ANDHI: A Study of the Safety and Effectiveness of Benralizumab to Treat Patients With Severe Uncontrolled Asthma.

Sponsor

AstraZeneca (Industry)

Overall Status

Completed

CT.gov ID

NCT03170271

Collaborator

(none)

660

Enrollment

213

Locations

Arms

39.5

Actual Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effect of benralizumab on the rate of asthma exacerbations, patient reported quality of life and lung function during the 24-week treatment in patients with uncontrolled, severe asthma with an eosinophilic phenotype. A subset of patients will be assessed for their ongoing chronic rhinosinusitis with nasal polyps. The study design has been updated to include a 56-week open label ANDHI in Practice (ANDHI IP) sub study upon the completion of the 24-week double-blind period of the ANDHI study.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Benralizumab (Medi-563) Drug: Placebo	Phase 3

Detailed Description

This is a Phase IIIb, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and the safety of repeat dosing of benralizumab 30 mg subcutaneous (sc) versus placebo on top of standard of care asthma therapy in patients with severe uncontrolled asthma. Approximately 630 patients with peripheral blood eosinophil counts ≥150 cells/μL will be randomized 2:1 to receive benralizumab 30 mg sc or matched placebo for 24 weeks.

After enrolment, eligible patients will enter an up to 42-day screening/run-in period. Patients who meet eligibility criteria will be randomized 2:1 on Day 0 to receive either benralizumab or placebo every 56 days (every 8 weeks) through Week 16, with end of treatment (EOT) at Day 168 (Week 24). At the completion of the 24-week doubleblind period of the ANDHI study, eligible patients in benralizumab and placebo arm may enter a 56-week open label period (ANDHI in Practice [ANDHI IP] substudy), in which concomitant asthma therapies will be tapered as directed by the protocol in those patients who achieve and maintain asthma control (defined as ACQ6 score <1.5 and no clinically significant asthma exacerbations that required a burst of systemic corticosteroid or a hospitalization due to asthma between reduction visits) with add-on benralizumab.

Study Design

Study Type:

Interventional

Actual Enrollment :

660 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3b Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients With Severe Asthma Uncontrolled on Standard of Care Treatment

Actual Study Start Date :

Jul 7, 2017

Actual Primary Completion Date :

Sep 25, 2019

Actual Study Completion Date :

Oct 21, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Benralizumab (Medi-563) Benralizumab (Medi563) Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).	Drug: Benralizumab (Medi-563) 30mg Benralizumab administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).
Placebo Comparator: Placebo Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)	Drug: Placebo Placebo administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)

Arm

Intervention/Treatment

Experimental: Benralizumab (Medi-563)

Benralizumab (Medi563) Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).

Drug: Benralizumab (Medi-563)

30mg Benralizumab administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).

Placebo Comparator: Placebo

Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)

Drug: Placebo

Placebo administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)

Outcome Measures

Primary Outcome Measures

Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24) [Baseline (Week 0) up to Week 24]
An asthma exacerbation was defined as a worsening of asthma that led to any of the following: Use of systemic corticosteroids (or temporary increase in stable oral corticosteroids [OCS] background dose) for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. An emergency room/urgent care visit (defined as evaluation and treatment for < 24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above). An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. Annual exacerbation rate = 365.25*total number of exacerbations / total duration of follow-up within the treatment group. Annual asthma exacerbation rates over the 24-week period were estimated using a negative binomial model.

Secondary Outcome Measures

Change From Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24) [Baseline (Week 0) and Week 24]
The SGRQ is a 50-item patient-reported outcome instrument which measures the health status of patients with airway obstruction diseases. The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ total score indicates the impact of disease on overall health status and is expressed as a percentage of overall impairment (scores range from 0 to100, with 100 representing worst possible health status and 0 indicating the best possible health status). The least squares (LS) mean change from baseline in SGRQ total score at Week 24 is presented.
Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24) [Baseline (Week 0) and Week 24]
Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorized delegate according to American Thoracic Society/European Respiratory Society guidelines. The LS mean change from baseline in pre-BD FEV1 at Week 24 is presented.
Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24) [Baseline (Week 0) and Week 24]
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath and wheezing) and short-acting β-2 receptor agonist use. Patients were asked to recall the status of their asthma during the previous week and respond to the questions of the ACQ-6 on a 7-point scale. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is computed as the mean of the responses from all the items in the questionnaire. Mean scores of ≤0.75 indicated well-controlled asthma, scores between 0.75 and <1.5 indicated partly-controlled asthma, and a score ≥1.5 indicated not well-controlled asthma. The LS mean change from baseline in ACQ-6 score at Week 24 is presented.
Time to First Asthma Exacerbation (up to Week 24) [Baseline (Week 0) up to Week 24]
Time to first asthma exacerbation was derived as follows: Start date of first asthma exacerbation - Date of randomization + 1. The time to first asthma exacerbation for patients who did not experience an asthma exacerbation during the treatment period was censored at the EOT visit (Week 24) for patients who completed the study. Patients who withdrew from the study or were lost to follow-up before the EOT visit were censored at the last visit date after which an exacerbation could not be assessed. The median time to first asthma exacerbation was not calculated, so the number of patients who experienced an asthma exacerbation is presented for the measured values.
Change From Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24) [Run-in baseline (from Day -28 to Day 0) and Week 24]
Home PEF testing was performed by the patient each morning after awakening and before taking their morning asthma medications, and each evening using a peak flow meter. Measurements were taken at approximately the same time each day and recorded in the Asthma Daily Diary. The maximum of the 3 measurements performed every morning and evening were used in the calculation of the weekly means. A weekly mean was calculated as the sum of all non-missing daily measures over the 7 sequential days divided by the number of non-missing daily measures. If more than 3 daily measures (> 50%) within a period were missing, then the weekly mean for that period was set to 'missing'. Change from run-in baseline in weekly means for morning PEF and evening PEF are presented. Baseline was the average for data collected over the last 7 days of the run-in period prior to randomization.
Change From Baseline in Short Form 36-item Health Survey, Version 2 (SF-36v2) to the EOT (Week 24) [Baseline (Week 0) and Week 24]
The SF-36v2 is a 36-item survey of functional health and well-being, with a 1 week recall period. The 8-domain profile consists of the following subscales: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The physical and mental health component summary scores are computed from subscale scores to give a broader metric of physical and mental health-related quality of life. Each domain score, as well as the physical and mental component scores, were scored on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Norm-based scoring was used to calculate the 8 SF-36v2 subscales and the 2 component scores. The LS mean change from baseline in each of the SF-36 subscale and component summary scores at Week 24 are presented.
Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24) [Baseline (Week 0) and Week 24]
The PGI-S is a single question asking the patient to rate the overall severity of their symptoms using a 6-point categorical response scale from 0 to 5 where 0=no symptoms and 5=very severe symptoms. Higher scores indicate a worse outcome. Improvement was defined as a PGI-S at EOT (Week 24) better than PGI-S at baseline. Important improvement was defined as PGI-S at baseline = moderate symptoms or severe symptoms or very severe symptoms shifting to PGI-S at EOT = no symptoms or very mild symptoms or mild symptoms. Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated PGI-S responder categories are presented.
Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24) [Baseline (Week 0) and Week 24]
The Investigator (clinician) and the patient were asked separately to rate the degree of change in the overall asthma status compared to the start of treatment, i.e. baseline randomization visit. A 7-point rating scale was used for the CGI-C (rated by Investigator) and PGI-C (rated by patient) where: 1=Very Much Improved; 2=Much Improved; 3=Minimally Improved; 4=No Changes; 5=Minimally Worse; 6=Much Worse, and 7=Very Much Worse. Higher scores indicate a worse outcome. Responder category definitions: Much improved = (Much improved, Very much improved); Very much improved = (Very much improved). Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated CGI-C and PGI-C responder categories are presented.
Change From Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24) [Baseline (Week 0) and Week 24]
For part 1 of the PSIA only administered at baseline, patients reviewed 8 concepts (including cardinal asthma symptoms, activities, awakenings, triggers) and selected those which were typically bothersome. Based on part 1 selections, part 2 of the PSIA produced a rank ordered list of bothersome concepts individualized per the patient for subsequent evaluation. For part 3 of the PSIA assessed at baseline and during the study, patients recorded the severity of each selected symptom or impairment using an 11-point numeric rating scale where: 0=Did not experience and 10=Worst I can imagine. Higher scores indicate a worse outcome. The LS mean change from baseline in PSIA severity score for the indicated categories at Week 24 are presented. A negative change from baseline indicates an improvement in symptoms. Note: Average PSIA was calculated only where all of top 3 ranked symptoms/impairments were available, otherwise average was set to missing.
Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24) [Baseline (Week 0) and Week 24]
The 22-item SNOT 22 questionnaire was used to assess the rhinosinusitis health status and quality of life of patients with baseline chronic rhinosinusitis with nasal polyposis. The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110. Higher scores indicate poorer outcomes. The LS mean changes from baseline in SNOT-22 total score in patients in the chronic rhinosinusitis with nasal polyposis sub-study analysis set at Week 24 are presented.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a history of physician-diagnosed asthma requiring treatment with medium-to-high dose Inhaled Corticosteroids (ICS) plus asthma controller, for at least 12 months prior to Visit 1.
Documented current treatment with high daily doses of ICS plus at least one other asthma controller for at least 3 months prior to Visit 1.
History of at least 2 asthma exacerbations while on ICS plus another asthma controller that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit 1.
ACQ6 score ≥1.5 at Visit 1.
Screening pre-bronchodilator (pre-BD) FEV1 of <80% predicted at Visit 2.
Excessive variability in lung function by satisfying ≥ 1 of the following criteria:
Airway reversibility (FEV1 ≥12%) using a short-acting bronchodilator demonstrated at Visit 2 or Visit 3.
Airway reversibility to short-acting bronchodilator (FEV1 ≥12%) documented during the 12 months prior to enrolment Visit 1.
Daily diurnal peak flow variability of >10% when averaged over 7 continuous days during the study run-in period
An increase in FEV1 of ≥12% and 200 mL after a therapeutic trial of systemic corticosteroid (eg, OCS), given outside of an asthma exacerbation, documented in the 12 months prior enrolment Visit 1.
Airway hyper-responsiveness (methacholine: PC20 of <8 mg/mL, histamine: PD20 of <7.8 μmol, mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 24 months prior to randomization Visit 4.
Peripheral blood eosinophil count either:

300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2

≥150 to <300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2, IF ≥1 of the following 5 clinical criteria (a to e) is met:

Using maintenance OCS (daily or every other day OCS requirement in order to maintain asthma control; maximum total daily dose 20 mg prednisone or equivalent) at screening
History of nasal polyposis
Age of asthma onset ≥18 years
Three or more documented exacerbations requiring systemic corticosteroid treatment during the 12 months prior to screening
Pre-bronchodilator forced vital capacity <65% of predicted, as assessed at Visit 2 (note that screening pre-BD FEV1 Inclusion Criterion #6 must still be satisfied)

For inclusion in the open label ANDHI IP sub study patients should meet the following criteria:

Patients study must have completed ANDHI EOT Visit 11.
Written informed consent must also be obtained prior to any study related procedures being performed in the open label ANDHI IP sub study.
Patients who have received any approved or investigational targeted biologic for the treatment of asthma (e.g. commercial mepolizumab, reslizumab, benralizumab) may be included if the last dose is ≥ 2 months of Visit 13.

Exclusion Criteria:

Clinically important pulmonary disease other than asthma
Acute upper or lower respiratory infections within 30 days prior to the date informed consent.
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to, standard of care therapy.
History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
A history of known immunodeficiency disorder.
Current smokers or former smokers with a smoking history of ≥10 pack years.
Previously received benralizumab (MEDI-563).
Receipt of any investigational medication as part of a research study within approximately 5 half-lives prior to randomization.
Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
Receipt of live attenuated vaccines 30 days prior to the date of randomization; other types of vaccines are allowed.
Concurrent enrolment in another interventional or post-authorization safety study

Exclusion criteria for the open label ANDHI IP sub study:

Patients should not enter the open label ANDHI IP sub study if any of the following exclusion criteria are fulfilled. Each exclusion criterion should be reviewed in all potential participants, including those who transition directly from the double-blind period and those with a delay between completing the EOT Visit 11 and the first open label visit (Visit 13).

Patients who participated in the double-blind period but failed to complete the ANDHI EOT Visit 11. Patients who completed the ANDHI FU Visit 12 are not excluded from participation in the ANDHI IP sub study.
Unable to commit to the monthly visits as required by the protocol, or unable to commit to undergoing protocol guided reductions in asthma therapy, as directed by the Investigator.
Patients who experienced a severe or serious treatment-related AE during the double-blind period and, and those whom Investigator judges it is not in the patient's best interest to extend possible treatment with benralizumab.
Approved or off-label use of systemic immunosuppressive medications within 3 months prior to the first open label visit (Visit 13). These include but are not limited to small molecules such as methotrexate, cyclosporine, azathioprine, and immunosuppressive/immunomodulating biologics such as tumour necrosis factor (TNF) blockers. Regular use of systemic OCS is also excluded except for the indication of asthma.
Receipt of live attenuated vaccines 30 days prior to the first visit in the open label ANDHI IP sub study (Visit 13); other types of vaccines are allowed.
Planned surgical procedures during the conduct of the study.
Positive urine pregnancy test at Visit 13, or currently breastfeeding or lactating women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35209
2	Research Site	Tucson	Arizona	United States	85724
3	Research Site	Little Rock	Arkansas	United States	72209
4	Research Site	Bakersfield	California	United States	93301
5	Research Site	Encinitas	California	United States	92024
6	Research Site	Long Beach	California	United States	90806
7	Research Site	Los Angeles	California	United States	90025
8	Research Site	Mission Viejo	California	United States	92691
9	Research Site	Newport Beach	California	United States	92663
10	Research Site	Riverside	California	United States	92506
11	Research Site	San Diego	California	United States	92108
12	Research Site	Stockton	California	United States	95207
13	Research Site	Walnut Creek	California	United States	94598
14	Research Site	Aurora	Colorado	United States	80045
15	Research Site	New Haven	Connecticut	United States	06519
16	Research Site	Waterbury	Connecticut	United States	06708
17	Research Site	Clearwater	Florida	United States	33765
18	Research Site	Jacksonville	Florida	United States	32099
19	Research Site	Kissimmee	Florida	United States	34741
20	Research Site	Miami	Florida	United States	33126
21	Research Site	Miami	Florida	United States	33173
22	Research Site	Winter Park	Florida	United States	32789
23	Research Site	Albany	Georgia	United States	31707
24	Research Site	Savannah	Georgia	United States	31406
25	Research Site	Peoria	Illinois	United States	61602
26	Research Site	South Bend	Indiana	United States	46617
27	Research Site	Iowa City	Iowa	United States	52242
28	Research Site	West Des Moines	Iowa	United States	50266
29	Research Site	Lakeside Park	Kentucky	United States	41017
30	Research Site	Owensboro	Kentucky	United States	42301
31	Research Site	Shreveport	Louisiana	United States	71106
32	Research Site	Chevy Chase	Maryland	United States	20815
33	Research Site	White Marsh	Maryland	United States	21162
34	Research Site	North Dartmouth	Massachusetts	United States	02747
35	Research Site	Ann Arbor	Michigan	United States	48109
36	Research Site	Ypsilanti	Michigan	United States	48197
37	Research Site	Minneapolis	Minnesota	United States	55402
38	Research Site	Saint Louis	Missouri	United States	63156
39	Research Site	Missoula	Montana	United States	59808
40	Research Site	Lincoln	Nebraska	United States	68510
41	Research Site	Highland Park	New Jersey	United States	08904
42	Research Site	Marlton	New Jersey	United States	08053
43	Research Site	Northfield	New Jersey	United States	08225
44	Research Site	Piscataway	New Jersey	United States	08854
45	Research Site	Toms River	New Jersey	United States	08755
46	Research Site	Verona	New Jersey	United States	07044
47	Research Site	Albuquerque	New Mexico	United States	87106
48	Research Site	Bronx	New York	United States	10459
49	Research Site	New Hyde Park	New York	United States	11042
50	Research Site	New York	New York	United States	10016
51	Research Site	Rochester	New York	United States	14618
52	Research Site	Staten Island	New York	United States	10305
53	Research Site	Staten Island	New York	United States	10310
54	Research Site	Charlotte	North Carolina	United States	28277
55	Research Site	Elizabeth City	North Carolina	United States	27909
56	Research Site	Gastonia	North Carolina	United States	28054
57	Research Site	Greenville	North Carolina	United States	27834
58	Research Site	High Point	North Carolina	United States	27262
59	Research Site	Winston-Salem	North Carolina	United States	27103
60	Research Site	Winston-Salem	North Carolina	United States	27157
61	Research Site	Cincinnati	Ohio	United States	45231
62	Research Site	Cincinnati	Ohio	United States	45242
63	Research Site	Grove City	Ohio	United States	43123
64	Research Site	Edmond	Oklahoma	United States	73034
65	Research Site	Tulsa	Oklahoma	United States	74136
66	Research Site	Clackamas	Oregon	United States	97015-5737
67	Research Site	Philadelphia	Pennsylvania	United States	19107
68	Research Site	Pittsburgh	Pennsylvania	United States	15213
69	Research Site	Pittsburgh	Pennsylvania	United States	15241
70	Research Site	Reading	Pennsylvania	United States	19610
71	Research Site	Anderson	South Carolina	United States	29621
72	Research Site	Gaffney	South Carolina	United States	29340
73	Research Site	Greenville	South Carolina	United States	29607
74	Research Site	Greenville	South Carolina	United States	29615
75	Research Site	North Charleston	South Carolina	United States	29420-4211
76	Research Site	Rock Hill	South Carolina	United States	29732
77	Research Site	Sioux Falls	South Dakota	United States	57108
78	Research Site	Franklin	Tennessee	United States	37067
79	Research Site	Cypress	Texas	United States	77429
80	Research Site	Dallas	Texas	United States	75225
81	Research Site	Dallas	Texas	United States	75246
82	Research Site	Fort Worth	Texas	United States	76109
83	Research Site	Galveston	Texas	United States	77555
84	Research Site	McKinney	Texas	United States	75069
85	Research Site	San Antonio	Texas	United States	78229
86	Research Site	San Antonio	Texas	United States	78249
87	Research Site	San Antonio	Texas	United States	78251
88	Research Site	Provo	Utah	United States	84604
89	Research Site	South Burlington	Vermont	United States	05403
90	Research Site	Abingdon	Virginia	United States	24210
91	Research Site	Fairfax	Virginia	United States	22030
92	Research Site	North Chesterfield	Virginia	United States	23225
93	Research Site	Williamsburg	Virginia	United States	23188
94	Research Site	Everett	Washington	United States	98208
95	Research Site	Spokane	Washington	United States	99204
96	Research Site	Tacoma	Washington	United States	98405
97	Research Site	Madison	Wisconsin	United States	53792
98	Research Site	Milwaukee	Wisconsin	United States	53226
99	Research Site	Milwaukee	Wisconsin	United States	53228
100	Research Site	West Allis	Wisconsin	United States	53227
101	Research Site	Feldbach		Austria	A-8330
102	Research Site	Wien		Austria	1130
103	Research Site	Liège		Belgium	4000
104	Research Site	Montigny-le-Tilleul		Belgium	6110
105	Research Site	Namur		Belgium	5101
106	Research Site	Calgary	Alberta	Canada	T2N 4Z6
107	Research Site	Vancouver	British Columbia	Canada	V5Z 1M9
108	Research Site	Vancouver	British Columbia	Canada	V6Z 1Y6
109	Research Site	Kelowna	Columbia Británica	Canada	V1W 1V3
110	Research Site	Winnipeg	Manitoba	Canada	R2H 2A6
111	Research Site	Ajax	Ontario	Canada	L1S 2J5
112	Research Site	Burlington	Ontario	Canada	L7N 3V2
113	Research Site	Mississauga	Ontario	Canada	L5A 3V4
114	Research Site	Toronto	Ontario	Canada	M5T 3A9
115	Research Site	Montreal	Quebec	Canada	H4A 3J1
116	Research Site	Quebec		Canada	G1V 4W2
117	Research Site	Aarhus N		Denmark	8200
118	Research Site	Odense C		Denmark	5000
119	Research Site	Vejle		Denmark	7100
120	Research Site	Helsinki		Finland	00290
121	Research Site	Turku		Finland	20520
122	Research Site	Bayonne		France	64100
123	Research Site	Besancon Cedex		France	25030
124	Research Site	Brest Cedex 2		France	29609
125	Research Site	Dijon		France	21079
126	Research Site	GRENOBLE Cedex 9		France	38043
127	Research Site	La Roche sur Yon		France	85925
128	Research Site	Le Kremlin-Bicêtre		France	94270
129	Research Site	Lille cedex		France	59037
130	Research Site	Lyon Cedex 4		France	69317
131	Research Site	Marseille		France	13015
132	Research Site	Montpellier		France	34090
133	Research Site	Nantes Cedex 1		France	44093
134	Research Site	Nice cedex 1		France	06002
135	Research Site	Paris Cedex 18		France	75877
136	Research Site	Pessac		France	33604
137	Research Site	Reims		France	51092
138	Research Site	Rouen Cedex		France	76031
139	Research Site	Saint-Quentin cedex		France	02321
140	Research Site	Strasbourg Cedex		France	67091
141	Research Site	Toulouse Cedex 09		France	31059
142	Research Site	Vandoeuvre-Les-Nancy		France	54511
143	Research Site	Berlin		Germany	14059
144	Research Site	Bochum		Germany	44789
145	Research Site	Bonn		Germany	53105
146	Research Site	Cottbus		Germany	03050
147	Research Site	Essen		Germany	45239
148	Research Site	Hamburg		Germany	20354
149	Research Site	Jena		Germany	07747
150	Research Site	Marburg		Germany	30625
151	Research Site	Oldenburg		Germany	23758
152	Research Site	Regensburg		Germany	93053
153	Research Site	Rheine		Germany	48431
154	Research Site	Rüdersdorf		Germany	15562
155	Research Site	Wangen		Germany	88239
156	Research Site	Brescia		Italy	25123
157	Research Site	Catania		Italy	95123
158	Research Site	Catanzaro		Italy	88100
159	Research Site	Cona		Italy	44124
160	Research Site	Foggia		Italy	71100
161	Research Site	Garbagnate Milanese		Italy	20024
162	Research Site	Legnago		Italy	37045
163	Research Site	Matera		Italy
164	Research Site	Milaan		Italy	20157
165	Research Site	Milano		Italy	20122
166	Research Site	Modena		Italy	41124
167	Research Site	Napoli		Italy	80131
168	Research Site	Padova		Italy	35128
169	Research Site	Palermo		Italy	90127
170	Research Site	Pavia		Italy	27100
171	Research Site	Piacenza		Italy	29100
172	Research Site	Pietra Ligure		Italy	17027
173	Research Site	Reggio Emilia		Italy	42123
174	Research Site	Roma		Italy	00168
175	Research Site	Rozzano		Italy	20089
176	Research Site	Verona		Italy	37126
177	Research Site	Amersfoort		Netherlands	3813 TZ
178	Research Site	Deventer		Netherlands	7416 SE
179	Research Site	Enschede		Netherlands	7513 ER
180	Research Site	Harderwijk		Netherlands	3844 DG
181	Research Site	Helmond		Netherlands	5707 HA
182	Research Site	Nijmegen		Netherlands	6532 SZ
183	Research Site	Zwolle		Netherlands	8025 AB
184	Research Site	Bergen		Norway	5021
185	Research Site	Lørenskog		Norway	N-1478
186	Research Site	Badalona(Barcelona)		Spain	08916
187	Research Site	Barcelona		Spain	08035
188	Research Site	Barcelona		Spain	08036
189	Research Site	Benalmádena		Spain	29631
190	Research Site	Jerez de la Frontera		Spain	11407
191	Research Site	Laredo		Spain	39770
192	Research Site	Madrid		Spain	28031
193	Research Site	Madrid		Spain	28034
194	Research Site	Malaga		Spain	29730
195	Research Site	Palma de Mallorca		Spain	07010
196	Research Site	Pozuelo de Alarcon		Spain	28223
197	Research Site	Sabadell		Spain	08208
198	Research Site	Salamanca		Spain	37007
199	Research Site	Santiago de Compostela		Spain	15706
200	Research Site	Sevilla		Spain	41009
201	Research Site	Taco		Spain	38108
202	Research Site	Valdemoro		Spain	28342
203	Research Site	Lund		Sweden	221 85
204	Research Site	Stockholm		Sweden	SE-181 58
205	Research Site	Östersund		Sweden	831 83
206	Research Site	Birmingham		United Kingdom	B9 5SS
207	Research Site	Bradford		United Kingdom	BND9 6RJ
208	Research Site	Cambridge		United Kingdom	CB2 2QQ
209	Research Site	Chertsey		United Kingdom	KT16 0PZ
210	Research Site	Dundee		United Kingdom	DD1 9SY
211	Research Site	Glasgow		United Kingdom	G51 4TF
212	Research Site	London		United Kingdom	EC1A 7BE
213	Research Site	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

AstraZeneca

Investigators

Principal Investigator: Brad Goodman, MD, Aero Allergy Research Lab of Savannah
Principal Investigator: Vinay Sikand, MD, Sikand Institute of Pulmonary Research
Principal Investigator: Willaim Cherry, MD, Riverside Medical Center

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.

Responsible Party:

AstraZeneca

ClinicalTrials.gov Identifier:

NCT03170271

Other Study ID Numbers:

D3250C00045
2017-001040-35

First Posted:

May 31, 2017

Last Update Posted:

Nov 1, 2021

Last Verified:

Oct 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by AstraZeneca

Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases

Additional relevant MeSH terms:

Asthma

Inflammation

Bronchial Diseases

Respiratory Tract Diseases

Lung Diseases, Obstructive

Lung Diseases Respiratory Hypersensitivity

Hypersensitivity, Immediate

Hypersensitivity

Immune System Diseases

Pathologic Processes

Additional relevant MeSH terms:

Asthma

Benralizumab

Study Results

Participant Flow

Recruitment Details

Patients with severe uncontrolled asthma and peripheral blood eosinophil counts of ≥150 cells/microliter (μL) (with major subgroups of 150-300 cells/μL plus clinical features and ≥300 cells/μL) were recruited to 221 centers in 14 countries. Patients were randomized in a 2:1 ratio to receive benralizumab or matched placebo for 24 weeks. Results are reported for the double-blind period of the study (data cut-off: 12 Sep 2019).

Pre-assignment Detail

Severe eosinophilic patients were to have had ≥ 2 asthma exacerbations while on maintenance inhaled corticosteroids (ICS) plus another asthma controller that required treatment with systemic corticosteroids in the 12 months prior to enrolment. Patients continued to receive their standard of care asthma therapy throughout the study period.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 milligrams (mg) administered subcutaneously (sc) in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An End of Treatment (EOT) visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Period Title: Overall Study
STARTED	431	229
Received Treatment	427	229
COMPLETED	398	218
NOT COMPLETED	33	11

Baseline Characteristics

Arm/Group Title	Benralizumab	Placebo	Total
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Total of all reporting groups
Overall Participants	427	229	656
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.5 (12.69)	53.3 (12.52)	52.8 (12.63)
Sex: Female, Male (Count of Participants)
Female	263 61.6%	136 59.4%	399 60.8%
Male	164 38.4%	93 40.6%	257 39.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	49 11.5%	25 10.9%	74 11.3%
Not Hispanic or Latino	318 74.5%	172 75.1%	490 74.7%
Unknown or Not Reported	60 14.1%	32 14%	92 14%
Race/Ethnicity, Customized (Count of Participants)
White	314 73.5%	168 73.4%	482 73.5%
Black or African American	35 8.2%	18 7.9%	53 8.1%
Asian	11 2.6%	7 3.1%	18 2.7%
Native Hawaiian or other Pacific Islander	0 0%	1 0.4%	1 0.2%
Other	5 1.2%	2 0.9%	7 1.1%
Missing	62 14.5%	33 14.4%	95 14.5%
Screening eosinophil count group (cells/µL) (Count of Participants)
≥ 150 - < 300	129 30.2%	63 27.5%	192 29.3%
≥ 300	297 69.6%	165 72.1%	462 70.4%
Missing	1 0.2%	1 0.4%	2 0.3%
Baseline eosinophil count group (cells/μL) (Count of Participants)
< 300	146 34.2%	74 32.3%	220 33.5%
≥ 300 - < 450	105 24.6%	56 24.5%	161 24.5%
≥ 450	176 41.2%	99 43.2%	275 41.9%

Outcome Measures

1. Primary Outcome

Title	Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)
Description	An asthma exacerbation was defined as a worsening of asthma that led to any of the following: Use of systemic corticosteroids (or temporary increase in stable oral corticosteroids [OCS] background dose) for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. An emergency room/urgent care visit (defined as evaluation and treatment for < 24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above). An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. Annual exacerbation rate = 365.25*total number of exacerbations / total duration of follow-up within the treatment group. Annual asthma exacerbation rates over the 24-week period were estimated using a negative binomial model.
Time Frame	Baseline (Week 0) up to Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	427	229
Number (95% Confidence Interval) [Events/year]	0.94	1.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Comparison of annual exacerbation rates for benralizumab vs placebo (rate ratio). Treatment group, region, number of exacerbations in previous year and maintenance OCS use at baseline were included in the negative binomial model as covariates. The log of each patient's corresponding follow-up time was used as an offset variable in the model to adjust for patients having different follow-up times during which events occurred.
	Type of Statistical Test	Superiority
	Comments	The null hypothesis was that the exacerbation rate of benralizumab was equal to the exacerbation rate of placebo.

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative binomial
	Comments

Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95% 0.39 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24)
Description	The SGRQ is a 50-item patient-reported outcome instrument which measures the health status of patients with airway obstruction diseases. The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ total score indicates the impact of disease on overall health status and is expressed as a percentage of overall impairment (scores range from 0 to100, with 100 representing worst possible health status and 0 indicating the best possible health status). The least squares (LS) mean change from baseline in SGRQ total score at Week 24 is presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	364	204
Least Squares Mean (Standard Error) [Scores on a scale]	-23.06 (1.00)	-14.94 (1.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SGRQ total score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a mixed-effect model for repeated measures (MMRM) analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-8.11
	Confidence Interval	(2-Sided) 95% -11.41 to -4.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SGRQ total score = Treatment + baseline SGRQ total score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

3. Secondary Outcome

Title	Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24)
Description	Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorized delegate according to American Thoracic Society/European Respiratory Society guidelines. The LS mean change from baseline in pre-BD FEV1 at Week 24 is presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	393	213
Least Squares Mean (Standard Error) [Liters (L)]	0.30 (0.02)	0.14 (0.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in pre-BD FEV1 at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95% 0.09 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in pre-BD FEV1 = Treatment + baseline pre-BD FEV1 + region + number of exacerbations in previous year + maintenance OCS use at baseline + gender + age + visit + treatment by visit.

4. Secondary Outcome

Title	Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24)
Description	The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath and wheezing) and short-acting β-2 receptor agonist use. Patients were asked to recall the status of their asthma during the previous week and respond to the questions of the ACQ-6 on a 7-point scale. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is computed as the mean of the responses from all the items in the questionnaire. Mean scores of ≤0.75 indicated well-controlled asthma, scores between 0.75 and <1.5 indicated partly-controlled asthma, and a score ≥1.5 indicated not well-controlled asthma. The LS mean change from baseline in ACQ-6 score at Week 24 is presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	393	216
Least Squares Mean (Standard Error) [Scores on a scale]	-1.47 (0.06)	-1.01 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in ACQ-6 score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95% -0.65 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in ACQ-6 score = Treatment + baseline ACQ-6 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

5. Secondary Outcome

Title	Time to First Asthma Exacerbation (up to Week 24)
Description	Time to first asthma exacerbation was derived as follows: Start date of first asthma exacerbation - Date of randomization + 1. The time to first asthma exacerbation for patients who did not experience an asthma exacerbation during the treatment period was censored at the EOT visit (Week 24) for patients who completed the study. Patients who withdrew from the study or were lost to follow-up before the EOT visit were censored at the last visit date after which an exacerbation could not be assessed. The median time to first asthma exacerbation was not calculated, so the number of patients who experienced an asthma exacerbation is presented for the measured values.
Time Frame	Baseline (Week 0) up to Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	427	229
Count of Participants [Participants]	123 28.8%	107 46.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Comparison of time to first asthma exacerbation for benralizumab vs placebo. Treatment group, region, number of exacerbations in previous year and maintenance OCS use at baseline were included in the Cox proportional hazard model as covariates.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Cox
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95% 0.40 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	A hazard ratio < 1 favours benralizumab to be associated with a longer time from randomization to the first exacerbation than placebo.

6. Secondary Outcome

Title	Change From Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24)
Description	Home PEF testing was performed by the patient each morning after awakening and before taking their morning asthma medications, and each evening using a peak flow meter. Measurements were taken at approximately the same time each day and recorded in the Asthma Daily Diary. The maximum of the 3 measurements performed every morning and evening were used in the calculation of the weekly means. A weekly mean was calculated as the sum of all non-missing daily measures over the 7 sequential days divided by the number of non-missing daily measures. If more than 3 daily measures (> 50%) within a period were missing, then the weekly mean for that period was set to 'missing'. Change from run-in baseline in weekly means for morning PEF and evening PEF are presented. Baseline was the average for data collected over the last 7 days of the run-in period prior to randomization.
Time Frame	Run-in baseline (from Day -28 to Day 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	427	229
Morning	27.17 (3.98)	7.06 (5.49)
Evening	16.47 (4.04)	-6.61 (5.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from run-in baseline in morning PEF at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	20.11
	Confidence Interval	(2-Sided) 95% 6.79 to 33.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in PEF = Treatment + baseline PEF + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from run-in baseline in evening PEF at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	23.09
	Confidence Interval	(2-Sided) 95% 9.62 to 36.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in PEF = Treatment + baseline PEF + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

7. Secondary Outcome

Title	Change From Baseline in Short Form 36-item Health Survey, Version 2 (SF-36v2) to the EOT (Week 24)
Description	The SF-36v2 is a 36-item survey of functional health and well-being, with a 1 week recall period. The 8-domain profile consists of the following subscales: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The physical and mental health component summary scores are computed from subscale scores to give a broader metric of physical and mental health-related quality of life. Each domain score, as well as the physical and mental component scores, were scored on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Norm-based scoring was used to calculate the 8 SF-36v2 subscales and the 2 component scores. The LS mean change from baseline in each of the SF-36 subscale and component summary scores at Week 24 are presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	287	169
Physical functioning	17.76 (1.21)	12.42 (1.59)
Role limitations due to physical health	17.62 (1.34)	10.82 (1.76)
Bodily pain	6.44 (1.37)	3.37 (1.79)
General health perceptions	12.92 (1.01)	7.29 (1.34)
Vitality	12.04 (1.10)	6.53 (1.44)
Social functioning	12.44 (1.34)	9.32 (1.75)
Role limitations due to emotional problems	8.23 (1.18)	5.79 (1.55)
Mental health	5.57 (0.90)	3.89 (1.18)
Physical health component summary score	6.09 (0.46)	3.77 (0.60)
Mental health component summary score	2.87 (0.48)	1.99 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for physical functioning at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0077
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	5.35
	Confidence Interval	(2-Sided) 95% 1.42 to 9.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for role limitations due to physical health at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	6.80
	Confidence Interval	(2-Sided) 95% 2.45 to 11.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for bodily pain at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1741
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.07
	Confidence Interval	(2-Sided) 95% -1.36 to 7.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for general health perceptions at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.62
	Confidence Interval	(2-Sided) 95% 2.32 to 8.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for vitality at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.51
	Confidence Interval	(2-Sided) 95% 1.95 to 9.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for social functioning at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1583
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.12
	Confidence Interval	(2-Sided) 95% -1.22 to 7.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for role limitations due to emotional problems at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2103
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.44
	Confidence Interval	(2-Sided) 95% -1.38 to 6.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 subscale score for mental health at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2581
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95% -1.23 to 4.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 physical health component summary score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.32
	Confidence Interval	(2-Sided) 95% 0.84 to 3.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SF-36v2 mental health component summary score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.2751
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95% -0.70 to 2.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

8. Secondary Outcome

Title	Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24)
Description	The PGI-S is a single question asking the patient to rate the overall severity of their symptoms using a 6-point categorical response scale from 0 to 5 where 0=no symptoms and 5=very severe symptoms. Higher scores indicate a worse outcome. Improvement was defined as a PGI-S at EOT (Week 24) better than PGI-S at baseline. Important improvement was defined as PGI-S at baseline = moderate symptoms or severe symptoms or very severe symptoms shifting to PGI-S at EOT = no symptoms or very mild symptoms or mild symptoms. Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated PGI-S responder categories are presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	345	187
Improvement	61.7	53.5
Important improvement	45.5	38.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a responder classified as type 'Improvement' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0233
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95% 1.06 to 2.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + baseline score + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a responder classified as type 'Important Improvement' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0401
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95% 1.02 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + baseline score + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

9. Secondary Outcome

Title	Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24)
Description	The Investigator (clinician) and the patient were asked separately to rate the degree of change in the overall asthma status compared to the start of treatment, i.e. baseline randomization visit. A 7-point rating scale was used for the CGI-C (rated by Investigator) and PGI-C (rated by patient) where: 1=Very Much Improved; 2=Much Improved; 3=Minimally Improved; 4=No Changes; 5=Minimally Worse; 6=Much Worse, and 7=Very Much Worse. Higher scores indicate a worse outcome. Responder category definitions: Much improved = (Much improved, Very much improved); Very much improved = (Very much improved). Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated CGI-C and PGI-C responder categories are presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	427	229
CGI-C: Much improved	52.9	35.2
CGI-C: Very much improved	15.0	4.8
PGI-C: Much improved	55.9	38.2
PGI-C: Very much improved	37.7	16.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a CGI-C responder classified as type 'Much improved' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.05
	Confidence Interval	(2-Sided) 95% 1.47 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a CGI-C responder classified as type 'Very much improved' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.45
	Confidence Interval	(2-Sided) 95% 1.77 to 6.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a PGI-C responder classified as type 'Much improved' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.06
	Confidence Interval	(2-Sided) 95% 1.48 to 2.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Estimate of the log odds of being a PGI-C responder classified as type 'Very much improved' at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.02
	Confidence Interval	(2-Sided) 95% 2.02 to 4.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

10. Secondary Outcome

Title	Change From Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24)
Description	For part 1 of the PSIA only administered at baseline, patients reviewed 8 concepts (including cardinal asthma symptoms, activities, awakenings, triggers) and selected those which were typically bothersome. Based on part 1 selections, part 2 of the PSIA produced a rank ordered list of bothersome concepts individualized per the patient for subsequent evaluation. For part 3 of the PSIA assessed at baseline and during the study, patients recorded the severity of each selected symptom or impairment using an 11-point numeric rating scale where: 0=Did not experience and 10=Worst I can imagine. Higher scores indicate a worse outcome. The LS mean change from baseline in PSIA severity score for the indicated categories at Week 24 are presented. A negative change from baseline indicates an improvement in symptoms. Note: Average PSIA was calculated only where all of top 3 ranked symptoms/impairments were available, otherwise average was set to missing.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The FAS included all randomized patients who received at least 1 dose of IP, irrespective of their protocol adherence and continued participation in the study. Only patients with data available at the timepoints of testing were included in the analysis.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	319	180
Average of top 3 ranked	-2.97 (0.14)	-1.82 (0.19)
Top ranked	-3.02 (0.15)	-1.87 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in PSIA severity score for the average of top 3 ranked symptoms/impairments at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95% -1.62 to -0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in average PSIA score (top 3 ranked) =Treatment + baseline average PSIA score (top 3 ranked) + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in PSIA severity score of top ranked symptom/impairment at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95% -1.64 to -0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in PSIA score (top ranked) =Treatment + baseline PSIA score (top ranked) + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

11. Secondary Outcome

Title	Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24)
Description	The 22-item SNOT 22 questionnaire was used to assess the rhinosinusitis health status and quality of life of patients with baseline chronic rhinosinusitis with nasal polyposis. The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110. Higher scores indicate poorer outcomes. The LS mean changes from baseline in SNOT-22 total score in patients in the chronic rhinosinusitis with nasal polyposis sub-study analysis set at Week 24 are presented.
Time Frame	Baseline (Week 0) and Week 24

Outcome Measure Data

Analysis Population Description
The chronic rhinosinusitis with nasal polyposis sub-study analysis set was defined as the subset of patients with doctor-diagnosed chronic rhinosinusitis and nasal polyposis included in their medical history who had signed the informed consent to participate in the sub-study and who had received at least 1 dose of IP.

Arm/Group Title	Benralizumab	Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.	Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
Measure Participants	92	50
Least Squares Mean (Standard Error) [Scores on a scale]	-19.02 (2.27)	-10.11 (3.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benralizumab, Placebo
	Comments	Change from baseline in SNOT-22 total score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0204
	Comments
	Method	Repeated measures analysis
	Comments

Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-8.91
	Confidence Interval	(2-Sided) 95% -16.42 to -1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model: Change from baseline in SNOT-22 total score = Treatment + baseline SNOT-22 total score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

Adverse Events

	Benralizumab		Placebo
Time Frame	Adverse event (AE) data is reported for the on-treatment period + follow-up (up to a maximum of 24 weeks). Assessed until 12 Sep 2019 analysis cut-off date.
Adverse Event Reporting Description	AE definition for on-treatment period: onset date ≥ first dose of IP and ≤ scheduled EOT visit, or IP discontinuation (IPD) visit for patients prematurely discontinuing IP. If both EOT and IPD visits were missing, upper limit of the on-treatment period was defined as day of last dose of IP + 56 days. If upper limit was after end of the on-study period, upper limit was set to end of on-study period.

Arm/Group Title	Benralizumab		Placebo
Arm/Group Description	Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.		Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/427 (0%)		0/229 (0%)
Serious Adverse Events
	Benralizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/427 (5.4%)		25/229 (10.9%)
Cardiac disorders
Atrial fibrillation	0/427 (0%)	0	1/229 (0.4%)	1
Eye disorders
Mydriasis	1/427 (0.2%)	1	0/229 (0%)	0
Gastrointestinal disorders
Food poisoning	1/427 (0.2%)	1	0/229 (0%)	0
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis	1/427 (0.2%)	1	0/229 (0%)	0
Cytokine release syndrome	1/427 (0.2%)	1	0/229 (0%)	0
Infections and infestations
Appendicitis	1/427 (0.2%)	1	0/229 (0%)	0
Cellulitis	0/427 (0%)	0	1/229 (0.4%)	1
Gastroenteritis	0/427 (0%)	0	1/229 (0.4%)	1
Pneumonia	2/427 (0.5%)	2	2/229 (0.9%)	2
Respiratory tract infection	0/427 (0%)	0	1/229 (0.4%)	1
Urinary tract infection	0/427 (0%)	0	1/229 (0.4%)	1
Injury, poisoning and procedural complications
Contusion	1/427 (0.2%)	1	0/229 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/427 (0.2%)	1	0/229 (0%)	0
Diabetic ketoacidosis	1/427 (0.2%)	1	0/229 (0%)	0
Hyperglycaemic hyperosmolar nonketotic syndrome	0/427 (0%)	0	1/229 (0.4%)	1
Hypokalaemia	0/427 (0%)	0	1/229 (0.4%)	1
Musculoskeletal and connective tissue disorders
Costochondritis	1/427 (0.2%)	1	0/229 (0%)	0
Osteoarthritis	0/427 (0%)	0	1/229 (0.4%)	1
Rotator cuff syndrome	1/427 (0.2%)	1	0/229 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ	0/427 (0%)	0	1/229 (0.4%)	1
Nervous system disorders
Cerebrovascular accident	0/427 (0%)	0	1/229 (0.4%)	1
Sciatica	0/427 (0%)	0	1/229 (0.4%)	1
Renal and urinary disorders
Acute kidney injury	0/427 (0%)	0	1/229 (0.4%)	1
Nephrolithiasis	1/427 (0.2%)	1	0/229 (0%)	0
Renal failure	1/427 (0.2%)	1	0/229 (0%)	0
Reproductive system and breast disorders
Female genital tract fistula	1/427 (0.2%)	1	0/229 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	9/427 (2.1%)	10	9/229 (3.9%)	11
Epistaxis	0/427 (0%)	0	1/229 (0.4%)	1
Pneumonitis	1/427 (0.2%)	1	0/229 (0%)	0
Pneumothorax	0/427 (0%)	0	1/229 (0.4%)	1
Respiratory failure	0/427 (0%)	0	2/229 (0.9%)	2
Skin and subcutaneous tissue disorders
Urticaria	1/427 (0.2%)	1	0/229 (0%)	0
Other (Not Including Serious) Adverse Events
	Benralizumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	136/427 (31.9%)		78/229 (34.1%)
General disorders
Pyrexia	26/427 (6.1%)	29	5/229 (2.2%)	8
Infections and infestations
Bronchitis	22/427 (5.2%)	23	18/229 (7.9%)	22
Nasopharyngitis	30/427 (7%)	36	17/229 (7.4%)	23
Sinusitis	28/427 (6.6%)	32	12/229 (5.2%)	17
Upper respiratory tract infection	17/427 (4%)	19	12/229 (5.2%)	13
Nervous system disorders
Headache	37/427 (8.7%)	50	7/229 (3.1%)	11
Respiratory, thoracic and mediastinal disorders
Cough	14/427 (3.3%)	16	13/229 (5.7%)	17
Dyspnoea	7/427 (1.6%)	9	13/229 (5.7%)	19

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	Global Clinical Lead
Organization	AstraZeneca
Phone	1-877-240-9479
Email	information.center@astrazeneca.com

Responsible Party:

AstraZeneca

ClinicalTrials.gov Identifier:

NCT03170271

Other Study ID Numbers:

D3250C00045
2017-001040-35

First Posted:

May 31, 2017

Last Update Posted:

Nov 1, 2021

Last Verified:

Oct 1, 2021

ANDHI: A Study of the Safety and Effectiveness of Benralizumab to Treat Patients With Severe Uncontrolled Asthma.

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Exclusion criteria for the open label ANDHI IP sub study:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Statistical Analysis 9

Statistical Analysis 10

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Statistical Analysis 1

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact