Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and
Safety Study Of Benralizumab in Patients with Severe Nasal Polyposis (OSTRO)
Summary
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EudraCT number |
2017-003675-61 |
Trial protocol |
DK AT BE HU PL DE |
Global end of trial date |
31 Jul 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Aug 2021
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First version publication date |
12 Aug 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D3252C00001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03401229 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AstraZeneca
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Sponsor organisation address |
Vastra Malarehamnen 9, Sodertalje, Sweden,
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Public contact |
AstraZeneca Information Center, AstraZeneca, +1 8002369933, information.center@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Sep 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jul 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jul 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the effect of benralizumab on nasal polyp burden and patient reported nasal blockage (NB).
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Protection of trial subjects |
This study is conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines; Applicable International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) Guidelines; Applicable laws and regulations.The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and other relevant documents (e.g. advertisements) must be submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study is initiated. Any amendments to the protocol will require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study patients. Where applicable as per relevant laws and regulations, amendments will also be submitted to, reviewed and approved by regulatory authorities/national competent authorities.
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Background therapy |
If a patient was using an alternative intranasal corticosteroids (INCS) product other than mometasone furoate nasal spray (MFNS) prior to visit 1, the Investigator would switch the INCS to MFNS at visit 1. Mometasone furoate (total daily dose of 400mcg) was required daily throughout the study. | ||
Evidence for comparator |
Placebo | ||
Actual start date of recruitment |
15 Jan 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 20
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Country: Number of subjects enrolled |
Belgium: 17
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Country: Number of subjects enrolled |
Canada: 70
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Country: Number of subjects enrolled |
Denmark: 51
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Country: Number of subjects enrolled |
Germany: 65
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Country: Number of subjects enrolled |
Hungary: 36
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Country: Number of subjects enrolled |
Poland: 73
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Country: Number of subjects enrolled |
United States: 78
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Worldwide total number of subjects |
410
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EEA total number of subjects |
262
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
351
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From 65 to 84 years |
59
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85 years and over |
0
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Recruitment
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Recruitment details |
413 participants were randomized to receive treatment in study D3250C00001 (OSTRO) with benralizumab 30 mg or placebo. Of the 413 patients randomized, 410 (99.3%) received treatment with study drug. 207 (50.5%) patients received benralizumab 30 mg and 203 (49.5%) patients received placebo | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
In OSTRO, at the first visit, ie, the enrollment visit 1, patients were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrolment, eligible patients entered a 5-week screening/run in period on a stable dose of study provided Mometasone Furoate Nasal Spray (MFNS). | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Data analyst, Assessor | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Benra 30 mg | |||||||||||||||||||||||||||
Arm description |
Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Benralizumab
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Investigational medicinal product code |
Benra
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48.
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Baseline characteristics reporting groups
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Reporting group title |
Benra 30 mg
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Reporting group description |
Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients randomized and receiving any IP irrespective of their protocol adherence and continued participation in the study. Patients are analyzed according to their randomized treatment.
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End points reporting groups
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Reporting group title |
Benra 30 mg
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Reporting group description |
Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | ||
Subject analysis set title |
Full analysis set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All patients randomized and receiving any IP irrespective of their protocol adherence and continued participation in the study. Patients are analyzed according to their randomized treatment.
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End point title |
Change from baseline in total NPS at week 40 | ||||||||||||
End point description |
Change from baseline in total nasal polyps score (NPS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The total NPS was the sum of the right and left nostril scores and maximum total NPS is 8, as evaluated by nasal endoscopy and the left and right score were based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
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End point type |
Primary
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End point timeframe |
Baseline to week 40
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Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
374
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.0001 [2] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.57
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.852 | ||||||||||||
upper limit |
-0.289 | ||||||||||||
Notes [1] - The primary analysis compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in total NPS and/or the change from baseline in NBS are similar between benralizumab and placebo. H1: Both of the change from baseline in total NPS and the change from baseline in NBS are different between benralizumab and placebo. [2] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate. Both of the co-primary endpoints were tested at 0.01 (two-sided). |
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End point title |
Change from baseline in NBS at week 40 | ||||||||||||
End point description |
Change from baseline in nasal blockage score (NBS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The NBS was captured by an item in NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0–none; 1–mild; 2–moderate; 3–severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
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End point type |
Primary
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End point timeframe |
Baseline to week 40
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Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
372
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.0048 [4] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.27
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.458 | ||||||||||||
upper limit |
-0.083 | ||||||||||||
Notes [3] - The primary analysis compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in total NPS and/or the change from baseline in NBS are similar between benralizumab and placebo. H1: Both of the change from baseline in total NPS and the change from baseline in NBS are different between benralizumab and placebo. [4] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate. Both of the co-primary endpoints were tested at 0.01 (two-sided). |
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End point title |
Change from baseline in SNOT-22 at week 40 | ||||||||||||
End point description |
Change from baseline in SinoNasal outcome test (SNOT-22) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after NP surgery and/or SCS_NP were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline to week 40
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Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
383
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | ||||||||||||
P-value |
= 0.0821 [6] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-5.212
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-11.087 | ||||||||||||
upper limit |
0.664 | ||||||||||||
Notes [5] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in SNOT-22 total score is similar between benralizumab and placebo. H1: The change from baseline in SNOT-22 total score is different between benralizumab and placebo. [6] - Since both primary endpoints were significant at significant level of 0.01 level, this endpoint was tested at significant level of 0.05. |
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End point title |
Time to first NP surgery and/or SCS use for NP up to week 56 | |||||||||
End point description |
The time to first nasal polyposis (NP) surgery and/or systemic corticosteroids (SCS) use for NP up to week 56 was calculated based on the earliest occurrence of NP surgery and/or SCS use for NP and was calculated as follows: Time to first NP surgery and/or SCS use for NP = Earlier of (Start date of first NP surgery, Start date of first SCS use for NP) – date of randomization + 1. For patients who did not experience any surgery or SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).
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End point type |
Secondary
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End point timeframe |
Baseline to week 56
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Statistical analysis title |
Cox regression | |||||||||
Statistical analysis description |
A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
410
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | |||||||||
P-value |
= 0.066 [8] | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.75
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.55 | |||||||||
upper limit |
1.02 | |||||||||
Notes [7] - This endpoint compared the rate of incidence of first NP surgery and/or SCS use for NP of benralizumab with placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio is benralizumab vs placebo and HR less than 1 indicates longer time to event [8] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value is considered nominal because test for change from baseline in SNOT-22 at week 40 was not statistically significant. |
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End point title |
Time to the first NP surgery up to week 56 | |||||||||
End point description |
The time to first nasal polyposis (NP) surgery up to week 56 was calculated based on the earliest occurrence of NP surgery and was calculated as follows: Time to first NP surgery=Start date of first NP surgery – date of randomization + 1. For patients who did not experience any surgery, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).
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End point type |
Secondary
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End point timeframe |
Baseline to week 56
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Statistical analysis title |
Cox regression | |||||||||
Statistical analysis description |
A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
410
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | |||||||||
P-value |
= 0.5008 [10] | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.85
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.53 | |||||||||
upper limit |
1.36 | |||||||||
Notes [9] - The endpoint compared the rate of incidence of first NP surgery of benralizumab with placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio (HR) is benralizumab vs placebo and HR less than 1 indicates longer time to event [10] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
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End point title |
Change from baseline in DSS at week 40 | ||||||||||||
End point description |
Change from baseline in difficulty with sense of smell (DSS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The DSS is captured by an item in the NPSD. Severity of worst difficulty with sense of smell over the past 24 hours was rated with response options: 0–none; 1–mild; 2–moderate; 3–severe. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids use for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
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End point type |
Secondary
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End point timeframe |
Baseline to week 40
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Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
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Comparison groups |
Benra 30 mg v Placebo
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Number of subjects included in analysis |
372
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Analysis specification |
Pre-specified
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Analysis type |
superiority [11] | ||||||||||||
P-value |
= 0.0029 [12] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.218
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.361 | ||||||||||||
upper limit |
-0.074 | ||||||||||||
Notes [11] - This endpoint compared the changes from baseline DSS score of benralizumab with placebo. H0: The change from baseline in DSS score is similar between benralizumab and placebo. H1: The change from baseline in DSS score is different between benralizumab and placebo. [12] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
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End point title |
Change from baseline in NPS at week 56 | ||||||||||||
End point description |
Change from baseline in total nasal polyps score (NPS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The total NPS is the sum of the right and left nostril scores, as evaluated by nasal endoscopy and the left and right score are based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
332
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [13] | ||||||||||||
P-value |
= 0.0054 [14] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.475
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.81 | ||||||||||||
upper limit |
-0.141 | ||||||||||||
Notes [13] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in NPS is similar between benralizumab and placebo. H1: The change from baseline in NPS is different between benralizumab and placebo. [14] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in NBS at week 56 | ||||||||||||
End point description |
Change from baseline in nasal blockage score (NBS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The NBS is captured by an item in the NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0–none; 1–mild; 2–moderate; 3–severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
354
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [15] | ||||||||||||
P-value |
= 0.0032 [16] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.287
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.477 | ||||||||||||
upper limit |
-0.096 | ||||||||||||
Notes [15] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in NBS is similar between benralizumab and placebo. H1: The change from baseline in NBS is different between benralizumab and placebo. [16] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in SNOT-22 at week 56 | ||||||||||||
End point description |
Change from baseline in SinoNasal outcome test (SNOT-22) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
374
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [17] | ||||||||||||
P-value |
= 0.0188 [18] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-7.492
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-13.741 | ||||||||||||
upper limit |
-1.243 | ||||||||||||
Notes [17] - This endpoint compared the changes from baseline of benralizumab with placebo. H0: The change from baseline in SNOT-22 total score is similar between benralizumab and placebo. H1: The change from baseline in SNOT-22 total score is different between benralizumab and placebo. [18] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in DSS at week 56 | ||||||||||||
End point description |
Change from baseline in difficulty with sense of smell (DSS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The DSS is captured by an item in the NPSD with response options: 0–none; 1–mild; 2–moderate; 3–severe to rate the severity of their worst difficulty with sense of smell over past 24 hours. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
354
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [19] | ||||||||||||
P-value |
= 0.0023 [20] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.237
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.389 | ||||||||||||
upper limit |
-0.084 | ||||||||||||
Notes [19] - This endpoint compared the changes from baseline DSS score of benralizumab with placebo. H0: The change from baseline in DSS score is similar between benralizumab and placebo. H1: The change from baseline in DSS score is different between benralizumab and placebo. [20] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in LMS at EOT/IPD | ||||||||||||
End point description |
Change from baseline in CT Lund Mackay Score (LMS) at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. The LMS evaluates the patency using a 0-2 scale (0‒normal; 1‒partial opacification; and 2‒total opacification) of each sinus (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, frontal sinus on each side). The osteomeatal complex is graded as 0- not occluded or 2‒occluded. The total CT score is the sum of the scores from all the sinus and ranges from 0 to 24. The analysis used the data collected after systemic corticosteroids for nasal polyposis (SCS_NP). A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to EOT/IPD
|
||||||||||||
|
|||||||||||||
Notes [21] - 92 subjects started the arm to the computed tomography (CT) subset. [22] - 90 subjects started the arm to the computed tomography (CT) subset. |
|||||||||||||
Statistical analysis title |
Change from baseline in LMS at EOT/IPD, ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following WP (WP for NP surgery), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
165
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [23] | ||||||||||||
P-value |
= 0.2375 [24] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.856
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.281 | ||||||||||||
upper limit |
0.57 | ||||||||||||
Notes [23] - This endpoint compared the changes from baseline LMS score of benralizumab with placebo. H0: The change from baseline in LMS score is similar between benralizumab and placebo. H1: The change from baseline in LMS score is different between benralizumab and placebo. [24] - Based on pre-specified testing strategy, this endpoint was not tested for statistical significance and the p-value was considered nominal. |
|
||||||||||
End point title |
Proportion of subjects with NP surgery | |||||||||
End point description |
The proportion of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline to week 56
|
|||||||||
|
||||||||||
Statistical analysis title |
CMH | |||||||||
Statistical analysis description |
The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
|
|||||||||
Comparison groups |
Benra 30 mg v Placebo
|
|||||||||
Number of subjects included in analysis |
410
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [25] | |||||||||
P-value |
= 0.5419 [26] | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.85
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.51 | |||||||||
upper limit |
1.43 | |||||||||
Notes [25] - This endpoint compared the proportion of subjects with NP surgery between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo. [26] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
||||||||||
End point title |
Proportion of subjects with SCS_NP | |||||||||
End point description |
The proportion of patients who had systemic corticosteroids (SCS) use for nasal polyposis (NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline to week 56
|
|||||||||
|
||||||||||
Statistical analysis title |
CMH | |||||||||
Statistical analysis description |
The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
|
|||||||||
Comparison groups |
Benra 30 mg v Placebo
|
|||||||||
Number of subjects included in analysis |
410
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [27] | |||||||||
P-value |
= 0.0913 [28] | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.69
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.44 | |||||||||
upper limit |
1.06 | |||||||||
Notes [27] - This endpoint compared the proportion of subjects with SCS_NP between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo. [28] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
||||||||||
End point title |
Proportion of subjects with NP surgery or SCS_NP | |||||||||
End point description |
The proportion of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran–Mantel–Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline to week 56
|
|||||||||
|
||||||||||
Statistical analysis title |
CMH | |||||||||
Statistical analysis description |
The odds ratio estimate was obtained from the Cochran-Mantel-Haenszel test controlling for region (US/non-US) and baseline comorbid asthma status.
|
|||||||||
Comparison groups |
Benra 30 mg v Placebo
|
|||||||||
Number of subjects included in analysis |
410
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [29] | |||||||||
P-value |
= 0.0362 [30] | |||||||||
Method |
Cochran-Mantel-Haenszel | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.65
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.44 | |||||||||
upper limit |
0.97 | |||||||||
Notes [29] - This endpoint compared the proportion of subjects with NP surgery or SCS_NP between benralizumab and placebo. H0: The proportion is similar between benralizumab and placebo. H1: The proportion is different between benralizumab and placebo. [30] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
||||||||||
End point title |
Time to first SCS_NP up to week 56 | |||||||||
End point description |
The time to first systemic corticosteroids for use for nasal polyposis (SCS_NP) up to week 56 was calculated based on the earliest occurrence of SCS_ NP and was calculated as follows: Time to first SCS_NP = Earlier of (Start date of first SCS use for NP) – date of randomization + 1. For patients who did not experience any SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation). The time to first SCS use for NP surgery was analyzed using a Cox proportional hazard model with treatment arm, region (US vs non-US) and baseline comorbid asthma status (yes vs no) as covariates. A hazard ratio less than 1 indicates a lower rate of incidence for subjects on benra.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline week 56
|
|||||||||
|
||||||||||
Statistical analysis title |
Cox Regression | |||||||||
Statistical analysis description |
A Cox proportional hazards model including covariates treatment group, region (US/Non-US) and baseline comorbid asthma status.
|
|||||||||
Comparison groups |
Benra 30 mg v Placebo
|
|||||||||
Number of subjects included in analysis |
410
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority [31] | |||||||||
P-value |
= 0.1505 [32] | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.77
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.53 | |||||||||
upper limit |
1.1 | |||||||||
Notes [31] - The endpoint compared the rate of incidence of SCS_NP use between benralizumab and placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Hazard ratio (HR) is benralizumab vs placebo and HR less than 1 indicates longer time to event [32] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Total number of courses of SCS for NP | ||||||||||||
End point description |
The total number of courses of systemic corticosteroids (SCS) use for nasal polyposis (NP) was summarized using descriptive statistics.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total SCS_NP dose (a) used (mg) | ||||||||||||
End point description |
The total systemic corticosteroids (SCS) for nasal polyposis (NP) dose used (mg) was summarized using descriptive statistics.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Notes [33] - Data reported include an outlier with an incorrect dose of betamethasone of 500mg instead of 0.5mg |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total duration of SCS_NP (days) | ||||||||||||
End point description |
The total duration of systemic corticosteroids (SCS) for nasal polyposis (NP) in days was summarized using descriptive statistics.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Annual SCS_NP use rate comparison by period, negative binomial model | ||||||||||||
End point description |
Annual systemic corticosteroids for nasal polyposis (SCS_NP) use rate =365.25×total number of courses of SCS_NP /total duration of follow-up within the treatment group (days). The estimated annual event rates, absolute differences, rate ratio and the corresponding confidence interval were based on a negative binomial model including covariates treatment group, region (US/non-US) and prior use of SCS_NP with total number of courses of SCS_NP as the outcome and the log of each subject’s corresponding follow-up time up to week 56 as an offset variable in the model to adjust for subject’s having different exposure times during which the events occur.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Negative binomial model | ||||||||||||
Statistical analysis description |
Model included treatment, US/non-US and prior use of SCS_NP with total number of courses of SCS_NP as outcome and log of follow-up time as an offset
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
410
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [34] | ||||||||||||
P-value |
= 0.2189 [35] | ||||||||||||
Method |
Negative Bionomial Model | ||||||||||||
Parameter type |
Rate Ratio | ||||||||||||
Point estimate |
0.79
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.54 | ||||||||||||
upper limit |
1.15 | ||||||||||||
Notes [34] - The endpoint compared the rate of SCS_NP use between benralizumab and placebo. H0: The rate is similar between benralizumab and placebo. H1: the rate is different between benralizumab and placebo. Rate ratio is benralizumab vs placebo and Rate ratio less than 1 indicates less likely of SCS_NP use. [35] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in TSS at week 40 | ||||||||||||
End point description |
Change from baseline in total symptom score (TSS) at week 40 was defined as the endpoint at week 40 minus baseline value. The TSS is defined as sum of first 8 NPSD components. Severity of each nasal symptoms over the past 24 hours is rated using response options: 0–none; 1–mild; 2–moderate; 3–severe. The TSS and the change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily TSS responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 40
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
372
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [36] | ||||||||||||
P-value |
= 0.0036 [37] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
-1.854
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-3.101 | ||||||||||||
upper limit |
-0.608 | ||||||||||||
Notes [36] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [37] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in difficulty with sleeping due to nasal symptoms at week 40 | ||||||||||||
End point description |
Change from baseline in difficulty with sleeping due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with sleeping due to nasal symptoms over past 24 hours was rated using options: 0–none; 1–mild; 2–moderate; 3–severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 40
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
372
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [38] | ||||||||||||
P-value |
= 0.0941 [39] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.166
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.36 | ||||||||||||
upper limit |
0.028 | ||||||||||||
Notes [38] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [39] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in difficulty with daily activities due to nasal symptoms at week 40 | ||||||||||||
End point description |
Change from baseline in difficulty with daily activities due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with daily activities due to nasal symptoms over the past 24 hours was rated using options: 0–none; 1–mild; 2–moderate; 3–severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was average of daily responses from Day ‒13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 40
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
372
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [40] | ||||||||||||
P-value |
= 0.0246 [41] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-0.213
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.399 | ||||||||||||
upper limit |
-0.027 | ||||||||||||
Notes [40] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [41] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in UPSIT score in males at week 40 | ||||||||||||
End point description |
Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores were based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 40
|
||||||||||||
|
|||||||||||||
Notes [42] - This analysis only includes Male. [43] - This analysis only includes Female. |
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
198
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [44] | ||||||||||||
P-value |
= 0.5833 [45] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
0.672
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.73 | ||||||||||||
upper limit |
3.074 | ||||||||||||
Notes [44] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [45] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in UPSIT score in females at week 40 | ||||||||||||
End point description |
Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores are based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 40
|
||||||||||||
|
|||||||||||||
Notes [46] - This analysis only includes females. [47] - This analysis only includes females. |
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
ANCOVA following hybrid WP/WOCF and MI (assuming MAR), adjusting for treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
127
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [48] | ||||||||||||
P-value |
= 0.0619 [49] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
2.684
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.134 | ||||||||||||
upper limit |
5.502 | ||||||||||||
Notes [48] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [49] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in sinus severity score at EOT/IPD | ||||||||||||
End point description |
Change from baseline in sinus severity score at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. Quantitative assessment of sinus CT image data was used to derive an objective measure of sinus disease burden called sinus severity score. The sinus severity score is defined as (sinus mucosal volume)/(sinus mucosal volume + sinus air volume)×100. A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place. In calculation of summary statistics (mean and standard deviation), the WP for NP surgery rescued subjects was applied. In ANCOVA, following WP (WP for NP surgery rescued subjects), model included treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to EOT/IPD
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
ANCOVA | ||||||||||||
Statistical analysis description |
Following WP (WP for NP surgery rescued subjects), model included treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status
|
||||||||||||
Comparison groups |
Benra 30 mg v Placebo
|
||||||||||||
Number of subjects included in analysis |
170
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [50] | ||||||||||||
P-value |
= 0.102 [51] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
-5.057
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-11.129 | ||||||||||||
upper limit |
1.015 | ||||||||||||
Notes [50] - This endpoint compared the changes from baseline score between benralizumab and placebo. H0: The change from baseline score is similar between benralizumab and placebo. H1: The change from baseline score is different between benralizumab and placebo. [51] - This endpoint was not a part of the pre-specified testing strategy and was not tested for statistical significance. The p-value was considered nominal. |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 physical component summary at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 physical component summary (PCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. PCS score is computed from 8 subscale scores to give a broader metric of physical health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 mental component summary at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 mental component summary (MCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. MCS score is computed from 8 subscale scores to give a broader metric of mental health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 physical functioning at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 physical functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Physical functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 role limitations due to physical health at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 role limitations due to physical health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to physical health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 bodily pain at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 bodily pain score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Bodily pain is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 general health perceptions at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 general health perceptions score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. General health perceptions is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing are excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 vitality at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 vitality score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Vitality is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 social functioning at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 social functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 are used to compute an 8-domain profile of functional health and well-being scores. Social functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 role limitations due to emotional problems at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 role limitations due to emotional problems score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to emotional problems is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change from baseline in SF-36v2 mental health at week 56 | ||||||||||||
End point description |
Change from baseline in SF-36v2 mental health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Mental health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued subjects whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to week 56
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From first dose of study drug until last study visit
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Benra 30 mg
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Reporting group description |
Benra administered every 4 weeks for the first 3 doses - Weeks 0, 4 and 8 and every 8 weeks thereafter - Weeks 16, 24, 32, 40 and 48. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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25 Apr 2018 |
Amended inclusion criterion 1 to highlight that nasal polyposis score (NPS) from V2 will be a randomization criterion. Amended to change the requirement for patients being on a stable dose of study provided intranasal corticosteroids (INCS) for 4 weeks prior to randomization to 4 weeks prior to V2. Information about Mometasone Furoate Nasal Spray (MFNS) intolerance was added. Additionally, information about systemic corticosteroids (SCS) intake during screening period and possible extension was added. Amended inclusion criterion 5 to include the requirement of 4 weeks of INCS intake prior V1. Updated Male contraception requirements in inclusion criterion 15. Amended exclusion criterion from 6 months to 3 months. Amended exclusion criterion 5 for asthma exacerbation asthma requiring systemic corticosteroids treatment or hospitalization for treatment asthma from 3 months to 4 weeks prior to V1. Amended exclusion criteria 16 to remove usage of SCS for condition other than short course of NP. Amended exclusion 17 to change the time period for previous use of biologic products from 4 to 6 months and to allow previous use of mepolizumab, reslizumab and dupliumab. Amended exclusion criterion 22 to change the time period for SCS intake from 2 months to 4 weeks prior V1. Note about sustained release steroids or depot injections was added. Amended to allow extension of the screening period and to clarify in which cases re-screening is allowed. Additionally, it was highlighted that patient can be considered for re-screening once under the specific conditions. Amended to remove Information that if patient experienced an asthma exacerbation and/or use of SCS during the screening, he/she should be screen failed. |
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20 Sep 2019 |
Updated of minimum observed mean difference that would be statistically significant at the two-sided alpha 0.05 level from -0.52 to -0.39 in total NPS and from ‒0.26 to –0.20 in nasal blockage score (NBS). Original critical values for two-sided alpha 0.01 level also included. The statistical methods were amended to add 2 endpoints, change from baseline in University of Pennsylvania smell identification test (UPSIT) score and time to nasal polyposis (NP) surgery and/or SCS use, to the multiplicity testing strategy and to update the power value from 95% to 99% and alpha level from 0.01 to 0.05. Amended to clarify disease under study definition and reporting criteria for adverse events. Amended to specify the estimate of the treatment effect at week 56 for SNOT-22 and UPSIT score for the analyses of key secondary endpoints was based on contrasts from the respective mixed-effects model for repeated measures (MMRM) models. |
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31 Jul 2020 |
Note: The actual protocol amendment date is 05-Aug-2020. The 31-Jul-2020 is the global end of trail date. Multiple changes were made to align the CSP with the amended SAP. These changes include changing the timepoint of primary analysis to week 40, updating the list of key secondary endpoints, updating the primary estimand, reverting power and type I error rate, updating model specification to ANCOVA, and adding a subgroup. Added total symptom score (TSS) as sum of first 8 items of nasal polyposis symptom scores diary (NPSD). Updated language of inclusion in extended follow-up (EFU) period for clarity. Added information about analysis of baseline PK samples and on-treatment PK samples. “A limited number of exploratory biomarkers may be reported in the CSR. Details regarding analyses can be found in the SAP. Any remaining exploratory biomarkers will be reported outside of the CSR.” - wording has been added. Additional text regarding Study Conduct Mitigation During evolving SARS-CoV-2 (COVID-19) pandemic or other study disruption has been added to maintain the conduct of study-related activities during crisis, while securing data integrity and patient safety. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
During COVID-19 pandemic, for ongoing patients, patient dosing, scheduled visits, and nasal endoscopies are inevitable impacted. Week 40 was made as the primary timepoint to mitigate the impact of COVID disruptions on the primary endpoint. |