臨床研究等提出・公開システム

A Multicentre, Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study of Benralizumab in Patients With Eosinophilic Chronic Rhinosinusitis With Nasal Polyps

ORCHID

Age, Categorical Number Analyzed: Benralizumab 144 / Placebo 143 / Total 287 <=18 years: 0 (0.0%) / 0 (0.0%) / 0 (0.0%) Between 18 and 65 years: 128 (88.9%) / 126 (88.1%) / 254 (88.5%) >=65 years: 16 (11.1%) / 17 (11.9%) / 33 (11.5%) Age, Continuous Mean (SD): Benralizumab 49.5 (12.7) years / Placebo 49.8 (12.7) years / Total 49.6 (12.7) years Sex Female: Benralizumab 61 (42.4%) / Placebo 54 (37.8%) / Total 115 (40.1%) Male: Benralizumab 83 (57.6%) / Placebo 89 (62.2%) / Total 172 (59.9%) Race White: Benralizumab 77 / Placebo 73 / Total 150 Asian: Benralizumab 66 / Placebo 66 / Total 132 Black or African American: Benralizumab 0 / Placebo 2 / Total 2 Other: Benralizumab 1 / Placebo 2 / Total 3

[Recruitment Details] A total of 723 participants were screened between 15NOV2019 and 01JUN2023. Of those, 295 were randomized (benralizumab 147, placebo 148). Eight participants were excluded due to Japan GCP breach. Therefore, 144 participants started in the benralizumab arm and 143 in the placebo arm (total 287). [Pre-assignment Details] All patients completed a 6-week run-in period during which inclusion/exclusion criteria were assessed, medical and surgical history documented, nasal endoscopy performed, and PROs, clinical labs, and diet questionnaires administered. [Double-Blind (DB) Period] Benralizumab Placebo Started 144 143 Completed 129 130 Not Completed 15 13 Reason: IP discontinuation (1/1), Withdrawal by subject (9/6), Pregnancy (1/0), Physician decision (1/2), Lost to follow-up (0/2), Adverse event (1/1), Site closure (2/0), Did not meet randomization criteria (0/1) [Open-Label Extension (OLE) Period - all participants received Benralizumab] Prior Benralizumab Prior Placebo Started 122 125 Completed 80 86 Not Completed 42 39 Reason: Study terminated by sponsor (19/26), Withdrawal by subject (18/6), Physician decision (3/2), Adverse event (1/3), Treatment failure (1/2)

[Time Frame] On-study AEs collected from first dose to last date in study, up to 112 weeks. DB period AEs: date of first dose (DB) <= AE onset <= end of DB (AEs starting on/after first OLE dose counted in OLE). OLE period AEs: date of first dose (OLE) <= AE onset <= study completion/withdrawal. [All-Cause Mortality] DB Benralizumab: 0/144 (0.00%) / DB Placebo: 0/143 (0.00%) OLE (prior Benralizumab): 0/122 (0.00%) / OLE (prior Placebo): 0/125 (0.00%) [Serious Adverse Events] DB Benralizumab: 12/144 (8.33%) / DB Placebo: 12/143 (8.39%) OLE (prior Benralizumab): 6/122 (4.92%) / OLE (prior Placebo): 9/125 (7.20%) Notable SAEs: COVID-19 pneumonia (DB Benralizumab 0; DB Placebo 0; OLE 2/1), Pneumonia (DB Placebo 2), Bacterial pneumonia (DB Benralizumab 1), Papillary thyroid cancer (1 each DB arm), Prostate cancer (DB Benralizumab 1), Asthma/Asthmatic crisis (DB Placebo 1; DB Benralizumab 1) [Other (Not Including Serious) Adverse Events - Frequency Threshold >=3%] DB Benralizumab: 78/144 (54.17%) / DB Placebo: 59/143 (41.26%) COVID-19: Benralizumab 22 (15.28%) / Placebo 16 (11.19%) Asthma: Benralizumab 16 (11.11%) / Placebo 22 (15.38%) Upper respiratory tract infection: Benralizumab 13 (9.03%) / Placebo 14 (9.79%) Headache: Benralizumab 11 (7.64%) / Placebo 7 (4.90%) Nasopharyngitis: Benralizumab 11 (7.64%) / Placebo 9 (6.29%) Back pain: Benralizumab 7 (4.86%) / Placebo 1 (0.70%) Influenza like illness: Benralizumab 7 (4.86%) / Placebo 4 (2.80%) Pyrexia: Benralizumab 7 (4.86%) / Placebo 3 (2.10%) Chronic gastritis: Benralizumab 6 (4.17%) / Placebo 1 (0.70%)

Primary Outcome Measure 1: Change From Baseline in Endoscopic Total Nasal Polyp Score (NPS) at Week 56 [Analysis Population] Primary full analysis set (Benralizumab n=127, Placebo n=121) Mean (SD): Benralizumab -0.3 (1.6) / Placebo -0.1 (1.3) Difference in LS Means: -0.247 (95%CI: -0.599 to 0.106) P-value: 0.1707 (not statistically significant) Method: ANCOVA (covariates: treatment, region, baseline BMI, baseline total NPS) Missing data: WP for surgery rescue; WOCF for SCS rescue; other missing: MI (MAR) x100 (Rubin's formula) Primary Outcome Measure 2: Change From Baseline in Mean Nasal Blockage Score (NBS) at Week 56 [Analysis Population] Primary full analysis set (Benralizumab n=114, Placebo n=118) Mean (SD): Benralizumab -0.64 (0.98) / Placebo -0.45 (0.90) Difference in LS Means: -0.155 (95%CI: -0.383 to 0.073) P-value: 0.1831 (not statistically significant) Method: ANCOVA (covariates: treatment, region, baseline BMI, baseline bi-weekly mean NBS) Neither primary endpoint achieved statistical significance for superiority of benralizumab over placebo.

Secondary Outcome Measure 1: Change From Baseline in Difficulty With Sense of Smell (DSS) at Week 56 Benralizumab: -0.26 (SD 0.78) / Placebo: -0.05 (SD 0.56) Difference: -0.191 (95%CI: -0.351 to -0.031), P=0.0196 (significant, unadjusted) Secondary Outcome Measure 2: Change From Baseline in Lund-Mackay Score (CT) at Week 56 Benralizumab: -1.3 (SD 3.4) / Placebo: -0.7 (SD 3.5) Difference: -0.663 (95%CI: -1.559 to 0.232), P=0.1456 (not significant) Secondary Outcome Measure 3: Change From Baseline in SNOT-22 at Week 56 Benralizumab: -18.0 (SE 29.6) / Placebo: -15.2 (SE 26.6) Difference: -1.783 (95%CI: -8.171 to 4.606), P=0.5844 (not significant) Secondary Outcome Measure 4: Time to First NP Surgery (median) Benralizumab: 6.31 months (3.3-10.5) / Placebo: 7.79 months (4.4-12.4) HR: 0.82 (95%CI: 0.31-2.09), P=0.6776 (nominal p-value) Secondary Outcome Measure 5: Time to First SCS Course (median) Benralizumab: 5.62 months (0.1-13.0) / Placebo: 6.37 months (0.1-11.4) HR: 0.93 (95%CI: 0.51-1.69), P=0.8033 (nominal p-value) Secondary Outcome Measure 6: % With Surgery and/or SCS for CRSwNP Benralizumab: 26/139 (18.7%) / Placebo: 30/135 (22.2%) OR: 0.82 (95%CI: 0.45-1.48), P=0.5130 (nominal p-value) Secondary Outcome Measure 7: % With Surgery for CRSwNP Benralizumab: 8/139 (5.8%) / Placebo: 10/135 (7.4%) OR: 0.75 (95%CI: 0.28-1.99), P=0.5662 (nominal p-value) Secondary Outcome Measure 8: % With SCS Use for CRSwNP Benralizumab: 21/139 (15.1%) / Placebo: 22/135 (16.3%) OR: 0.94 (95%CI: 0.49-1.81), P=0.8454 (nominal p-value) Secondary Outcome Measure 9: Change From Baseline in NPSD Total Symptom Score at Week 56 Benralizumab: -3.19 (SD 5.78) / Placebo: -2.32 (SD 5.83) Difference: -0.860 (95%CI: -2.235 to 0.515), P=0.2201 (nominal p-value)

Benralizumab did not significantly reduce NPS or nasal blockage at Week 56, though both coprimary endpoints numerically favoured benralizumab. DSS improved nominally; sinus opacification and HRQoL also numerically favoured benralizumab. Near-complete eosinophil depletion was maintained throughout DB and OLE. Patients switching from placebo achieved steady-state by Week 80. No ADA effect was observed. Benralizumab was well tolerated with no new safety signals, consistent with its known profile.

July. 31, 2026

Yes

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Tsugumi Hirotaka

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

RD-clinical-information-Japan@astrazeneca.com

Tsugumi Hirotaka

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

+81-6-4802-3600

RD-clinical-information-Japan@astrazeneca.com

completed

Nov. 25, 2019

Interventional

Randomized, Parallel Assignment, Triple

treatment purpose

3

1. Female or male patients aged 18 to 75 years inclusive

2. Stable Intranasal corticosteroids (INCS) use for at least 4 weeks prior to enrolment and throughout screening

3. History of treatment with systemic corticosteroids (SCS) or prior surgery for CRSwNP

4. Bilateral sinonasal polyposis with a nasal polyp score (NPS) of 5 at enrolment and randomization (unilateral score of at least 2 for each nostril)

5. Ongoing symptoms for at least 12 weeks prior to enrolment

6. Patient-reported moderate to severe nasal blockage score (NBS) 2 or more at enrolment

7. Bi-weekly mean NBS 1.5 or more at randomization

8. SNOT-22 total score 20 or more at enrolment and randomization

9. Documented physician-diagnosed asthma

10. Blood eosinophil count of >2% or 150/microL or more at enrolment

1. Any nasal and/or sinus surgery within 3 months prior to enrolment

2. Patients with conditions that makes them non evaluable for the co-primary efficacy endpoint including but not limited to:

- Unilateral antrochoanal polyps

- Nasal septal deviation that occludes at least one nostril

- Current rhinitis medicamentosa

- Allergic fungal rhinosinusitis or allergic fungal sinusitis;

3. Clinically important comorbidities that may put the patient at risk, or may confound interpretation of clinical efficacy and/or safety results

4. Receipt of SCS for within 4 weeks prior to screening, or a scheduled SCS treatment during the study period.

5. Receipt of any marketed or investigational biologic product within 6 months of enrolment

6. Currently pregnant or breastfeeding

Both

Nasal Polyposis

investigational material(s)
Generic name etc : Benralizumab
INN of investigational material : -
Therapeutic category code : 449 Other antiallergic agents
Dosage and Administration for Investigational material : Benralizumab 30 mg subcutaneously will be injected every 4 weeks for the first 3 doses and every 8 weeks thereafter.

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Matching placebo subcutaneously will be injected every 4 weeks for the first 3 doses and every 8 weeks thereafter.

safety
efficacy
exploratory
pharmacokinetics
-

safety
efficacy
exploratory
pharmacokinetics
-

Oct. 11, 2019