Nasal Polyps
Conditions
Brief summary
Primary Objective: To evaluate the efficacy of dupilumab (SAR231893/REGN668) in the treatment of bilateral Nasal Polyposis (NP) by assessment of the endoscopic nasal polyp score (NPS) in comparison to placebo. Secondary Objectives: To evaluate effect of dupilumab with regards to: * symptoms of sinusitis, * sinus computed tomography (CT) scan, * NPS in the sub-group of participants with co-morbid asthma, * Safety and tolerability.
Detailed description
Screening period (4 weeks) + Randomized Treatment Period (16 weeks) + Post-Treatment Period (16 weeks) = 36 weeks. To ensure at least 28 participants with co-morbid asthma needed for subgroup analysis, recruitment of NP participants without co-morbid asthma would stop when approximately 28 participants without asthma were randomized.
Interventions
Solution for injection; Subcutaneous injection.
DRUGDupilumab
Solution for injection; Subcutaneous injection.
DRUGMometasone furoate nasal spray
Nasal spray, 2 actuations in each nostril twice daily.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
participants with: * A minimum bilateral nasal polyp score of 5 out of a maximum score of 8 (with a unilateral score of at least 2 for each nostril) despite completion of a prior intranasal corticosteroid (INCS) treatment for at least 8 weeks before screening. * Presence of at least two of the following symptoms prior to screening: nasal blockade/obstruction/congestion or nasal discharge (anterior/posterior nasal drip); facial pain/pressure; reduction or loss of smell.
Exclusion criteria
* Participants \<18 or \>65 years of age. * Sinonasal outcome test (SNOT-22) \<7. * Participants who had taken other investigational drugs or prohibited therapy for this study within 2 months before screening or 5 half-lives, whichever was longer: * Burst of systemic corticosteroids within the 2 months before screening or were scheduled to receive systemic corticosteroids during the study period for another condition * INCS drops within 1 month prior to screening * Monoclonal antibody (mAB) and immunosuppressive treatment * Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days of Visit 1 * Leukotriene antagonists/modifiers unless participant was on a continuous treatment for at least 30 days prior to Visit 1. * Participants who had undergone any nasal surgery (including polypectomy) within 6 months before screening or have had more than 5 sinonasal surgeries in the past of which maximal 2 were surgeries changing the lateral wall structure of the nose. * Participants with asthma having: * Forced Expiratory Volume (FEV1) ≤ 60%, or .Asthma exacerbation requiring systemic (oral and/or parenteral) steroid treatment or hospitalization for \>24 hours for treatment of asthma, within 3 months prior to screening or were on a dose of greater than 1000 microgram (mcg) fluticasone or an equivalent INCS. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Baseline, Week 16 | 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 \[no polyp\] to 4 \[large polyps\] for each nostril), with a lower score indicating smaller-sized polyps. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Bilateral Endoscopic NPS at Week 16 in Participants With Asthma | Baseline, Week 16 | 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 \[no polyp\] to 4 \[large polyps\] for each nostril), with a lower score indicating smaller-sized polyps. |
| Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Baseline, Week 16 | 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 (no symptoms) - 3 (severe symptoms) categorical scale where higher score indicated severe symptoms. |
| Change From Baseline in Visual Analogue Scale (VAS) for Rhinosinusitis Symptoms Severity at Week 16 | Baseline, Week 16 | Severity of rhinosinusitis symptoms were assessed on a 0 cm (not troublesome) - 10 cm (worst thinkable troublesome) VAS where higher score indicated worst thinkable troublesome. |
| Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | Baseline, Week 16 | 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. |
| Change From Baseline in Smell Test (University of Pennsylvania Smell Identification Test [UPSIT]) Scores at Week 16 | Baseline, Week 16 | UPSIT was a 40-item test to measure the individual's ability to detect odors. Total score ranges from 0 (anosmia)-40 (normal sense of smell), lower score indicated severe smell loss. |
| Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Lund-Mackay Score | Baseline, Week 16 | CT scan assessment included Lund-Mackay score and percent of the maxillary sinuses occupied by disease. The Lund-Mackay scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses. The total score ranges from 0 (normal) - 24 (more opacified); higher score indicated worse status. |
| Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Percent Area Occupied by Disease | Baseline, Week 16 | CT scan assessment included Lund-Mackay score and percentage of the area of maxillary sinuses occupied by disease. |
| Time to First Response in NPS: Kaplan-Meier Estimate at Week 16 | Baseline to Week 16 | The time-to-first response in NPS: time from the date of randomization to the date of first NPS (defined as \>=1 point reduction from baseline score); for participants without NPS \>=1 point reduction, it was censored at the end of treatment date. The median time to first response was not estimated because the number of responses was too low in the Dupilumab arm. Therefore, alternative Kaplan-Meier statistics, the probability of response at Week 16, are presented as the descriptive measure statistics. |
| Change From Baseline in 22-Item Sinonasal Outcome Test (SNOT-22) at Week 16 | Baseline, Week 16 | 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 (no problem)-110 (worst quality of life), higher scores represented worst quality of life; minimal clinically important change ≥ 8.90. |
Countries
Belgium, Spain, Sweden, United States
Participant flow
Recruitment details
The study was conducted at 14 sites in 4 countries. A total of 60 participants were randomized between August 2013 and March 2014.
Pre-assignment details
Randomization was stratified according to medical history of asthma (with/without asthma) and by nasal biopsy (biopsy performed,Yes/No). Assignment was done centrally using Interactive Voice/Web Response System in 1:1 ratio (dupilumab:placebo)after 4-week run-in period on Mometasone furoate nasal spray (MFNS) and confirmation of selection criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for dupilumab), 2 subcutaneous injections on Day 1 as a loading dose followed by a single injection QW from Week 1 to 15 added to MFNS. | 30 |
| Dupilumab 300 mg QW Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection QW from Week 1 to 15 added to MFNS. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lack of Efficacy | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Dupilumab 300 mg QW | Placebo |
|---|---|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 9.4 | 47.4 years STANDARD_DEVIATION 9.8 | 49.3 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 28 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of participants with asthma No | 25 Participants | 14 Participants | 11 Participants |
| Number of participants with asthma Yes | 35 Participants | 16 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 59 Participants | 29 Participants | 30 Participants |
| Sex: Female, Male Female | 26 Participants | 12 Participants | 14 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 22 / 30 | 27 / 30 |
| serious Total, serious adverse events | 4 / 30 | 2 / 30 |
Outcome results
Primary
Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16
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 \[no polyp\] to 4 \[large polyps\] for each nostril), with a lower score indicating smaller-sized polyps.
Time frame: Baseline, Week 16
Population: Intent-to-treat (ITT) population included all randomized participants analyzed according to the treatment group allocated by randomization. Here, number analyzed = number of participants with available data for specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Change from baseline at Week 16 | -0.26 score on a scale | Standard Deviation 1.32 |
| Placebo | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Baseline | 5.67 score on a scale | Standard Deviation 0.88 |
| Placebo | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Week 16 | 5.39 score on a scale | Standard Deviation 1.47 |
| Dupilumab 300 mg QW | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Week 16 | 3.97 score on a scale | Standard Deviation 1.9 |
| Dupilumab 300 mg QW | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Baseline | 5.87 score on a scale | Standard Deviation 1.01 |
| Dupilumab 300 mg QW | Change From Baseline in Bilateral Endoscopic Nasal Polyp Score (NPS) at Week 16 | Change from baseline at Week 16 | -1.9 score on a scale | Standard Deviation 1.76 |
Comparison: Analysis was performed by a mixed model repeated measures (MMRM) model.p-value: 0.000995% CI: [-2.43, -0.67]Mixed Models Analysis
Secondary
Change From Baseline in 22-Item Sinonasal Outcome Test (SNOT-22) at Week 16
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 (no problem)-110 (worst quality of life), higher scores represented worst quality of life; minimal clinically important change ≥ 8.90.
Time frame: Baseline, Week 16
Population: Participants from ITT population with SNOT-22 data available at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 22-Item Sinonasal Outcome Test (SNOT-22) at Week 16 | -8.26 score on a scale | Standard Deviation 17.63 |
| Dupilumab 300 mg QW | Change From Baseline in 22-Item Sinonasal Outcome Test (SNOT-22) at Week 16 | -29.1 score on a scale | Standard Deviation 19.9 |
Secondary
Change From Baseline in Bilateral Endoscopic NPS at Week 16 in Participants With Asthma
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 \[no polyp\] to 4 \[large polyps\] for each nostril), with a lower score indicating smaller-sized polyps.
Time frame: Baseline, Week 16
Population: Participants of the ITT population with asthma and with available data at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Bilateral Endoscopic NPS at Week 16 in Participants With Asthma | 0.27 score on a scale | Standard Deviation 0.88 |
| Dupilumab 300 mg QW | Change From Baseline in Bilateral Endoscopic NPS at Week 16 in Participants With Asthma | -2.4 score on a scale | Standard Deviation 2.03 |
Secondary
Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16
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.
Time frame: Baseline, Week 16
Population: Participants from ITT population with data available for NPIF at Week 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | NPIF-Morning | 28.81 liter/minute | Standard Deviation 34.26 |
| Placebo | Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | NPIF-Evening | 26.65 liter/minute | Standard Deviation 34.31 |
| Dupilumab 300 mg QW | Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | NPIF-Morning | 61.91 liter/minute | Standard Deviation 43.39 |
| Dupilumab 300 mg QW | Change From Baseline in Nasal Peak Inspiratory Flow (NPIF) at Week 16 | NPIF-Evening | 61.25 liter/minute | Standard Deviation 45.91 |
Secondary
Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16
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 (no symptoms) - 3 (severe symptoms) categorical scale where higher score indicated severe symptoms.
Time frame: Baseline, Week 16
Population: Participants from ITT population with data available for symptom score at Week 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Congestion/obstruction | -0.26 score on a scale | Standard Deviation 0.7 |
| Placebo | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Runny nose | -0.1 score on a scale | Standard Deviation 0.58 |
| Placebo | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Post nasal drip | -0.15 score on a scale | Standard Deviation 0.59 |
| Placebo | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Loss of sense of smell | -0.3 score on a scale | Standard Deviation 0.6 |
| Dupilumab 300 mg QW | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Loss of sense of smell | -1.36 score on a scale | Standard Deviation 1.08 |
| Dupilumab 300 mg QW | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Congestion/obstruction | -0.95 score on a scale | Standard Deviation 0.86 |
| Dupilumab 300 mg QW | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Post nasal drip | -0.49 score on a scale | Standard Deviation 0.78 |
| Dupilumab 300 mg QW | Change From Baseline in Participant Reported Symptoms Scores of Sinusitis at Week 16 | Runny nose | -0.62 score on a scale | Standard Deviation 0.9 |
Secondary
Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Lund-Mackay Score
CT scan assessment included Lund-Mackay score and percent of the maxillary sinuses occupied by disease. The Lund-Mackay scoring system rated each of both the left and right frontal, maxillary, sphenoid, ostiomeatal complex, anterior ethmoid and posterior ethmoid sinuses. The total score ranges from 0 (normal) - 24 (more opacified); higher score indicated worse status.
Time frame: Baseline, Week 16
Population: Participants from ITT population with CT scan data available at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Lund-Mackay Score | -0.23 score on scale | Standard Deviation 3.74 |
| Dupilumab 300 mg QW | Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Lund-Mackay Score | -9.24 score on scale | Standard Deviation 4.58 |
Secondary
Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Percent Area Occupied by Disease
CT scan assessment included Lund-Mackay score and percentage of the area of maxillary sinuses occupied by disease.
Time frame: Baseline, Week 16
Population: Participants from ITT population with CT scan data available at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Percent Area Occupied by Disease | -3.92 percent area | Standard Deviation 20.54 |
| Dupilumab 300 mg QW | Change From Baseline in Sinus Computed Tomography (CT) Scan Assessments at Week 16: Percent Area Occupied by Disease | -35.66 percent area | Standard Deviation 24.28 |
Secondary
Change From Baseline in Smell Test (University of Pennsylvania Smell Identification Test [UPSIT]) Scores at Week 16
UPSIT was a 40-item test to measure the individual's ability to detect odors. Total score ranges from 0 (anosmia)-40 (normal sense of smell), lower score indicated severe smell loss.
Time frame: Baseline, Week 16
Population: Participants from ITT population with data available for UPSIT at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Smell Test (University of Pennsylvania Smell Identification Test [UPSIT]) Scores at Week 16 | -0.17 score on scale | Standard Deviation 5.1 |
| Dupilumab 300 mg QW | Change From Baseline in Smell Test (University of Pennsylvania Smell Identification Test [UPSIT]) Scores at Week 16 | 15.36 score on scale | Standard Deviation 9.61 |
Secondary
Change From Baseline in Visual Analogue Scale (VAS) for Rhinosinusitis Symptoms Severity at Week 16
Severity of rhinosinusitis symptoms were assessed on a 0 cm (not troublesome) - 10 cm (worst thinkable troublesome) VAS where higher score indicated worst thinkable troublesome.
Time frame: Baseline, Week 16
Population: Participants from ITT population with data available for Rhinosinusitis Symptoms Severity VAS at Week 16.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Visual Analogue Scale (VAS) for Rhinosinusitis Symptoms Severity at Week 16 | -1.84 centimetre (cm) | Standard Deviation 3.6 |
| Dupilumab 300 mg QW | Change From Baseline in Visual Analogue Scale (VAS) for Rhinosinusitis Symptoms Severity at Week 16 | -4.32 centimetre (cm) | Standard Deviation 2.75 |
Secondary
Time to First Response in NPS: Kaplan-Meier Estimate at Week 16
The time-to-first response in NPS: time from the date of randomization to the date of first NPS (defined as \>=1 point reduction from baseline score); for participants without NPS \>=1 point reduction, it was censored at the end of treatment date. The median time to first response was not estimated because the number of responses was too low in the Dupilumab arm. Therefore, alternative Kaplan-Meier statistics, the probability of response at Week 16, are presented as the descriptive measure statistics.
Time frame: Baseline to Week 16
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Response in NPS: Kaplan-Meier Estimate at Week 16 | 0.44 Probability of response |
| Dupilumab 300 mg QW | Time to First Response in NPS: Kaplan-Meier Estimate at Week 16 | 0.828 Probability of response |
Post Hoc
Change From Baseline in Nasal Total Symptoms Score (nTSS) at Week 16
nTSS was the sum of participant-assessed nasal symptom scores for nasal congestion/obstruction, decreased/loss of sense of smell, and rhinorrhea (anterior/posterior nasal discharge), each accessed on 0-3 categorical scale. Total score ranges from 0 (no symptoms) to 9 (severe symptoms). Higher score indicated severe symptoms.
Time frame: Baseline, Week 16
Population: Participants from ITT population with nTSS data available at Week 16.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Nasal Total Symptoms Score (nTSS) at Week 16 | nTSS - Morning | -0.68 score on a scale | Standard Deviation 1.44 |
| Placebo | Change From Baseline in Nasal Total Symptoms Score (nTSS) at Week 16 | nTSS - Evening | -0.77 score on a scale | Standard Deviation 1.48 |
| Dupilumab 300 mg QW | Change From Baseline in Nasal Total Symptoms Score (nTSS) at Week 16 | nTSS - Morning | -2.87 score on a scale | Standard Deviation 2.09 |
| Dupilumab 300 mg QW | Change From Baseline in Nasal Total Symptoms Score (nTSS) at Week 16 | nTSS - Evening | -2.9 score on a scale | Standard Deviation 2.04 |