Clinical Trial Results:
A Randomized, Double-Blind, Phase 2, Placebo Controlled, 2 Arm Study To Evaluate Dupilumab In Patients With Bilateral Nasal Polyposis And Chronic Symptoms Of Sinusitis
Summary
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EudraCT number |
2013-001803-35 |
Trial protocol |
BE SE ES |
Global end of trial date |
05 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Apr 2016
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First version publication date |
06 Apr 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ACT12340
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01920893 | ||
WHO universal trial number (UTN) |
U1111-1130-6475 | ||
Sponsors
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Sponsor organisation name |
Sanofi aventis recherche & développement
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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 & Developpement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi Aventis Recherche & Developpement, 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 |
03 Dec 2014
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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 |
05 Nov 2014
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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 |
The main objective of the study was to evaluate the efficacy of dupilumab in the treatment of bilateral nasal polyp by assessment of the endoscopic nasal polyp score (NPS) in comparison to placebo.
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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 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 |
Mometasone furoate nasal spray (MFNS - 100 μg in each nostril twice daily) was administered during a 4-week run-in period and then continued throughout the study. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Aug 2013
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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 |
Spain: 18
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Country: Number of subjects enrolled |
Sweden: 8
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Country: Number of subjects enrolled |
Belgium: 18
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Country: Number of subjects enrolled |
United States: 16
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Worldwide total number of subjects |
60
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EEA total number of subjects |
44
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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) |
60
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 14 sites in 4 countries. A total of 60 subjects were randomized between August 2013 and March 2014. | |||||||||||||||||||||
Pre-assignment
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Screening details |
Randomization was stratified according to medical history of asthma (with/without asthma) and by nasal biopsy (biopsy performed Yes/No). Assignment to arms was done centrally using Interactive Voice/Web Response System in 1:1 ratio (dupilumab : placebo) after the 4-week run-in period on MFNS and confirmation of selection criteria. | |||||||||||||||||||||
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 | |||||||||||||||||||||
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), 2 subcutaneous injections on Day 1 as a loading dose followed by a single injection every week from Week 1 to 15 in combination with MFNS. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo (for dupilumab)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subcutaneous injection (2 mL) in the abdomen or upper thigh.
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Arm title
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Dupilumab | |||||||||||||||||||||
Arm description |
Dupilumab, 2 Subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection every week from Week 1 to 15 in combination with MFNS. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Dupilumab
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Investigational medicinal product code |
SAR231893, REGN668
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subcutaneous injection (150 mg/mL) in the abdomen or upper thigh.
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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), 2 subcutaneous injections on Day 1 as a loading dose followed by a single injection every week from Week 1 to 15 in combination with MFNS. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab
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Reporting group description |
Dupilumab, 2 Subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection every week from Week 1 to 15 in combination with MFNS. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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), 2 subcutaneous injections on Day 1 as a loading dose followed by a single injection every week from Week 1 to 15 in combination with MFNS. | ||
Reporting group title |
Dupilumab
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Reporting group description |
Dupilumab, 2 Subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection every week from Week 1 to 15 in combination with MFNS. |
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End point title |
Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | |||||||||||||||||||||
End point description |
NPS was the sum of the right and left nostril scores, as evaluated by means of nasal endoscopy. Total score ranges from 0 to 8 (scored 0 to 4 for each nostril), with a lower score indicating smaller-sized polyps. Analysis population = Intent-to-treat (ITT) population (ie. all randomized subjects analyzed according to the treatment group allocated by randomization). Here, ‘n’ signifies the number of subjects with available data for NPS.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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Statistical analysis title |
Dupilumab vs Placebo | |||||||||||||||||||||
Statistical analysis description |
Analysis was performed by a mixed model repeated measures (MMRM) model.
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Comparison groups |
Dupilumab v Placebo
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||||||||
P-value |
= 0.0009 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Least Square (LS) mean difference | |||||||||||||||||||||
Point estimate |
-1.55
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-2.43 | |||||||||||||||||||||
upper limit |
-0.67 | |||||||||||||||||||||
Notes [1] - Threshold for significance at 0.05. |
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End point title |
Change from Baseline in Bilateral Endoscopic NPS at Week 16 in Subjects with Asthma | ||||||||||||
End point description |
Analysis population = subjects of the ITT population with asthma and with available data at Week 16
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Subject Reported Symptoms of Sinusitis at Week 16 | |||||||||||||||||||||||||||
End point description |
Morning symptoms of sinusitis (nasal congestion/obstruction, anterior rhinorrhea [runny nose], posterior rhinorrhea [post nasal drip], and loss of sense of smell) were assessed using a 0-3 categorical scale where higher score indicates severe symptoms.
Severity of rhinosinusitis symptoms were assessed on a 0-10 Visual Analogue Scale (VAS) where higher score indicates worst thinkable troublesome.
Analysis population = ITT population.
Here, ‘n’ signifies the number of subjects with available data for individual symptom score.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | ||||||||||||||||||
End point description |
NPIF evaluation represents a physiologic measure of the air flow through both nasal cavities during forced inspiration and/or expiration expressed in liter per minute.
Analysis population = subjects from ITT population with data available for NPIF at Week 16.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Smell Test (University of Pennsylvania Smell Identification Test [UPSIT]) at Week 16 | ||||||||||||
End point description |
UPSIT was a 40-item test to measure the individual's ability to detect odors. Total score ranges from 0-40; lower score indicates severe smell loss. Analysis population = subjects from ITT population with data available for UPSIT at Week 16.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16 | ||||||||||||||||||
End point description |
CT scan assessment included Lund-Mackay score and percent of the maxillary sinuses occupied by disease. The Lund-Mackay scoring system rates each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses. The total score ranges from 0-24; higher score indicates worse status. Analysis population = subjects from ITT population with CT scan data available at Week 16.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Time to First Response in NPS: Kaplan-Meier Estimate at Week 16 | ||||||||||||
End point description |
NPS response was defined as ≥1 point reduction from baseline. The probability of response at Week 16 is provided. Analysis population = ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in 22-item Sinonasal Outcome Test (SNOT-22) at Week 16 | ||||||||||||
End point description |
The SNOT-22 was a validated questionnaire to assess the impact of chronic rhinosinusitis on quality of life. The total score may range from 0-110, higher score represents worst quality of life; minimal clinically important change ≥8.90. Analysis population = subjects from ITT population with SNOT-22 data available at Week 16
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Nasal Total Symptoms Score (nTSS) at Week 16 | ||||||||||||||||||
End point description |
nTSS was the sum of subject-assessed nasal symptom scores for nasal congestion/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge) using a 0-3 categorical scale. Total score ranges from 0 to 9. Higher score indicates severe symptoms.
Analysis population =subjects from ITT population with nTSS data available at Week 16.
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End point type |
Post-hoc
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End point timeframe |
Baseline, Week 16
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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 Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 32) regardless of seriousness or relationship to investigational medicinal product (IMP).
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Adverse event reporting additional description |
Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the 'treatment emergent period' (from the first dose of the double-blind IMP injection up to the end of the 16 weeks post-treatment period).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects exposed to placebo (for dupilumab) in combination with MFNS (mean exposure of 96.2 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Dupilumab
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Reporting group description |
Subjects exposed to dupilumab in combination with MFNS (mean exposure of 108.6 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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13 Aug 2013 |
Addition of a nasal secretion sampling at screening visit for the purpose of assay validation of biomarker in the unique biomatrix; Permitted concomitant medication was changed to provide more information on a potential effect of dupilumab on CYP450 and a list of CYP450 substrates with narrow therapeutic index to ensure monitoring and if needed dose adjustment following the initiation and stopping of dupilumab; Clinical Study Director was changed.
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27 Nov 2013 |
Simplification of the protocol concerning tissue collection and processing of nasal polyp biopsies. |
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16 Dec 2013 |
Simplification of exclusion criteria (clarification for previous treatment with dupilumab, definition of wash-out periods after systematic corticosteroids, details concerning nasal surgeries); Correction of two errors in the Study Flow Chart of the protocol; Clarification for allergen immunotherapy in regards prohibited and permitted concomitant medication; Deletion of one sentence concerning IMP administration at home in the safety instructions as IMP was to be administered at the site only; Forced expiratory volume (FEV) threshold at screening in subjects with asthma was changed from FEV ≥60% to FEV >60% of predicted normal. |
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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 | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/26836729 |