased
subjects affected / exposed	0 / 79 (0.00%)	1 / 80 (1.25%)	3 / 80 (3.75%)	1 / 82 (1.22%)	4 / 299 (1.34%)
occurrences all number	0	1	3	1	4
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 79 (0.00%)	2 / 80 (2.50%)	1 / 80 (1.25%)	0 / 82 (0.00%)	0 / 299 (0.00%)
occurrences all number	0	2	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 79 (3.80%)	5 / 80 (6.25%)	6 / 80 (7.50%)	6 / 82 (7.32%)	1 / 299 (0.33%)
occurrences all number	3	5	6	6	1
Gastrointestinal disorders
Toothache
subjects affected / exposed	1 / 79 (1.27%)	0 / 80 (0.00%)	0 / 80 (0.00%)	2 / 82 (2.44%)	0 / 299 (0.00%)
occurrences all number	1	0	0	2	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 79 (3.80%)	1 / 80 (1.25%)	1 / 80 (1.25%)	1 / 82 (1.22%)	0 / 299 (0.00%)
occurrences all number	3	1	1	1	0
Nasal congestion
subjects affected / exposed	2 / 79 (2.53%)	2 / 80 (2.50%)	5 / 80 (6.25%)	3 / 82 (3.66%)	2 / 299 (0.67%)
occurrences all number	2	2	5	3	2
Nasal dryness
subjects affected / exposed	0 / 79 (0.00%)	0 / 80 (0.00%)	1 / 80 (1.25%)	3 / 82 (3.66%)	1 / 299 (0.33%)
occurrences all number	0	0	1	3	1
Nasal mucosal disorder
subjects affected / exposed	2 / 79 (2.53%)	6 / 80 (7.50%)	8 / 80 (10.00%)	5 / 82 (6.10%)	6 / 299 (2.01%)
occurrences all number	2	6	8	5	6
Nasal septum disorder
subjects affected / exposed	2 / 79 (2.53%)	5 / 80 (6.25%)	4 / 80 (5.00%)	4 / 82 (4.88%)	4 / 299 (1.34%)
occurrences all number	2	5	4	4	4
Nasal septum ulceration
subjects affected / exposed	3 / 79 (3.80%)	3 / 80 (3.75%)	6 / 80 (7.50%)	8 / 82 (9.76%)	9 / 299 (3.01%)
occurrences all number	3	3	6	8	9
Epistaxis
Additional description: Identified by investigator on routine nasal endoscopy or spontaneously reported by subject.
subjects affected / exposed	4 / 79 (5.06%)	14 / 80 (17.50%)	19 / 80 (23.75%)	18 / 82 (21.95%)	26 / 299 (8.70%)
occurrences all number	4	14	19	18	26
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 79 (0.00%)	2 / 80 (2.50%)	0 / 80 (0.00%)	0 / 82 (0.00%)	0 / 299 (0.00%)
occurrences all number	0	2	0	0	0
Infections and infestations
Acute sinusitis
subjects affected / exposed	2 / 79 (2.53%)	0 / 80 (0.00%)	1 / 80 (1.25%)	0 / 82 (0.00%)	3 / 299 (1.00%)
occurrences all number	2	0	1	0	3
Bronchitis
subjects affected / exposed	2 / 79 (2.53%)	2 / 80 (2.50%)	2 / 80 (2.50%)	1 / 82 (1.22%)	3 / 299 (1.00%)
occurrences all number	2	2	2	1	3
Influenza
subjects affected / exposed	2 / 79 (2.53%)	1 / 80 (1.25%)	2 / 80 (2.50%)	2 / 82 (2.44%)	0 / 299 (0.00%)
occurrences all number	2	1	2	2	0
Nasopharyngitis
subjects affected / exposed	4 / 79 (5.06%)	2 / 80 (2.50%)	1 / 80 (1.25%)	8 / 82 (9.76%)	3 / 299 (1.00%)
occurrences all number	4	2	1	8	3
Pharyngitis
subjects affected / exposed	0 / 79 (0.00%)	2 / 80 (2.50%)	1 / 80 (1.25%)	2 / 82 (2.44%)	0 / 299 (0.00%)
occurrences all number	0	2	1	2	0
URTI
subjects affected / exposed	10 / 79 (12.66%)	4 / 80 (5.00%)	6 / 80 (7.50%)	4 / 82 (4.88%)	3 / 299 (1.00%)
occurrences all number	10	4	6	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

07 Jan 2013

The amendment included clarification for the scheduled study procedures and evaluations, in addition to clarification for the efficacy assessments for polyp grading.

07 Mar 2013

The amendment included changes to the nasoendoscopy procedures to reduce burden for the subject. Additional guidance was also added to scheduled study procedures and evaluations, and efficacy assessments.

18 Dec 2013

The amendment included additional clarification to the scheduled study procedures including the addition of the ophthalmology worksheet and change to the stratification.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Primary: Change in 7-day Average Instantaneous Morning Diary Congestion/Obstruction Symptoms

Primary: Change in 7-day Average Instantaneous Morning Diary Congestion/Obstruction Symptoms

Primary: Change in Total Polyp Grade

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