NCT02898454: SINUS-52

Controlled Clinical Study of Dupilumab in Patients With Nasal Polyps

Completed Phase 3 Results posted Last updated 23 October 2019

What this trial tests

Phase 3 trial testing Dupilumab SAR231893 (REGN668) in Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP) in 448 participants. Completed in 16 November 2018.

Timeline

28 November 2016

Primary endpoint
27 August 2018

16 November 2018

Quick facts

Lead sponsor	Sanofi
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	448
Start date	28 November 2016
Primary completion	27 August 2018
Estimated completion	16 November 2018
Sites	123 locations across Japan, Russia, Belgium, Chile, Sweden, Israel, Mexico, Argentina

Drugs / interventions tested

• Dupilumab SAR231893 (REGN668)
• Placebo
• Mometasone furoate nasal spray — full drug profile →

Conditions studied

• Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP) — all drugs for Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP) →

Sponsor

Sanofi — full company profile →

Who can join

18 and older, any sex, with Chronic Rhinosinusitis Phenotype With Nasal Polyps (CRSwNP). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline at Week 24 in Nasal Congestion/Obstruction Symptom Severity Score Primary · Baseline, Week 24

NC symptom severity was assessed by the participants 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 participants randomized to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analyzed as a pooled population for Week 24 assessments.

Group	Value	95% CI
Placebo	-0.38	± 0.07
Dupilumab 300 mg (24 Weeks Pooled Arm)	-1.25	± 0.06

Change From Baseline at Week 24 in Nasal Polyp Score Primary · Baseline, Week 24

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 centralized, blinded, independent review of the nasal endoscopy video recordings. LS means and SE were obtained from ANCOVA model described in Statistical Analysis Overview. All participants rand

Group	Value	95% CI
Placebo	0.10	± 0.14
Dupilumab 300 mg (24 Weeks Pooled Arm)	-1.71	± 0.11

Change From Baseline at Week 24 in Opacification of Sinuses Measured by Lund Mackay (LMK) Score Secondary · Baseline, Week 24

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 outcome measure and is

Group	Value	95% CI
Placebo	-0.09	± 0.31
Dupilumab 300 mg (24 Weeks Pooled Arm)	-5.21	± 0.24

Change From Baseline at Week 24 in Total Symptom Score (TSS) Secondary · Baseline, Week 24

The TSS was the sum of participant-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 participants randomized to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and

Group	Value	95% CI
Placebo	-1.00	± 0.20
Dupilumab 300 mg (24 Weeks Pooled Arm)	-3.45	± 0.15

Change From Baseline at Week 24 in the University of Pennsylvania Smell Identification Test (UPSIT) Score Secondary · Baseline, Week 24

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 participants randomized to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analyzed as a pooled population for Week 24 assessments.

Group	Value	95% CI
Placebo	-0.81	± 0.71
Dupilumab 300 mg (24 Weeks Pooled Arm)	9.71	± 0.56

Change From Baseline at Week 24 in Severity of Decreased/Loss of Smell as Assessed by Participant Daily Secondary · Baseline, Week 24

The severity of decreased/loss of sense of smell was reported by the participants 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 participants randomized to receive Dupilumab had been on 300 mg q2w regimen until Week 24 and analyzed as a pooled population for Week 24 assessments.

Group	Value	95% CI
Placebo	-0.23	± 0.08
Dupilumab 300 mg (24 Weeks Pooled Arm)	-1.21	± 0.06

Change From Baseline at Week 24 in 22-item Sino-nasal Outcome Test (SNOT-22) Scores Secondary · Baseline, Week 24

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 participants randomized to receive Dupilumab had been on 300 mg q2

Group	Value	95% CI
Placebo	-10.40	± 1.61
Dupilumab 300 mg (24 Weeks Pooled Arm)	-27.77	± 1.26

Change From Baseline at Week 52 in Nasal Polyp Score Secondary · Baseline, Week 52

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 centralized, blinded, independent review of the nasal endoscopy video recordings. Data were analyzed using a hybrid met

Group	Value	95% CI
Placebo	0.16	± 0.15
Dupilumab 300 mg q2w Then q4w	-2.05	± 0.15
Dupilumab 300 mg q2w	-2.24	± 0.15

Change From Baseline at Week 52 in Nasal Congestion/Obstruction Symptom Severity Score Secondary · Baseline, Week 52

NC symptom severity was assessed by the participants 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.

Group	Value	95% CI
Placebo	-0.37	± 0.08
Dupilumab 300 mg q2w Then q4w	-1.48	± 0.08
Dupilumab 300 mg q2w	-1.36	± 0.07

Change From Baseline at Week 52 in 22-item Sino-nasal Outcome Test Scores Secondary · Baseline, Week 52

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.

Group	Value	95% CI
Placebo	-9.06	± 1.61
Dupilumab 300 mg q2w Then q4w	-30.42	± 1.65
Dupilumab 300 mg q2w	-29.79	± 1.64

Rescue Treatment Use: Estimate of Percentage of Participants With Greater Than or Equal to (>=) 1 Event by Week 52 Obtained Using Kaplan-Meier Method Secondary · Baseline up to 52 weeks

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 participants with event

SCS treatment

Group	Value	95% CI
Placebo	42.5	34.5 – 50.2
Dupilumab 300 mg (Pooled Arm)	13.1	9.0 – 18.0

NP surgery

Group	Value	95% CI
Placebo	28.3	21.2 – 35.7
Dupilumab 300 mg (Pooled Arm)	5.5	2.9 – 9.4

Change From Baseline at Week 52 in Total Symptom Score Secondary · Baseline, Week 52

The TSS was the sum of participant-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 analyzed using a hybrid method of the WOCF and MI. The imputed completed data were analyzed by fitting an ANCOVA model with corresponding baseline value, treatment group, asthma/NS

Group	Value	95% CI
Placebo	-0.93	± 0.20
Dupilumab 300 mg q2w Then q4w	-4.17	± 0.20
Dupilumab 300 mg q2w	-3.79	± 0.20

Adverse events — posted to ClinicalTrials.gov

Time frame: All Adverse Events (AEs) were collected from signature of the informed consent form up to 64 weeks regardless of seriousness or relationship to investigational product.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 16/150 (11%)

Deaths: 0/150

Dupilumab 300 mg q2w Then q4w

Serious: 12/148 (8%)

Deaths: 1/148

Dupilumab 300 mg q2w

Serious: 8/149 (5%)

Deaths: 0/149

Serious adverse events (40 terms)

Reaction	System	Placebo	Dupilumab 300 mg q2w Then …	Dupilumab 300 mg q2w
Nasal Polyps	Respiratory, thoracic and mediastinal disorders	—	—	—
Facial Bones Fracture	Injury, poisoning and procedural complications	—	—	—
Eosinophilia	Blood and lymphatic system disorders	—	—	—
Deafness Neurosensory	Ear and labyrinth disorders	—	—	—
Vestibular Disorder	Ear and labyrinth disorders	—	—	—
Retinal Vein Thrombosis	Eye disorders	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—
Abdominal Pain Upper	Gastrointestinal disorders	—	—	—
Gastrointestinal Angiectasia	Gastrointestinal disorders	—	—	—
Oesophageal Perforation	Gastrointestinal disorders	—	—	—
Pancreatitis	Gastrointestinal disorders	—	—	—
Pyrexia	General disorders	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—
Eosinophilic Granulomatosis With Polyangiitis	Immune system disorders	—	—	—
Appendicitis	Infections and infestations	—	—	—
Chronic Sinusitis	Infections and infestations	—	—	—
Corneal Abscess	Infections and infestations	—	—	—
Diverticulitis	Infections and infestations	—	—	—
Infectious Pleural Effusion	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—
Septic Shock	Infections and infestations	—	—	—
Wound Infection	Infections and infestations	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Femur Fracture	Injury, poisoning and procedural complications	—	—	—
Hand Fracture	Injury, poisoning and procedural complications	—	—	—

Other adverse events (15 terms — click to expand)

Reaction	System	Placebo	Dupilumab 300 mg q2w Then …	Dupilumab 300 mg q2w
Nasopharyngitis	Infections and infestations	—	—	—
Nasal Polyps	Respiratory, thoracic and mediastinal disorders	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—
Asthma	Respiratory, thoracic and mediastinal disorders	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Sinusitis	Infections and infestations	—	—	—
Acute Sinusitis	Infections and infestations	—	—	—
Accidental Overdose	Injury, poisoning and procedural complications	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Injection Site Erythema	General disorders	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Injection Site Reaction	General disorders	—	—	—

Most-reported serious reactions: Nasal Polyps, Facial Bones Fracture, Eosinophilia, Deafness Neurosensory, Vestibular Disorder, Retinal Vein Thrombosis, Abdominal Pain, Abdominal Pain Upper.

Data from ClinicalTrials.gov NCT02898454 adverse events section.

Sponsor's own description

Primary Objective:

To evaluate the efficacy of dupilumab 300 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 polyp score (NPS) in participants with bilateral nasal polyps (NP). In addition for Japanese participants, reduction in computed tomography (CT) scan opacification of the sinuses was a co-primary objective.

Secondary Objectives:

* To evaluate the efficacy of dupilumab in improving total symptoms score.
* To evaluate the efficacy of dupilumab in improving sense of smell.
* To evaluate the efficacy of dupilumab in reducing CT scan opacification of the sinuses (primary objective for Japanese participants).
* To evaluate ability of dupilumab in reducing proportion of participants who required treatment with systemic corticosteroids (SCS) or surgery for NP.
* To evaluate the effect of dupilumab on participant reported outcomes and health related quality of life.
* To evaluate the efficacy of dupilumab 300 mg q2w up to Week 52.
* To evaluate the efficacy of dupilumab 300 mg q2w up to Week 24 followed by 300 mg every 4 weeks (q4w) up to Week 52.
* To evaluate the effect of dupilumab in the subgroups of participants with prior surgery and comorbid asthma including non-steroid anti-inflammatory drug exacerbated respiratory disease.
* To evaluate the safety of dupilumab in participants with bilateral NP.
* To evaluate functional dupilumab concentrations (systemic exposure) and incidence of treatment emergent anti-drug antibodies.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.
   Bachert C, Han JK, Desrosiers M, Hellings PW, et al · · 2019 · cited 991× · PMID 31543428 · DOI 10.1016/s0140-6736(19)31881-1
2. Antibodies to watch in 2018.
   Kaplon H, Reichert JM. · · 2018 · cited 179× · PMID 29300693 · DOI 10.1080/19420862.2018.1415671
3. Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.
   Hamilton JD, Harel S, Swanson BN, Brian W, et al · · 2021 · cited 139× · PMID 34037993 · DOI 10.1111/cea.13954
4. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis.
   Jonstam K, Swanson BN, Mannent LP, Cardell LO, et al · · 2019 · cited 116× · PMID 30488542 · DOI 10.1111/all.13685
5. Interleukin-13 in Asthma and Other Eosinophilic Disorders.
   Doran E, Cai F, Holweg CTJ, Wong K, et al · · 2017 · cited 101× · PMID 29034234 · DOI 10.3389/fmed.2017.00139
6. Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma.
   Laidlaw TM, Bachert C, Amin N, Desrosiers M, et al · · 2021 · cited 84× · PMID 33465455 · DOI 10.1016/j.anai.2021.01.012
7. Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials.
   Mullol J, Laidlaw TM, Bachert C, Mannent LP, et al · · 2022 · cited 77× · PMID 34459002 · DOI 10.1111/all.15067
8. Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status.
   Fujieda S, Matsune S, Takeno S, Ohta N, et al · · 2022 · cited 71× · PMID 33993501 · DOI 10.1111/all.14906