Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis

Change from baseline in SinoNasal outcome test (SNOT-22) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after NP surgery and/or SCS_NP were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

The cumulative percentage and the corresponding 95% CI are based on the Kaplan-Meier estimates. Patients can have more than 1 rescue category during the study, and the first rescue per patient is considered. The time to first nasal polyposis (NP) surgery and/or systemic corticosteroids (SCS) use for NP up to week 56 was calculated based on the earliest occurrence of NP surgery and/or SCS use for NP and was calculated as follows: Time to first NP surgery and/or SCS use for NP = Earlier of (Start date of first NP surgery, Start date of first SCS use for NP) - date of randomization + 1. For patients who did not experience any surgery or SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).

The cumulative percentage and the corresponding 95% CI are based on the Kaplan-Meier estimates. Patients can have more than 1 rescue category during the study, and the first rescue per patient is considered. The time to first nasal polyposis (NP) surgery up to week 56 was calculated based on the earliest occurrence of NP surgery and was calculated as follows: Time to first NP surgery=Start date of first NP surgery - date of randomization + 1. For patients who did not experience any surgery, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation).

Change from baseline in difficulty with sense of smell (DSS) at week 40 was defined as the endpoint value at week 40 minus the baseline value. The DSS is captured by an item in the NPSD. Severity of worst difficulty with sense of smell over the past 24 hours was rated with response options: 0-none; 1-mild; 2-moderate; 3-severe. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids use for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in total nasal polyps score (NPS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The total NPS is the sum of the right and left nostril scores, as evaluated by nasal endoscopy and the left and right score are based on central read with scale from 0 to 4 where higher score reflects heavier bilateral nasal polyp burden. Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in nasal blockage score (NBS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The NBS is captured by an item in the NPSD. Patients were asked to rate the severity of their worst nasal blockage over the past 24 hours using the following response options: 0-none; 1-mild; 2-moderate; 3-severe. The NBS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in SinoNasal outcome test (SNOT-22) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The SNOT-22 is a condition specific health-related quality of life assessment which captures patient-reported physical problems, functional limitations, and emotional consequences of sinonasal conditions. The total score is range from 0 to 110 (higher scores indicate poorer outcomes). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in difficulty with sense of smell (DSS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The DSS is captured by an item in the NPSD with response options: 0-none; 1-mild; 2-moderate; 3-severe to rate the severity of their worst difficulty with sense of smell over past 24 hours. The DSS and the changes from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in Computed tomography (CT) Lund Mackay Score (LMS) at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. The LMS evaluates the patency using a 0-2 scale (0-normal; 1-partial opacification; and 2-total opacification) of each sinus (maxillary, anterior ethmoid, posterior ethmoid, sphenoid, frontal sinus on each side). The osteomeatal complex is graded as 0- not occluded or 2-occluded. The total CT score is the sum of the scores from all the sinus and ranges from 0 to 24. The minimum is 0 and higher score indicates worse outcome. The analysis used the data collected after systemic corticosteroids for nasal polyposis (SCS_NP). A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place.

The percentage of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran-Mantel-Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).

The percentage of patients who had systemic corticosteroids (SCS) use for nasal polyposis (NP) surgery up to week 56 was summarized and analyzed using the Cochran-Mantel-Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).

The percentage of patients who had nasal polyposis (NP) surgery or systemic corticosteroids use for nasal polyposis (SCS_NP) surgery up to week 56 was summarized and analyzed using the Cochran-Mantel-Haenszel test stratified by region (US vs non-US) and baseline comorbid asthma status (yes vs no).

The cumulative percentage and the corresponding 95% CI are based on the Kaplan-Meier estimates. Patients can have more than 1 rescue category during the study, and the first rescue per patient is considered. The time to first systemic corticosteroids for use for nasal polyposis (SCS_NP) up to week 56 was calculated based on the earliest occurrence of SCS_ NP and was calculated as follows: Time to first SCS_NP = Earlier of (Start date of first SCS use for NP) - date of randomization + 1. For patients who did not experience any SCS use for NP, the time to event was censored at earlier of (date of their week 56 visit, date of discontinuation). The time to first SCS use for NP surgery was analyzed using a Cox proportional hazard model with treatment arm, region (US vs non-US) and baseline comorbid asthma status (yes vs no) as covariates. A hazard ratio less than 1 indicates a lower rate of incidence for subjects on benra.

The total number of courses of systemic corticosteroids (SCS) use for nasal polyposis (NP) was summarized using descriptive statistics.

The total systemic corticosteroids (SCS) for nasal polyposis (NP) dose used (mg) was summarized using descriptive statistics.

The total duration of systemic corticosteroids (SCS) for nasal polyposis (NP) in days was summarized using descriptive statistics.

Annual systemic corticosteroids for nasal polyposis (SCS_NP) use rate =365.25×total number of courses of SCS_NP /total duration of follow-up within the treatment group (days). The estimated annual event rates, absolute differences, rate ratio and the corresponding confidence interval were based on a negative binomial model including covariates treatment group, region (US/non-US) and prior use of SCS_NP with total number of courses of SCS_NP as the outcome and the log of each subject's corresponding follow-up time up to week 56 as an offset variable in the model to adjust for subject's having different exposure times during which the events occur.

Change from baseline in total symptom score (TSS) at week 40 was defined as the endpoint at week 40 minus baseline value. The TSS is defined as sum of first 8 NPSD components. Severity of each nasal symptoms over the past 24 hours is rated using response options: 0-none; 1-mild; 2-moderate; 3-severe. The TSS and the change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily TSS responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.

Change from baseline in difficulty with sleeping due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with sleeping due to nasal symptoms over past 24 hours was rated using options: 0-none; 1-mild; 2-moderate; 3-severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was the average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis

Change from baseline in difficulty with daily activities due to nasal symptoms score at week 40 was defined as the endpoint at week 40 minus baseline value. The score was captured by an item in NPSD. The severity of difficulty with daily activities due to nasal symptoms over the past 24 hours was rated using options: 0-none; 1-mild; 2-moderate; 3-severe. The score and change from baseline were summarized every two weeks (bi-weekly). Baseline was average of daily responses from Day -13 to Day 1. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming MAR were used to build the complete imputation datasets for the analysis.

Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores were based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) score at week 40 was defined as the endpoint value at week 40 minus the baseline value. The UPSIT is quantitative test of olfactory function. Scores are based on number of correctly identified odors (score range 0 to 40). Baseline was the last valid value on or prior to the date of randomization. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for nasal polyposis (SCS_NP) were set to missing. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied. In ANCOVA, a hybrid method of the WP after NP surgery, WOCF after SCS_NP and multiple imputation (MI) assuming missing at random were used to build the complete imputation datasets for the analysis.

Change from baseline in sinus severity score at end of treatment (EOT)/investigational product discontinuation (IPD) was defined as the endpoint value at EOT/IPD minus the baseline value. Quantitative assessment of sinus CT image data was used to derive an objective measure of sinus disease burden called sinus severity score. The sinus severity score is defined as (sinus mucosal volume)/(sinus mucosal volume + sinus air volume)×100. A composite strategy was used for NP surgery. If a patient had NP surgery before EOT/IPD CT scan, the data was censored after the time of the first NP surgery and the worst possible value (WP) was imputed in its place. In calculation of summary statistics (mean and standard deviation), the WP for NP surgery rescued subjects was applied. In ANCOVA, following WP (WP for NP surgery rescued subjects), model included treatment, baseline score, region (US/Non-US) and baseline comorbid asthma status.

Change from baseline in SF-36v2 physical component summary (PCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. PCS score is computed from 8 subscale scores to give a broader metric of physical health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 mental component summary (MCS) at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. MCS score is computed from 8 subscale scores to give a broader metric of mental health-related quality of life. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 physical functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Physical functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 role limitations due to physical health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to physical health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 bodily pain score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Bodily pain is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 general health perceptions score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. General health perceptions is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing are excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 vitality score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Vitality is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 social functioning score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 are used to compute an 8-domain profile of functional health and well-being scores. Social functioning is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 role limitations due to emotional problems score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Role limitations due to emotional problems is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.

Change from baseline in SF-36v2 mental health score at week 56 was defined as the endpoint value at week 56 minus the baseline value. The Short Form 36-item Health survey (SF-36v2) is a 36-item, self-report survey of functional health and wellbeing, with 4-week recall period. Responses to SF-36v2 were used to compute an 8-domain profile of functional health and well-being scores. Mental health is one of the 8-domain profile. Data collected after nasal polyposis (NP) surgery and/or systemic corticosteroids for NP (SCS_NP) were set to missing. Non-rescued patients whose post-baseline observations were all missing were excluded from this analysis. In calculation of summary statistics (mean and standard deviation), the worst-possible (WP) after NP surgery and worst-observation carried forward (WOCF) after SCS_NP were applied.