Clinical Trial Results:
A Randomized, Double-blind, 52-week, Placebo Controlled Efficacy and Safety Study of Dupilumab, in Patients with Bilateral Nasal Polyposis on a Background Therapy with Intranasal Corticosteroids
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Summary
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EudraCT number |
2015-001314-10 |
Trial protocol |
SE PT ES BE |
Global end of trial date |
16 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Nov 2019
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First version publication date |
29 Nov 2019
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Other versions |
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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 |
EFC14280
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02898454 | ||
WHO universal trial number (UTN) |
U1111-1170-7180 | ||
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Sponsors
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Sponsor organisation name |
Sanofi
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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 Feb 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Nov 2018
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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 efficacy of dupilumab 300 milligram (mg) every 2 weeks (q2w) compared to placebo on a background of mometasone furoate nasal spray (MFNS) in reducing nasal congestion (NC)/obstruction severity and endoscopic nasal polyposis score (NPS) in subjects with bilateral nasal polyposis (NP). In addition for Japanese subjects, reduction in computed tomography (CT) scan opacification of the sinuses was a co-primary objective.
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency.
Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Nov 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Argentina: 36
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Country: Number of subjects enrolled |
Australia: 29
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Country: Number of subjects enrolled |
Canada: 34
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Country: Number of subjects enrolled |
Chile: 80
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Country: Number of subjects enrolled |
Israel: 14
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Country: Number of subjects enrolled |
Japan: 49
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Country: Number of subjects enrolled |
Mexico: 21
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Country: Number of subjects enrolled |
Russian Federation: 21
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Country: Number of subjects enrolled |
Turkey: 22
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Country: Number of subjects enrolled |
United States: 55
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Country: Number of subjects enrolled |
Portugal: 34
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Country: Number of subjects enrolled |
Spain: 21
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Country: Number of subjects enrolled |
Sweden: 5
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Country: Number of subjects enrolled |
Belgium: 27
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Worldwide total number of subjects |
448
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EEA total number of subjects |
87
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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) |
367
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From 65 to 84 years |
81
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85 years and over |
0
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Recruitment
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Recruitment details |
Study subjects were involved in the study from 28 November 2016 to 16 November 2018 at 117centres in 14 countries. A total of 806 subjects were screened, of which 448 subjects were enrolled and randomised to receive dupilumab 300 mg or placebo. A total of 358 subjects had screen failures due to failure to meet inclusion criteria. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Randomisation was stratified according to asthma and/or non-steroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD) history (yes/no), prior nasal polyps (NP) surgery (yes or not), and country. | ||||||||||||||||||||||||||||||||||||||||||||||||
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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, Carer, Assessor | ||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Placebo (for dupilumab), 1 subcutaneous (SC) injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo (matched to dupilumab 300 mg)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2 millilitre (mL), SC injection, q2w using a prefilled syringe for 52 weeks.
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Arm title
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Dupilumab 300 mg q2w Then q4w | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg every 4 weeks (q4w) until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, dupilumab administration was alternated with matched placebo injection every other week up to Week 50. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dupilumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2 mL, SC injection q2w using a prefilled syringe for 24 weeks and then q4w until 52 weeks.
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Arm title
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Dupilumab 300 mg q2w | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Dupilumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
2 mL, SC injection once q2w using a prefilled syringe for 52 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo (for dupilumab), 1 subcutaneous (SC) injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab 300 mg q2w Then q4w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg every 4 weeks (q4w) until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, dupilumab administration was alternated with matched placebo injection every other week up to Week 50. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab 300 mg q2w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo (for dupilumab), 1 subcutaneous (SC) injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||
Reporting group title |
Dupilumab 300 mg q2w Then q4w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg every 4 weeks (q4w) until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, dupilumab administration was alternated with matched placebo injection every other week up to Week 50. | ||
Reporting group title |
Dupilumab 300 mg q2w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. | ||
Subject analysis set title |
Dupilumab 300 mg (24 Weeks Pooled Arm)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Pooled arm consisted of all subjects from both dupilumab treatment arms up to 24 weeks as both arms to this time point used the 300 mg q2w regimen.
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Subject analysis set title |
Dupilumab 300 mg q2w Then q4w
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg q4w until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, dupilumab administration was alternated with matched placebo injection every other week up to Week 50. One subject randomised to dupilumab 300 mg q2w arm received 1 dose of placebo and was therefore counted in the 300 mg q2w then q4w arm.
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Subject analysis set title |
Dupilumab 300 mg q2w Then q4w
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg q4w until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, dupilumab administration was alternated with matched placebo injection every other week up to Week 50. Two subjects randomised to placebo arm accidently received 1 dose of dupilumab 300 mg and therefore counted in the 300 mg q2w then q4w arm. Similarly one subject randomised to the dupilumab 300 mg q2w arm received 1 dose of placebo and was therefore counted in the 300 mg q2w then q4w arm.
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Subject analysis set title |
Dupilumab 300 mg (Pooled Arm)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Pooled arm consisted of all subjects who either received Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 52 or Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg q4w until Week 52, added to background therapy of intranasal MFNS at stable dose.
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End point title |
Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score [1] | ||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Least squares (LS) means and standard error (SE) were obtained from Analysis of covariance (ANCOVA) model described in Statistical Analysis Overview. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. The analysis was performed on intent-to-treat (ITT) population which included all randomised subjects who were analysed according to the treatment group allocated by randomisation. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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| Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
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Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data was analysed using a hybrid method of the worst-observation carried forward (WOCF) and multiple imputation (MI). The imputed completed data were analysed by fitting ANCOVA model with the corresponding baseline, treatment group, asthma/NASID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
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Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
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Number of subjects included in analysis |
448
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-0.87
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.03 | ||||||||||||
upper limit |
-0.71 | ||||||||||||
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End point title |
Change From Baseline at Week 24 in Nasal Polyp Score [2] | ||||||||||||
End point description |
NPS: sum of right, left nostril scores, evaluated by nasal endoscopy. For each nostril, NPS was graded based on polyp size from 0 = no polyps to 4 = large polyps causing complete obstruction of inferior nasal cavity; lower score = smaller sized polyps. Total NPS: sum of right and left nostril scores, ranges from 0 (no polyps) to 8 (large polyps), higher score = more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point. Data for this end point measure was planned to be analysed for the combined population of subjects who received Dupilumab.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
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Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin’s rule.
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Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
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Number of subjects included in analysis |
446
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-1.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2.1 | ||||||||||||
upper limit |
-1.51 | ||||||||||||
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End point title |
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay (LMK) Score [3] | ||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. NOTE: For Japan regulatory submission only, this endpoint is not included as a secondary end point and is instead one of the co-primary end points. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
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Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
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Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
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Number of subjects included in analysis |
439
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
< 0.0001 [5] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-5.13
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-5.8 | ||||||||||||
upper limit |
-4.46 | ||||||||||||
| Notes [4] - Hierarchical testing procedure was used to control type I error. For regions outside of Japan, this first secondary endpoint was not tested unless both co-primary endpoints were significant at the 0.05 level. Hierarchical testing continued only when previous endpoint was statistically significant. For Japan submission, LMK was instead a co-primary endpoint which also had to be met before secondary endpoints were tested in the hierarchy. Last endpoint in hierarchy is Week 52 SNOT-22. [5] - Threshold for significance at 0.05 level. |
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End point title |
Change From Baseline at Week 24 in Total Symptom Score (TSS) [6] | ||||||||||||
End point description |
The TSS was the sum of subject-assessed nasal symptom scores for NC/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). Total score ranged from 0 (no symptoms) to 9 (severe symptoms). Higher score indicated more severe symptoms. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
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|||||||||||||
Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||
Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
|
||||||||||||
Number of subjects included in analysis |
448
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [7] | ||||||||||||
P-value |
< 0.0001 [8] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-2.44
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.87 | ||||||||||||
upper limit |
-2.02 | ||||||||||||
| Notes [7] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [8] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in the University of Pennsylvania Smell Identification Test (UPSIT) Score [9] | ||||||||||||
End point description |
The UPSIT was a 40-item test to measure the individual’s ability to detect odors. Total score ranges from 0 (anosmia) to 40 (normal sense of smell), lower score indicated severe smell loss. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||
Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
|
||||||||||||
Number of subjects included in analysis |
437
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [10] | ||||||||||||
P-value |
< 0.0001 [11] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
10.52
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
8.98 | ||||||||||||
upper limit |
12.07 | ||||||||||||
| Notes [10] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [11] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Severity of Decreased/Loss of Smell as Assessed by Subject Daily [12] | ||||||||||||
End point description |
The severity of decreased/loss of sense of smell was reported by the subjects using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), higher score indicated more severe symptoms. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All subjects randomised to receive dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||
Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
|
||||||||||||
Number of subjects included in analysis |
448
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [13] | ||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-0.98
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.15 | ||||||||||||
upper limit |
-0.81 | ||||||||||||
| Notes [13] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [14] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in 22-item Sino-nasal Outcome Test (SNOT-22) Scores [15] | ||||||||||||
End point description |
The SNOT-22 is a validated questionnaire was used to assess the impact of chronic rhinosinusitis phenotype with nasal polyps (CRSwNP) on health-related quality of life (HRQoL). It is a 22 item questionnaire with each item assigned a score ranging from 0 (no problem) to 5 (problem as bad as it can be). The total score may range from 0 (no disease) to 110 (worst disease), lower scores representing better health related quality of life. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All subjects randomised to receive dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Dupilumab 300 mg (Pooled Arm) versus Placebo | ||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||
Comparison groups |
Placebo v Dupilumab 300 mg (24 Weeks Pooled Arm)
|
||||||||||||
Number of subjects included in analysis |
444
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [16] | ||||||||||||
P-value |
< 0.0001 [17] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-17.36
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-20.87 | ||||||||||||
upper limit |
-13.85 | ||||||||||||
| Notes [16] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [17] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Polyp Score | ||||||||||||||||
End point description |
NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded based on polyp size from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. Analysis was performed on ITT population. Here, "number of subjects analysed"= subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w Then q4w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w Then q4w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
297
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [18] | ||||||||||||||||
P-value |
< 0.0001 [19] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-2.21
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.59 | ||||||||||||||||
upper limit |
-1.83 | ||||||||||||||||
| Notes [18] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [19] - Threshold for significance at 0.05 level. |
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
301
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [20] | ||||||||||||||||
P-value |
< 0.0001 [21] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-2.41
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.78 | ||||||||||||||||
upper limit |
-2.03 | ||||||||||||||||
| Notes [20] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [21] - Threshold for significance at 0.05 level. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Congestion/Obstruction Symptom Severity Score | ||||||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w Then q4w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w Then q4w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
298
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [22] | ||||||||||||||||
P-value |
< 0.0001 [23] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-1.11
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-1.3 | ||||||||||||||||
upper limit |
-0.92 | ||||||||||||||||
| Notes [22] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [23] - Threshold for significance at 0.05 level. |
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
303
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [24] | ||||||||||||||||
P-value |
< 0.0001 [25] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-0.99
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-1.18 | ||||||||||||||||
upper limit |
-0.8 | ||||||||||||||||
| Notes [24] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [25] - Threshold for significance at 0.05 level. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in 22-item Sino-nasal Outcome Test Scores | ||||||||||||||||
End point description |
The SNOT-22 is a validated questionnaire that was used to assess the impact of CRSwNP on HRQoL. It is a 22 item questionnaire with each item assigned a score ranging from 0 (no problem) to 5 (problem as bad as it can be). The total score may range from 0 (no disease) to 110 (worst disease), lower scores representing better health related quality of life. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w Then q4w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w Then q4w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
297
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [26] | ||||||||||||||||
P-value |
< 0.0001 [27] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-21.36
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-25.45 | ||||||||||||||||
upper limit |
-17.27 | ||||||||||||||||
| Notes [26] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [27] - Threshold for significance at 0.05 level. |
|||||||||||||||||
Statistical analysis title |
Dupilumab 300 mg q2w versus Placebo | ||||||||||||||||
Statistical analysis description |
Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Statistical inference obtained from all imputed data was combined using Rubin's rule.
|
||||||||||||||||
Comparison groups |
Dupilumab 300 mg q2w v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
299
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority [28] | ||||||||||||||||
P-value |
< 0.0001 [29] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||
Point estimate |
-20.73
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-24.81 | ||||||||||||||||
upper limit |
-16.65 | ||||||||||||||||
| Notes [28] - Testing according to the hierarchical testing procedure (only performed if previous end points were statistically significant). [29] - Threshold for significance at 0.05 level. |
|||||||||||||||||
|
|||||||||||||||||||
End point title |
Rescue Treatment Use: Estimate of Percentage of Subjects With Greater than or Equal to (>=) 1 Event by Week 52 Obtained Using Kaplan-Meier Method [30] | ||||||||||||||||||
End point description |
Rescue treatment was defined as usage of systemic corticosteroids (SCS) or NP surgery (actual or planned) during the treatment period. Rescue treatment included:
• SCS: betamethasone, deflazacort, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, meprednisone, methylprednisolone, methylprednisolone sodium succinate, prednisolone, prednisolone sodium succinate, prednisone, stelamin, triamcinolone, and triamcinolone acetonide.
• Sino-nasal surgery for nasal polyps when there was worsening of signs and/or symptoms during the study.
Estimate of percentage of subjects with event by Week 24 was obtained using Kaplan-Meier method.
Analysis was performed on ITT population. Data for this end point was planned to be collected and analysed for the pooled population of subjects receiving Dupilumab.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline up to 52 weeks
|
||||||||||||||||||
| Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Total Symptom Score | ||||||||||||||||
End point description |
The TSS was the sum of subject-assessed nasal symptom scores for NC/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0-3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms). Total score ranged from 0 (no symptoms) to 9 (severe symptoms). Higher score indicated more severe symptoms. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in the University of Pennsylvania Smell Identification Test Score | ||||||||||||||||
End point description |
The UPSIT was a 40-item test to measure the individual’s ability to detect odors. Total score ranges from 0 (anosmia) to 40 (normal sense of smell), lower score indicated severe smell loss. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Severity of Decreased/Loss of Smell | ||||||||||||||||
End point description |
The severity of decreased/loss of sense of smell was reported by the subjects using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), higher score indicated more severe symptoms. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Opacification of Sinuses Measured by Lund-Mackay Score | ||||||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Visual Analogue Scale (VAS) for Rhinosinusitis [31] | ||||||||||||
End point description |
The VAS for rhinosinusitis was used to evaluate the total disease severity. Subjects were asked to indicate on a 10 centimetres VAS the answer to the question, “How troublesome are your symptoms of your rhinosinusitis?” The range of VAS was from 0 (not troublesome) to 10 (worse thinkable troublesome), where higher score indicated worse thinkable troublesome. Data was analysed using a hybrid method of WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Visual Analogue Scale for Rhinosinusitis | ||||||||||||||||
End point description |
The VAS for rhinosinusitis was used to evaluate the total disease severity. The subjects were asked to indicate on a 10 centimetres VAS the answer to the question, “How troublesome are your symptoms of your rhinosinusitis?” The range of the VAS was from 0 (not troublesome) to 10 (worse thinkable troublesome), where higher score indicated worse thinkable troublesome. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Nasal Peak Inspiratory Flow (NPIF) [32] | ||||||||||||
End point description |
NPIF evaluation represented a physiologic measure of the air flow through both nasal cavities during forced inspiration expressed in litres per minute. Higher NPIF values were indicative of better nasal air flow. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Data for this end point was planned to be analysed for the combined population of subjects who received dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Rhinorrhea Daily Symptom Score [33] | ||||||||||||
End point description |
Rhinorrhea was reported by the subjects using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), where higher scores indicated more severe symptoms. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Rhinorrhea Daily Symptom Score | ||||||||||||||||
End point description |
Rhinorrhea was reported by the subjects using a 0 to 3 categorical scale (where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms), where higher scores indicated more severe symptoms. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Mean Total Systemic Corticosteroids Rescue Dose Prescribed During Treatment Period | ||||||||||||||||
End point description |
SCS included: Betamethasone, deflazacort, dexamethasone, dexamethasone sodium phosphate, hydrocortisone, meprednisone, methylprednisolone, methylprednisolone sodium succinate, prednisolone, prednisolone sodium succinate, prednisone, stelamin, triamcinolone, and triamcinolone acetonide. For every subject, the total dose was calculated as (prescribed total daily dose*duration of SCS use). Then, mean of the total dose of 64 subjects (placebo group), 17 subjects (dupilumab 300 mg q2w then q4w) and 22 subjects (dupilumab 300 mg q2w) was derived. The analysis was performed on ITT population. Here, “number of subjects analysed” = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Total Systemic Corticosteroids Rescue Intake Duration: Average Duration Per Subject | ||||||||||||||||
End point description |
Rescue treatment was defined as usage of SCS or NP surgery (actual or planned) during the treatment period. SCS Rescue intake duration was defined as the duration (in days) from start of SCS rescue medication till the end of SCS rescue treatment. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline to Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Changed From Baseline at Week 24 in Forced Expiratory Volume in 1 Second (FEV1) for Subjects With Asthma [34] | ||||||||||||
End point description |
FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, prior surgery history, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point. Data for this end point was planned to be analysed for the combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Forced Expiratory Volume in 1 Second for Subjects With Asthma | ||||||||||||||||
End point description |
FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Asthma Control Questionnaire-6 (ACQ-6) for Subjects With Asthma [35] | ||||||||||||
End point description |
ACQ-6:6 questions to assess common asthma symptoms (woken by asthma, symptoms on waking, activity limitation, shortness of breath, wheezing, puffs/inhalations use). Subjects respond to asthma symptom questions on 7-point scale (range0 = no impairment to 6 = maximum impairment. ACQ-6 score was mean of all 6 questions scores; range0 (totally controlled) to 6 (severely uncontrolled), higher scores = low asthma control. Data analysed using hybrid method of WOCF and MI. The imputed completed data analysed by an ANCOVA model with corresponding baseline value, treatment, asthma status, prior surgery history and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24;analysed as pooled population for Week 24 assessments. Analysis performed on subset of subjects included all randomised subjects with asthma, had available data for this end point. Data was planned to be analysed for combined population of subjects who received Dupilumab.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Asthma Control Questionnaire-6 for Subjects With Asthma | ||||||||||||||||
End point description |
ACQ-6 had 6 questions which assessed the most common asthma symptoms (woken by asthma, symptoms on waking, activity limitation, shortness of breath, wheezing, puffs/inhalations use). Subjects were asked to recall how their asthma had been during the previous week and to respond to the symptom questions on a 7-point scale ranged from 0 = no impairment to 6 = maximum impairment. The ACQ-6 score was the mean of the scores of all 6 questions and therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), with higher scores indicated lower asthma control. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment, asthma status, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with Asthma and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score: Subgroup of Subjects With Asthma [36] | ||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with asthma.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Congestion/Obstruction Symptom Severity Score: Subgroup of Subjects With Asthma | ||||||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score: Subgroup of Subjects With Prior Nasal Polyp Surgery [37] | ||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting ANCOVA model with corresponding baseline, treatment group, prior surgery history, and regions as covariates. All subjects randomised to receive dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Congestion/Obstruction Symptom Severity Score: Subgroup of Subjects With Prior Nasal Polyp Surgery | ||||||||||||||||
End point description |
NC symptom severity was assessed by the subjects on a daily basis from Visit 1 and throughout the study using an e-diary on a scale of 0 to 3, where 0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms and 3 = severe symptoms, with higher scores indicated more severity. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Asthma [38] | ||||||||||||
End point description |
NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Polyp Score: Subgroup of Subjects With Asthma | ||||||||||||||||
End point description |
NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Nasal Polyp Score: Subgroup of Subjects With Prior Nasal Polyp Surgery [39] | ||||||||||||
End point description |
NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history and had available data for this end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Nasal Polyp Score: Subgroup of Subjects With Prior Nasal Polyp Surgery | ||||||||||||||||
End point description |
NPS was the sum of right and left nostril scores, as evaluated by means of nasal endoscopy. For each nostril, NPS was graded from 0 to 4 (0 = no polyps to 4 = large polyps causing complete obstruction of the inferior nasal cavity), with a lower score indicating smaller-sized polyps. Total NPS was the sum of right and left nostril scores and ranges from 0 (no polyp) to 8 (large polyp), with highest score representing more severe disease. NPS was assessed by centralised, blinded, independent review of the nasal endoscopy video recordings. Data were analysed using a hybrid method of the WOCF and MI. LS mean and SE were obtained from ANCOVA model. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Asthma [40] | ||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. All subjects randomised to receive dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Asthma | ||||||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data was analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NSAID-ERD status, prior surgery history, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with asthma and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Prior Nasal Surgery [41] | ||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates. All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history and had available data for this end point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
| Notes [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline at Week 52 in Opacification of Sinuses Measured by Lund Mackay Score: Subgroup of Subjects With Prior Nasal Polyp Surgery | ||||||||||||||||
End point description |
The LMK scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses using following grading: 0 = normal, 1 = partial opacification, 2 = total opacification. The total score was the sum of scores from each side and ranges from 0 (normal) to 24 (more opacified); higher score indicated more severe disease. Data were analysed using a hybrid method of the WOCF and MI. The imputed completed data were analysed by fitting an ANCOVA model with corresponding baseline, treatment group, asthma/NSAID-ERD status, and regions as covariates. Analysis was performed on a subset of subjects which included all randomised subjects with prior NP surgery history and had available data for this end point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Week 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and TEAEs Leading to Treatment Discontinuation [42] | ||||||||||||||||||||||||||||||||
End point description |
An Adverse Event (AE) was defined as any untoward medical occurrence that did not necessarily have to have a causal relationship with the study treatment. TEAEs were defined as AEs that developed or worsened in grade or became serious during TEAE period which was defined as the period from the time of first dose of drug until 84 days following the last administration of drug. SAE was defined as any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event. Analysis was performed on safety population which included all subjects who received at least 1 dose or part of a dose of the investigational medicinal product (IMP), analysed according to the treatment actually received.
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End point type |
Secondary
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End point timeframe |
Baseline up to 84 days after last dose of study drug (up to 64 weeks)
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| Notes [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Dupilumab 300 mg q2w Then q4w arm is included in the form of subject analysis set. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline at Week 24 in European Quality of Life 5 Dimension Scale (EQ-5D) Visual Analog Scale Score [43] | ||||||||||||
End point description |
The EQ-5D was a standardized HRQoL questionnaire consisting of EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. EQ VAS recorded the subject’s self-rated health on a vertical VAS that allowed them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable). All subjects randomised to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analysed as a pooled population for Week 24 assessments. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point. Data for this end point planned to be analysed for the combined population of subjects who received Dupilumab.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Analysis was performed on pooled dupilumab arm. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline at Week 52 in European Quality of Life 5 Dimension Scale Visual Analog Scale Score | ||||||||||||||||
End point description |
The EQ-5D was a standardized HRQoL questionnaire consisting of EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. EQ VAS recorded the subject’s self-rated health on a vertical VAS that allowed them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable). Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this end point.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Functional Dupilumab Concentration in Serum [44] | ||||||||||||||||||||||||||||||||||||
End point description |
Analysis performed on pharmacokinetics population which included all subjects who received at least 1 dose of IMP with at least 1 evaluable functional dupilumab concentration result. Here, ‘n’ = number of subjects with available data for each time point. Data for this end point was not planned to be collected and analysed for placebo. One subject randomised to dupilumab 300 mg q2w arm received 1 dose of placebo and was therefore counted in the 300 mg q2w then q4w arm.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 2, Week 4, Week 16, Week 24, Week 40, End of treatment (Week 52), End of study (Week 64)
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| Notes [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is not analysed for placebo. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With Treatment-Emergent And Treatment-Boosted Anti-drug Antibodies (ADA) Response [45] | ||||||||||||||||||||||||
End point description |
ADA response were categorised as: treatment emergent and treatment boosted response. 1) Treatment emergent was defined as a positive response in the ADA assay post first dose, when baseline results are negative or missing. 2) Treatment boosted was defined as: an ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over baseline titer levels, when baseline results are positive. The analysis was performed on ADA population which included subjects who received at least 1 dose of IMP with at least one evaluable ADA serum sample that was assayed successfully in the ADA assay (either ‘ADA negative’ or ‘ADA positive’) following the first dose of the study medication. Two subjects randomised to placebo arm accidently received 1 dose of dupilumab 300 mg and therefore counted in the 300 mg q2w then q4w arm. One subject randomised to the dupilumab 300 mg q2w arm received 1 dose of placebo and was therefore counted in the 300 mg q2w then q4w arm.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 52
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| Notes [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Dupilumab 300 mg q2w Then q4w arm is included in the form of subject analysis set. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All AEs were collected from signature of the informed consent form up to 64 weeks regardless of seriousness or relationship to investigational product.
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Adverse event reporting additional description |
Reported AEs were TEAEs that developed/worsened during the ‘on treatment period’ (defined as the period from the time of first dose of drug until 84 days following the last administration of drug). Analysis was performed on safety population.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo (for dupilumab), 1 SC injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. Two subjects randomised to this arm received 1 dose of dupilimab were included in Dupilumab 300 mg q2w then q4w arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab 300 mg q2w Then q4w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 24 and then 300 mg q4w until Week 52 added to background therapy of intranasal MFNS at stable dose. After Week 24, Dupilumab administration was alternated with matched placebo injection every other week up to Week 50. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab 300 mg q2w
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Reporting group description |
Dupilumab 300 mg SC injection q2w from Day 1 of Week 0 up to Week 52 added to background therapy of intranasal MFNS at stable dose. One subject randomised to this arm received 1 dose of Placebo were included in Dupilumab 300 mg q2w then q4w arm. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 May 2017 |
- Reworded for clarity the procedures to be performed at permanent treatment discontinuation. In addition, added the assessment of rhinorrhea anterior and posterior following early treatment discontinuation to support total symptom score analysis.
- Permitted 1 retest of dynamic laboratory tests (i.e., those subject to variability) during screening at the discretion of the Investigator.
- Clarified that the analysis of the proportion of subjects who used SCS was to include all SCSs (not just oral corticosteroid)
- EQ-5D from exploratory endpoint to secondary efficacy endpoint
- Clarified that CT scan was mandatory unless not approved by local ethics committee or institutional review board
- Intranasal decongestants added to list of prohibited medications except as needed for nasal endoscopy procedure
- Permitted study procedures to be performed over 3 days, if necessary, as long as within the visit window
- Deleted the requirement for male birth control (to be consistent with most current safety information)
- Correction of typographical and other minor changes |
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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. | |||
| None reported | |||
