SOLANA: A Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02869438
• Collaborator: (none)
• Enrollment: 233
• Locations: 54
• Arms: 2
• Actual Duration (Months): 20.7
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the onset and maintenance of effect of benralizumab on lung function, blood eosinophils, asthma control metrics and quality of life during 12-week treatment in patients with uncontrolled, severe asthma with eosinophilic inflammation. A subset of patients will take part in body plethysmography substudy to further investigate the effect on lung function.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Benralizumab; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 233 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3b Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation
• Actual Study Start Date: Nov 9, 2016
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Benralizumab arm Benralizumab administered subcutaneously	Drug: Benralizumab; Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
Placebo Comparator: Placebo arm Placebo administered subcutaneously	Other: Placebo; Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1 [From first IP dose to Day 84]

   The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect.

2. Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV) [From first IP dose to Day 84]

   Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines.

Secondary Outcome Measures

1. Percent Change From Baseline to End of Treatment in Eosinophils Counts [From first IP dose to Day 84]

   Percent change from baseline to Day 84

2. Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1 [From first IP dose to Day 84]

   Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, Day 84. [Note: Day 28, 56, 84 are presented in the Primary measure.]

3. Change From Baseline to Post Baseline for Pre-BD FVC [From first IP dose to Day 84]

   Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84.

4. Percentage of Pre-BD FEV1 Responder [From first IP dose to Day 84]

   Pre-BD FEV1 responder is defined as change from baseline in FEV1 >=100 ml

5. Change From Baseline in ACQ-6 [From first IP dose to Day 84]

   ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.

6. Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) [From first IP dose to Day 84]

   The SGRQ is designed to measure health impairment in patients with asthma and COPD. It contains two parts: Part 1 (Questions 1 to 8) covers the patients' recollection of their symptoms over a preceding 4 weeks; Part 2, 42 items, relates to the daily activity and psychosocial impacts of the individual's respiratory condition. Total score is presented as a percentage of overall impairment, in which 100 represents the worst possible health status, while 0 indicates the best.

7. Change From Baseline to End of Treatment in FeNO [From first IP dose to Day 84]

   Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement.

8. Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients [From first IP dose to Day 84]

   Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

9. Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients [From first IP dose to Day 84]

   Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

10. Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients [From first IP dose to Day 84]

    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

11. Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients [From first IP dose to Day 84]

    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

12. Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients [From first IP dose to Day 84]

    Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

13. Duration of IP Administration [From first IP to last IP]

    Duration of IP administration is last IP dose date - first IP dose +1.

Other Outcome Measures

1. Serum Concentration of Benralizumab [From first dose to end of treatment period (Day 84)]

   PK sample was collected pre-dose at each visit

2. PK Parameter of Benralizumab (Cmax) [First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28)]

   PK parameters are derived in patients with at least three qualifiable serum PK concentrations post first dose (collected on Day 3, 7, and either 14, or 28)

3. Anti-drug Antibody Responses [From first IP dose to end of treatment period (Day 84)]

   Anti-drug antibody responses at baseline and post baseline, including nAb responses

4. Change From Baseline to End of Treatment in PGI-S [From first IP dose to Day 84]

   The patient global impression of severity (PGI-S) is a single item designed to capture the patient's perception of overall symptom severity at the time of the completion using a 6-point categorical response scale (no symptom [0] to very severe symptom [5])

5. Change From Baseline to End of Treatment in CGI-C [From first IP dose to Day 84]

   Clinician global impression of change (CGI-C) is used for an overall evaluation of response to treatment. The investigator is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.

6. Change From Baseline to End of Treatment in PGI-C [From first IP dose to Day 84]

   Patient global impression of change (PGI-C) is used for an overall evaluation of response to treatment. The patient is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.

7. Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients [From first IP dose to Day 84]

   Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

8. Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients [From first IP dose to Day 84]

   Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria

1. Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.

2. Female and male aged 18 to 75 years inclusively at the time of Visit 1

3. Documented current treatment with ICS and LABA for at least 30 days prior to Visit 1. The ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry powder formulation or equivalent daily. Additional asthma controller medications, eg, oral corticosteroids, long-acting antimuscarinics (LAMAs), LTRAs, theophylline etc. are allowed if they have been used for at least 30 days prior to Visit 1

4. History of at least 2 asthma exacerbations that required treatment with systemic corticosteroids (intramuscular (IM), intravenous (IV), or oral) in the 12 months prior to Visit 1. For patients receiving corticosteroids as a maintenance therapy, the corticosteroid treatment for the exacerbation is defined as a temporary increase of their maintenance dose.

5. Pre-bronchodilator (pre-BD) FEV1 of < 80% predicted at Visit 2 or Visit 3

6. ACQ-6 score ≥1.5 at Visit 1

7. Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 ml) demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2 only

8. Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1

9. Women of childbearing potential (WOCBP) must use an effective form of birth control confirmed by the Investigator. WOCBP must also have negative serum pregnancy test result on Visit 1.

Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months prior to the planned date of randomization without an alternative medical cause. The following agespecific requirements apply:

• Women <50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.

• Women ≥50 years old are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.

1. All male patients who are sexually active must agree to use a double barrier method of contraception (condom with spermicide) from the first dose of IP until 16 weeks after their last dose

2. Weight of ≥40 kg

Additional inclusion criteria applicable for the Body Plethysmography substudy 1.Residual volume ≥125% of predicted at Visit 3.

Inclusion criteria at randomization visit

1. At least 1 of the following within 7 days prior to randomization:

• Daytime or nighttime asthma symptoms for 2 or more days;

• Rescue SABA use for 2 or more days;

• Nighttime awakenings due to asthma at least 1 night during the 7-day period

1. ACQ >0.75 at Visit 4 prior to randomization.

2. A negative urine pregnancy test in WOCBP prior to administration of IP

Exclusion criteria

1. Clinically important pulmonary disease other than asthma (eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome)

2. Life-threatening asthma defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.

3. Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period

4. An upper respiratory tract infection or an asthma exacerbation that required treatment with systemic corticosteroids or an increase in regular maintenance dose of OCS during the screening/run-in period prior to randomization Visit 4

5. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

• Affect the safety of the patient throughout the study

• Influence the findings of the studies or their interpretations

• Impede the patient's ability to complete the entire duration of study

1. Known history of allergy or reaction to any component of the investigational product formulation

2. History of anaphylaxis to any biologic therapy

3. History of Guillain-Barré syndrome

4. 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

5. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study

6. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening/run-in period, which in the opinion of the Investigator may put the patient at risk or interfere with study assessments

7. History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained

8. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll

9. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test

10. Current smokers or former smokers with a smoking history of ≥10 pack years. A former smoker is defined as a patient who quit smoking at least 6 months prior to Visit 1

11. Current malignancy, or history of malignancy, except for:

• Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.

• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained.

1. Use of immunosuppressive medication (including but not limited to: oral corticosteroids [for reasons other than asthma], methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any experimental anti-inflammatory therapy) within 3 months prior to the date informed consent

2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times the upper limit of normal (ULN) confirmed during screening period

3. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained

4. Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer

5. Receipt of live attenuated vaccines 30 days prior to the date of randomization

6. Receipt of any investigational medication within 30 days or 5 half-lives prior to randomization, whichever is longer

7. Previously received benralizumab (MEDI-563)

8. Planned surgical procedures during the conduct of the study

9. Currently breastfeeding or lactating women

10. Previous randomization in the present study

11. Concurrent enrolment in another interventional or post-authorization safety study (PASS).

12. AstraZeneca staff involved in the planning and/or conduct of the study

13. Employees of the study center or any other individuals involved with the conduct of the study or immediate family members of such individuals

Exclusion criteria at randomization Visit 4

1. Greater than/equal to 20% change in mean Pre BD FEV1 value at randomization Visit 4 from the mean pre BD FEV1 calculated from the pre BD FEV1 recorded at Visit 2 and Visit 3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Scottsboro	Alabama	United States	35768
2	Research Site	Gilbert	Arizona	United States	85234
3	Research Site	Denver	Colorado	United States	80206
4	Research Site	Miami	Florida	United States	33174
5	Research Site	Tampa	Florida	United States	33607
6	Research Site	Vero Beach	Florida	United States	32960
7	Research Site	Winter Park	Florida	United States	32789
8	Research Site	Fort Mitchell	Kentucky	United States	41017
9	Research Site	Rochester	Minnesota	United States	55905
10	Research Site	New Bern	North Carolina	United States	28562
11	Research Site	Cincinnati	Ohio	United States	45231
12	Research Site	Oklahoma City	Oklahoma	United States	73103
13	Research Site	Medford	Oregon	United States	97504
14	Research Site	Philadelphia	Pennsylvania	United States	19140
15	Research Site	Lampasas	Texas	United States	76550
16	Research Site	McKinney	Texas	United States	75069
17	Research Site	Curico		Chile	3341643
18	Research Site	Santiago		Chile	404366
19	Research Site	Santiago		Chile	7500692
20	Research Site	Santiago		Chile	7750495
21	Research Site	Bamberg		Germany	96049
22	Research Site	Darmstadt		Germany	64283
23	Research Site	Frankfurt am Main		Germany	60389
24	Research Site	Frankfurt am Main		Germany	60596
25	Research Site	Frankfurt		Germany	60596
26	Research Site	Hamburg		Germany	20354
27	Research Site	Hamburg		Germany	22299
28	Research Site	Hannover		Germany	30167
29	Research Site	Hannover		Germany	30625
30	Research Site	Hannover		Germany	D-30173
31	Research Site	Mainz		Germany	55131
32	Research Site	München		Germany	81377
33	Research Site	Balassagyarmat		Hungary	2660
34	Research Site	Edelény		Hungary	3780
35	Research Site	Farkasgyepü		Hungary	8582
36	Research Site	Gödöllő		Hungary	2100
37	Research Site	Hajdúnánás		Hungary	4080
38	Research Site	Komárom		Hungary	2900
39	Research Site	Miskolc		Hungary	3529
40	Research Site	Pécs		Hungary	7626
41	Research Site	Pécs		Hungary	7635
42	Research Site	Cheongju-si		Korea, Republic of	28644
43	Research Site	Daegu		Korea, Republic of	42415
44	Research Site	Jeonju-si		Korea, Republic of	54907
45	Research Site	Seoul		Korea, Republic of	03080
46	Research Site	Seoul		Korea, Republic of	03312
47	Research Site	Seoul		Korea, Republic of	03722
48	Research Site	Seoul		Korea, Republic of	05505
49	Research Site	Seoul		Korea, Republic of	06351
50	Research Site	Seoul		Korea, Republic of	06591
51	Research Site	Iloilo City		Philippines	5000
52	Research Site	Lipa City		Philippines
53	Research Site	Manila		Philippines	1000
54	Research Site	Quezon City		Philippines	0870

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Reynold A Panettieri, Doctor of Medicine, Child Health Institute of NJ, 89 French Street, Suite 4210, New Brunswick, NJ, 08901, USA

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 13, 2018
• Study Protocol - Aug 2, 2016

More Information

Additional Information:

• Protocol
• SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02869438
• Other Study ID Numbers: D3250C00038; 2016-002094-36; U1111-1185-6625
• First Posted: Aug 17, 2016
• Last Update Posted: Oct 29, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by AstraZeneca: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases
• Additional relevant MeSH terms: Asthma; Inflammation; Benralizumab

Study Results

Participant Flow

Pre-assignment Detail	233 participants were randomized to receive treatment in study D3250C00038 (Solana) with benralizumab 30 mg or placebo. Of the 233 patients randomised, all (100.0%) received treatment with study drug. 118 (50.6%) patients received benralizumab 30 mg and 115 (49.4%) patients received placebo.

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Period Title: Overall Study
STARTED	118	115
COMPLETED	115	113
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Benra 30 mg	Placebo	Total
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	Total of all reporting groups
Overall Participants	118	115	233
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.9 (13.62)	50.9 (12.34)	51.4 (12.99)
Sex: Female, Male (Count of Participants)
Female	74 62.7%	83 72.2%	157 67.4%
Male	44 37.3%	32 27.8%	76 32.6%
Race/Ethnicity, Customized (Number) [Number]
White	69 58.5%	67 58.3%	136 58.4%
Black or African American	3 2.5%	4 3.5%	7 3%
Asian	39 33.1%	40 34.8%	79 33.9%
Other	7 5.9%	4 3.5%	11 4.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline (Visit 4) to Day 28 (Visit 8), Day 56 (Visit 9), and Day 84 (Visit 10) in Pre-BD FEV1
Description	The average over the mean differences between benralizumab and placebo for change from baseline in pre-BD FEV1 is used to determine if the study is positive and to determine maintenance of effect. The first post baseline time point where the p-value for the mean difference between benralizumab and placebo is less than or equal to 0.05 is used to determine time to onset of effect.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 28	0.21 (0.335)	0.132 (0.316)
Day 56	0.22 (0.367)	0.203 (0.349)
Day 84	0.209 (0.344)	0.149 (0.366)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0707
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.077
	Confidence Interval	(2-Sided) 95%; -0.007 to 0.161
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 28

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7747
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.013
	Confidence Interval	(2-Sided) 95%; -0.077 to 0.104
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 56

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0969
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.079
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.173
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1558
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.057
	Confidence Interval	(2-Sided) 95%; -0.022 to 0.135
	Parameter Dispersion	Type: Value:
	Estimation Comments	For average over Day 28, 56, and 84

2. Primary Outcome

Title	Change From Baseline (Visit 4) to End of Treatment Day 84 (Visit 10) in Residual Volume (RV)
Description	Body plethysmography was performed for sub-study patients. Lung volume subdivisions measures were performed by the investigator or qualified designee according to ATS/ERS guidelines.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [Liter]	-0.415 (0.609)	-0.208 (0.528)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2847
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline RV, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.176
	Confidence Interval	(2-Sided) 95%; -0.505 to 0.153
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change From Baseline to End of Treatment in Eosinophils Counts
Description	Percent change from baseline to Day 84
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Mean (Full Range) [Percent change]	-88.55	11.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline eosinophils counts, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-101.0
	Confidence Interval	(2-Sided) 95%; -118.9 to -83.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline (Visit 4) to Post Baseline Visits in Pre-BD FEV1
Description	Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, Day 84. [Note: Day 28, 56, 84 are presented in the Primary measure.]
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 3	0.104 (0.223)	0.081 (0.269)
Day 7	0.125 (0.229)	0.081 (0.263)
Day 14	0.126 (0.3)	0.1 (0.287)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6384
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.049 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 3

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.148
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.046
	Confidence Interval	(2-Sided) 95%; -0.016 to 0.109
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 7

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4959
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95%; -0.049 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 14

5. Secondary Outcome

Title	Change From Baseline to Post Baseline for Pre-BD FVC
Description	Post baseline visits include Day 3, Day 7, Day 14, Day 28, Day 56, and Day 84.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 3	0.122 (0.247)	0.11 (0.267)
Day 7	0.138 (0.277)	0.099 (0.292)
Day 14	0.126 (0.331)	0.111 (0.312)
Day 28	0.21 (0.347)	0.134 (0.34)
Day 56	0.211 (0.404)	0.187 (0.369)
Day 84	0.213 (0.376)	0.131 (0.359)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8667
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.006
	Confidence Interval	(2-Sided) 95%; -0.062 to 0.073
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 3

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2734
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; -0.033 to 0.115
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 7

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7252
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.015
	Confidence Interval	(2-Sided) 95%; -0.068 to 0.098
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 14

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0976
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.075
	Confidence Interval	(2-Sided) 95%; -0.014 to 0.164
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 28

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6536
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.023
	Confidence Interval	(2-Sided) 95%; -0.077 to 0.122
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 56

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0595
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; -0.004 to 0.188
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1377
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline pre-BD FVC, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.063
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.147
	Parameter Dispersion	Type: Value:
	Estimation Comments	For average of Day 28, 56, 84.

6. Secondary Outcome

Title	Percentage of Pre-BD FEV1 Responder
Description	Pre-BD FEV1 responder is defined as change from baseline in FEV1 >=100 ml
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 3	48.2 40.8%	37.4 32.5%
Day 7	48.3 40.9%	42.0 36.5%
Day 14	50.0 42.4%	38.9 33.8%
Day 28	57.6 48.8%	46.9 40.8%
Day 56	62.1 52.6%	55.8 48.5%
Day 84	57.9 49.1%	51.8 45%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1604
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.85 to 2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 3

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3400
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 7

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0924
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.58
	Confidence Interval	(2-Sided) 95%; 0.93 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 14

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1052
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 0.91 to 2.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 28

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3271
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.77 to 2.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 56

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3017
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, baseline pre-BD FEV1, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 0.77 to 2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

7. Secondary Outcome

Title	Change From Baseline in ACQ-6
Description	ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 14	-0.989 (0.901)	-0.665 (0.837)
Day 28	-1.126 (0.947)	-0.693 (0.869)
Day 56	-1.164 (1.132)	-0.827 (1.023)
Day 84	-1.355 (1.146)	-0.867 (1.114)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline ACQ-6 score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.293
	Confidence Interval	(2-Sided) 95%; -0.481 to -0.105
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 14

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline ACQ-6 score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.402
	Confidence Interval	(2-Sided) 95%; -0.609 to -0.195
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 28

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0117
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline ACQ-6 score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.312
	Confidence Interval	(2-Sided) 95%; -0.554 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 56

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline ACQ-6 score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.472
	Confidence Interval	(2-Sided) 95%; -0.731 to -0.213
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline ACQ-6 score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.395
	Confidence Interval	(2-Sided) 95%; -0.603 to -0.188
	Parameter Dispersion	Type: Value:
	Estimation Comments	For average of Day 28, 56, 84.

8. Secondary Outcome

Title	Change From Baseline in St. George's Respiratory Questionnaire (SGRQ)
Description	The SGRQ is designed to measure health impairment in patients with asthma and COPD. It contains two parts: Part 1 (Questions 1 to 8) covers the patients' recollection of their symptoms over a preceding 4 weeks; Part 2, 42 items, relates to the daily activity and psychosocial impacts of the individual's respiratory condition. Total score is presented as a percentage of overall impairment, in which 100 represents the worst possible health status, while 0 indicates the best.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Day 28	-16.956 (15.51)	-9.444 (14.136)
Day 56	-19.941 (21.528)	-13.802 (16.705)
Day 84	-23.343 (20.302)	-14.385 (18.836)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline SGRQ score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.229
	Confidence Interval	(2-Sided) 95%; -10.832 to -3.626
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 28

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0115
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline SGRQ score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.942
	Confidence Interval	(2-Sided) 95%; -10.538 to -1.346
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 56

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline SGRQ score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.599
	Confidence Interval	(2-Sided) 95%; -13.3 to -3.898
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline SGRQ score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.257
	Confidence Interval	(2-Sided) 95%; -11.133 to -3.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	For average of Day 28, 56, 84.

9. Secondary Outcome

Title	Change From Baseline to End of Treatment in FeNO
Description	Airway inflammation was evaluated via fractional exhaled nitric oxide (FeNO) measurement.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Mean (Standard Deviation) [ppb]	5.92 (45.295)	0.05 (27.634)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2825
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline FeNO value, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.414
	Confidence Interval	(2-Sided) 95%; -4.492 to 15.321
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline to End of Treatment in Total Lung Capacity (TLC) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [Liter]	-0.276 (0.677)	-0.175 (0.418)

11. Secondary Outcome

Title	Change From Baseline to End of Treatment in Ratio of Residual Volume (RV) and Total Lung Capacity (TLC) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [ratio]	-0.05 (0.056)	-0.026 (0.087)

12. Secondary Outcome

Title	Change From Baseline to End of Treatment in Inspiratory Capacity (IC) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [Liter]	0.119 (0.447)	-0.268 (0.603)

13. Secondary Outcome

Title	Change From Baseline to End of Treatment in Functional Residual Capacity (FRC) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [Liter]	-0.394 (0.783)	0.093 (0.466)

14. Secondary Outcome

Title	Change From Baseline to End of Treatment in Vital Capacity (VC) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [Liter]	0.139 (0.245)	0.033 (0.676)

15. Secondary Outcome

Title	Duration of IP Administration
Description	Duration of IP administration is last IP dose date - first IP dose +1.
Time Frame	From first IP to last IP

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Mean (Standard Deviation) [Days]	55.9 (7.83)	56.2 (7.61)

16. Other Pre-specified Outcome

Title	Serum Concentration of Benralizumab
Description	PK sample was collected pre-dose at each visit
Time Frame	From first dose to end of treatment period (Day 84)

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Benra 30 mg
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	117
Baseline	1.95 (NA)
Day 3	1266.78 (199.59)
Day 7	1449.47 (125.02)
Day 14	1317.92 (79.53)
Day 28	738.47 (80.77)
Day 56	1015.72 (59.74)
Day 84	1079.22 (73.24)

17. Other Pre-specified Outcome

Title	PK Parameter of Benralizumab (Cmax)
Description	PK parameters are derived in patients with at least three qualifiable serum PK concentrations post first dose (collected on Day 3, 7, and either 14, or 28)
Time Frame	First IP dose cycle (ie, data collected on Days 3, 7, 14 and 28)

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Benra 30 mg
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	117
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1729.6 (36.8)

18. Other Pre-specified Outcome

Title	Anti-drug Antibody Responses
Description	Anti-drug antibody responses at baseline and post baseline, including nAb responses
Time Frame	From first IP dose to end of treatment period (Day 84)

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
ADA prevalence	7 5.9%	2 1.7%
nAb prevalence	2 1.7%	0 0%
Both baseline and post baseline positive	1 0.8%	2 1.7%
Only post baseline positive	5 4.2%	0 0%
Only baseline positive	1 0.8%	0 0%

19. Other Pre-specified Outcome

Title	Change From Baseline to End of Treatment in PGI-S
Description	The patient global impression of severity (PGI-S) is a single item designed to capture the patient's perception of overall symptom severity at the time of the completion using a 6-point categorical response scale (no symptom [0] to very severe symptom [5])
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Mean (Standard Deviation) [Score on a scale]	-1.2 (1.31)	-0.8 (1.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0120
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes covariates of treatment, baseline PGI-S score, region, visit, treatment by visit interaction.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.365
	Confidence Interval	(2-Sided) 95%; -0.649 to -0.081
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

20. Other Pre-specified Outcome

Title	Change From Baseline to End of Treatment in CGI-C
Description	Clinician global impression of change (CGI-C) is used for an overall evaluation of response to treatment. The investigator is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Very much improved	18 15.3%	10 8.7%
Much improved	39 33.1%	36 31.3%
Minimally improved	39 33.1%	28 24.3%
No change	17 14.4%	28 24.3%
Minimally worse	0 0%	7 6.1%
Much worse	0 0%	1 0.9%
Very much worse	0 0%	0 0%
Missing	5 4.2%	5 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments	Responder analysis: responder is defined as Very much improved, improved, and minimally improved.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, region.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.97
	Confidence Interval	(2-Sided) 95%; 1.50 to 5.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

21. Other Pre-specified Outcome

Title	Change From Baseline to End of Treatment in PGI-C
Description	Patient global impression of change (PGI-C) is used for an overall evaluation of response to treatment. The patient is asked to rate the degree of change in overall asthma status compare to the start of treatment. A 7-point rating scale is used from 1=very much improved to 7=very much worse.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	118	115
Very much improved	32 27.1%	17 14.8%
Much improved	42 35.6%	35 30.4%
Minimally improved	23 19.5%	29 25.2%
No change	14 11.9%	27 23.5%
Minimally worse	1 0.8%	4 3.5%
Much worse	1 0.8%	1 0.9%
Very much worse	1 0.8%	0 0%
Missing	4 3.4%	2 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg, Placebo
	Comments	Responder analysis: responder is defined as Very much improved, improved, and minimally improved.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0107
	Comments
	Method	Regression, Logistic
	Comments	Model includes covariates of treatment, region.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.51
	Confidence Interval	(2-Sided) 95%; 1.24 to 5.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	For Day 84

22. Other Pre-specified Outcome

Title	Change From Baseline to End of Treatment in Specific Airway Resistance (SGaw) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [1/(kPa*sec)]	-0.05 (0.146)	0.052 (0.224)

23. Other Pre-specified Outcome

Title	Change From Baseline to End of Treatment in Airway Resistance (Raw) for Sub-study Patients
Description	Lung volume subdivisions include total lung capacity (TLC), residual volume (RV), vital capacity (VC), functional residual capacity (FRC), and inspiratory capacity (IC), as well as airway resistance (Raw and SGaw) measurements.
Time Frame	From first IP dose to Day 84

Outcome Measure Data

Analysis Population Description

Body plethysmography sub-study analysis set

Arm/Group Title	Benra 30 mg	Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).	12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
Measure Participants	18	22
Mean (Standard Deviation) [kPa/L/sec]	-0.233 (1.509)	-0.2 (0.532)

Adverse Events

Time Frame	From informed consent form was signed to end of study (ie, Day 112 follow-up)
Arm/Group Title	Benra 30 mg		Placebo
Arm/Group Description	12-week treatment period and receive Benra 30 mg at Day 0, Day 28 (±3 days), and Day 56 (±3 days).		12-week treatment period and receive Placebo at Day 0, Day 28 (±3 days), and Day 56 (±3 days).
All Cause Mortality
	Benra 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/118 (0%)		0/115 (0%)
Serious Adverse Events
	Benra 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/118 (0.8%)		7/115 (6.1%)
Cardiac disorders
Coronary artery disease	0/118 (0%)	0	1/115 (0.9%)	1
Immune system disorders
Drug hypersensitivity	1/118 (0.8%)	1	0/115 (0%)	0
Infections and infestations
Lower respiratory tract infection	0/118 (0%)	0	1/115 (0.9%)	1
Pneumonia	0/118 (0%)	0	2/115 (1.7%)	2
Nervous system disorders
Generalised tonic-clonic seizure	0/118 (0%)	0	1/115 (0.9%)	1
Migraine	0/118 (0%)	0	1/115 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/118 (0%)	0	2/115 (1.7%)	2
Other (Not Including Serious) Adverse Events
	Benra 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/118 (23.7%)		30/115 (26.1%)
Infections and infestations
Bronchitis	6/118 (5.1%)	6	3/115 (2.6%)	3
Nasopharyngitis	8/118 (6.8%)	9	6/115 (5.2%)	7
Upper respiratory tract infection	6/118 (5.1%)	7	6/115 (5.2%)	8
Respiratory, thoracic and mediastinal disorders
Asthma	11/118 (9.3%)	11	18/115 (15.7%)	22

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

≥ 60 days prior to submission of material for publication/presentation, Institution and PI shall jointly provide AZ with material for review. No publication/presentation may include any of AZ's Confidential Information without AZ's written approval. AZ can request Inst. and PI to withhold material from submission for publication/presentation for an additional 90 days to allow AZ to establish and preserve its proprietary rights in the material being submitted for publication or presentation.