SOURCE: Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03406078
• Collaborator: Amgen (Industry)
• Enrollment: 150
• Locations: 60
• Arms: 2
• Actual Duration (Months): 30.7
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma

Condition or Disease	Intervention/Treatment	Phase
Asthma	Biological: Tezepelumab; Other: Placebo	Phase 3

Detailed Description

A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneouslySubjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Double-Blind
• Primary Purpose: Treatment
• Official Title: A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma (SOURCE)
• Actual Study Start Date: Mar 5, 2018
• Actual Primary Completion Date: Sep 25, 2020
• Actual Study Completion Date: Sep 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tezepelumab Tezepelumab subcutaneous injection	Biological: Tezepelumab; Tezepelumab subcutaneous injection
Placebo Comparator: Placebo Placebo subcutaneous injection	Other: Placebo; Placebo subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. Categorized Percent Reduction From Baseline in the Daily OCS Dose While Not Losing Asthma Control [Baseline to Week 48]

   Categorized percent reduction from baseline at Week 48. Percent change from baseline is defined as {final dose-baseline dose)/baseline dose}*100, and the categories of percent change from baseline in daily OCS dose are defined as: ≥90% to ≤100% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and, no change or any increase.

Secondary Outcome Measures

1. Annualised Asthma Exacerbation Rate (AAER) [Baseline to Week 48]

   The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 48 weeks.

2. Proportion of Subjects With 100% Reduction From Baseline in Daily OCS Dose at Week 48 [Baseline to Week 48]

   Proportion (expressed as a percentage) of subjects with 100% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.

3. Proportion of Subjects With Daily OCS Dose ≤5 mg at Week 48 [Week 48]

   Proportion (expressed as a percentage) of subjects with daily OCS dose ≤5 mg at Week 48.

4. Proportion of Subjects With ≥50% Reduction From Baseline in Daily OCS Dose at Week 48 [Baseline to Week 48]

   Proportion (expressed as a percentage) of subjects with ≥50% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.

5. Change From Baseline in Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in 1 Second (FEV1) [Baseline to Week 48]

   Change from baseline in pre-BD FEV1 at Week 48. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration.

6. Change From Baseline in Weekly Mean Daily Asthma Symptom Score Via the Daily Asthma Symptom Diary [Baseline to Week 48]

   Change from baseline in Asthma Symptom Diary score at Week 48. The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4, where 0 indicates no asthma symptoms.

7. Change From Baseline in Weekly Mean Rescue Medication Use [Baseline to Week 48]

   Change from baseline in weekly mean rescue medication use at Week 48. Daily rescue medication use is defined as: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of daytime inhaler puffs + 2 x [number of day nebulizer times]. Each timepoint is calculated as weekly means based on daily diary data.

8. Change From Baseline in Weekly Mean Home Peak Expiratory Flow (PEF) (Morning and Evening) [Baseline to Week 48]

   Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) at Week 48. Home PEF testing will be performed by the subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means using at least 4 of the 7 days of PEF data.

9. Change From Baseline in Weekly Mean Number of Night-time Awakening Due to Asthma [Baseline to Week 48]

   Change from baseline in weekly mean number (expressed as a percentage) of night time awakenings at Week 48. Night-time awakenings percentage defined as number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%. At least 4 out of 7 days of data is required to calculate a weekly mean.

10. Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score [Baseline to Week 48]

    Change from baseline in ACQ-6 at Week 48. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses.

11. Change From Baseline in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(s)+12) Total Score [Baseline to Week 48]

    Change from baseline in AQLQ(S)+12 as compared to placebo at Week 48. The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma subjects. The total score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment).

12. Change From Baseline in European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) Score [Baseline to Week 48]

    Change from baseline in EQ-5D-5L at Week 48. The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no/slight/moderate/severe/extreme problems) that reflect increasing levels of difficulty. The EQ-5D-5L scores are converted into a single index-based value (Health State Valuation), using the UK population-based weights. The Helth State Valuation is scored between 0 to 1, where higher score indicates a better health state.

13. Number of Participants With Asthma Specific Resource Utilizations [Baseline to Week 48]

    Number of participants with asthma specific resource utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 48 weeks.

14. Change From Baseline in Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire (WPAI+CIQ) Score [Baseline to Week 48]

    Change from baseline in WPAI+CIQ score at Week 48. The WPAI+CIQ consists of 10 questions about how asthma and asthma related issues impact a subject's ability to work, attend classes, and perform regular daily activities. Work (Class) productivity loss is derived by sum of percentage of missed work (class hours) due to asthma and product of percentage of actual working hours (class) times degree of asthma affecting work (class) productivity while working. Percentage of missed work (class hours) due to asthma is calculated by number of hours missed work (class) due to asthma divided by total number of hours missed work (class) plus number of hours actually worked (in class). Activity impairment is the degree health affected regular activities (other than work or class) rated from 0 to 10, with 0 meaning no effect, divided by 10, and then expressed as a percentage.

15. Change From Baseline in FENO [Baseline to Week 48]

    Change from baseline in fractional exhaled nitric oxide (FeNO) at week 48.

16. Change From Baseline in Peripheral Blood Eosinophils [Baseline to Week 48]

    Change from baseline in blood eosinophil counts at week 48.

17. Change From Baseline From Total Serum IgE [Baseline to Week 48]

    Change from baseline in total serum IgE at week 48.

18. PK: Serum Trough Concentrations [Pre-dose samples at Baseline, Week 4, Week 12, Week 24, Week 40, Week 48, Week 60]

    Serum trough concentrations at each scheduled visit.

19. Immunogenicity: Incidence of Anti-drug Antibodies (ADA) [Baseline to Week 60]

    Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Treatment boosted ADA defined as baseline positive ADA that was boosted to a 4 fold or higher level following treatment. Treatment emergent ADA defined as sum of treatment induced ADA and treatment boosted ADA.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subjects must have received a physician-prescribed medium- or high-dose ICS as per GINA guideline for at least 12 months

2. Subjects must have received physician prescribed LABA and high dose ICS (total daily dose >500μg fluticasone propionate dry powder formulation equivalent) for at least 3 months. The ICS and LABA can be parts of a combination product, or given by separate inhalers.

3. Additional maintenance asthma controller medications are allowed according to standard practice of care i.e., leukotriene receptor antagonists (LTRAs), theophylline, long-acting muscarinic antagonists (LAMAs), secondary ICS and cromones. The use of these medications must be documented for at least 3 months

4. Subjects must have received OCS for the treatment of asthma for at least 6 months prior to screening and on a stable dose of between ≥ 7.5 to ≤ 30mg (prednisone or prednisolone equivalent) daily or daily equivalent for at least 1 month. The OCS dose may be administered every other day (or different doses every other day); Average dose over two days = The daily dose.

5. Morning pre-bronchodilator (BD) FEV1 must be < 80% predicted normal

6. Subjects must have evidence of asthma as documented by post-BD (albuterol/salbutatomol) reversibility of FEV1 ≥12% and ≥200 mL (15-30 min after administration of 4 puffs of albuterol/salbutamol), documented either in the previous 12 months

7. Subjects must have a history of at least 1 asthma exacerbation event within 12 months

8. Minimum 10 days compliance with the morning and evening eDiary completion and OCS,ICS,LABA as well as other asthma controller medications as captured in the eDiary during the 14 days prior to randomization

9. Documented physician-diagnosed asthma for at least 12 months

Exclusion Criteria:

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

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

Affect the safety of the subject throughout the study Influence the findings of the study or the interpretation Impede the subject's ability to complete the entire duration of study

1. History of cancer: Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to visit 1.Subjects who have had other malignancies are eligible provided that curative therapy was completed at least 5 years

2. A helminth parasitic infection diagnosed within 6 months prior to screening that has not been treated with, or has failed to respond to, standard of care therapy.

3. Current smokers or subjects with smoking history ≥ 10 pack-years and subjects using vaping products, including electronic cigarettes. Former smokers with a smoking history of <10 pack years and users of vaping or e-cigarette products must have stopped for at least 6 months prior to visit 1 to be eligible.

4. History of chronic alcohol or drug abuse within 12 months

5. Tuberculosis requiring treatment within the 12 months

6. History of any known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.

7. Major surgery within 8 weeks prior to visit 1 or planned surgical procedures requiring general anaesthesia or in-subject status for >1 day during the conduct of the study.

8. Clinically significant asthma exacerbation, in the opinion of the Investigator, including those requiring use of systemic corticosteroids or increase in the maintenance dose of OCS within 30 days

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Bakersfield	California	United States	93301
2	Research Site	Newark	Delaware	United States	19713
3	Research Site	Kissimmee	Florida	United States	34741
4	Research Site	Kissimmee	Florida	United States	34746
5	Research Site	Fall River	Massachusetts	United States	02721
6	Research Site	Ann Arbor	Michigan	United States	48109
7	Research Site	Saint Louis	Missouri	United States	63141
8	Research Site	Bronx	New York	United States	10461
9	Research Site	Durham	North Carolina	United States	27705
10	Research Site	Greenville	North Carolina	United States	27834
11	Research Site	Cincinnati	Ohio	United States	45231
12	Research Site	Cleveland	Ohio	United States	44130
13	Research Site	Toledo	Ohio	United States	43617
14	Research Site	Oklahoma City	Oklahoma	United States	73109
15	Research Site	Altoona	Pennsylvania	United States	16602
16	Research Site	Homestead	Pennsylvania	United States	15120
17	Research Site	Philadelphia	Pennsylvania	United States	19140
18	Research Site	Anderson	South Carolina	United States	29621
19	Research Site	North Charleston	South Carolina	United States	29406
20	Research Site	McKinney	Texas	United States	75069
21	Research Site	San Antonio	Texas	United States	78251
22	Research Site	Buenos Aires		Argentina	C1414AIF
23	Research Site	Ciudad de Buenos Aire		Argentina	C1425BEN
24	Research Site	Córdoba		Argentina	X5003DCE
25	Research Site	Mendoza		Argentina	5500
26	Research Site	Quilmes		Argentina	B1878FNR
27	Research Site	San Fernando		Argentina	1646
28	Research Site	San Miguel de Tucuman		Argentina	T4000IAR
29	Research Site	Aschaffenburg		Germany	63739
30	Research Site	Bamberg		Germany	96049
31	Research Site	Berlin		Germany	10367
32	Research Site	Berlin		Germany	10717
33	Research Site	Berlin		Germany	10969
34	Research Site	Hamburg		Germany	22299
35	Research Site	Hannover		Germany	30625
36	Research Site	Hannover		Germany	D-30173
37	Research Site	Koblenz		Germany	56068
38	Research Site	Lübeck		Germany	23552
39	Research Site	Mainz Am Rhein		Germany	55131
40	Research Site	München		Germany	81377
41	Research Site	Daegu		Korea, Republic of	42415
42	Research Site	Seoul		Korea, Republic of	03082
43	Research Site	Seoul		Korea, Republic of	03312
44	Research Site	Seoul		Korea, Republic of	03722
45	Research Site	Seoul		Korea, Republic of	05505
46	Research Site	Seoul		Korea, Republic of	06351
47	Research Site	Seoul		Korea, Republic of	06591
48	Research Site	Kraków		Poland	31-559
49	Research Site	Wrocław		Poland	53-301
50	Research Site	Łódź		Poland	90-153
51	Research Site	Adana		Turkey	01330
52	Research Site	Ankara		Turkey	06230
53	Research Site	Ankara		Turkey	06280
54	Research Site	Bursa		Turkey	16059
55	Research Site	Istanbul		Turkey	34098
56	Research Site	Manisa		Turkey	45030
57	Research Site	Dnipro		Ukraine	49007
58	Research Site	Kherson		Ukraine	73000
59	Research Site	Lutsk		Ukraine	4300
60	Research Site	Vinnytsia		Ukraine	21029

Sponsors and Collaborators

• AstraZeneca
• Amgen

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 14, 2020
• Statistical Analysis Plan - Oct 22, 2020

More Information

Additional Information:

• CSP redacted
• SAP redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03406078
• Other Study ID Numbers: D5180C00009
• First Posted: Jan 23, 2018
• Last Update Posted: Dec 9, 2021
• Last Verified: Nov 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: No
• Keywords provided by AstraZeneca: Asthma
• Additional relevant MeSH terms: Asthma

Study Results

Participant Flow

Recruitment Details	The study was conducted at 60 centres in 7 countries. A total of 243 subjects were screened between 5MAR2018 and 27SEP2019, of which 150 were randomized and treated. 93 subjects were screen failures mainly due to exclusion criteria met and/or inclusion criteria not met. Assignment was done by Interactive Voice/Web Response System(IVRS/IWRS).
Pre-assignment Detail	The screening period included a Run-in (2 weeks) and an OCS optimization phase (up to 8 weeks). At the end of period, subjects were randomized in 1:1 ratio for tezepelumab or placebo. Randomization was stratified by region (Central/Eastern Europe, Western Europe and North America, Rest of the World).

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Period Title: Overall Study
STARTED	74	76
COMPLETED	68	73
NOT COMPLETED	6	3

Baseline Characteristics

Arm/Group Title	Tezepelumab	Placebo	Total
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously	Total of all reporting groups
Overall Participants	74	76	150
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.5 (12.1)	53.4 (11.9)	53.4 (12.0)
Sex: Female, Male (Count of Participants)
Female	49 66.2%	45 59.2%	94 62.7%
Male	25 33.8%	31 40.8%	56 37.3%
Race/Ethnicity, Customized (Number) [Number]
White	62 83.8%	64 84.2%	126 84%
Black or African American	1 1.4%	0 0%	1 0.7%
Asian	11 14.9%	11 14.5%	22 14.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	0 0%
Other	0 0%	1 1.3%	1 0.7%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	10 13.5%	14 18.4%	24 16%
Not Hispanic or Latino	64 86.5%	62 81.6%	126 84%

Outcome Measures

1. Primary Outcome

Title	Categorized Percent Reduction From Baseline in the Daily OCS Dose While Not Losing Asthma Control
Description	Categorized percent reduction from baseline at Week 48. Percent change from baseline is defined as {final dose-baseline dose)/baseline dose}*100, and the categories of percent change from baseline in daily OCS dose are defined as: ≥90% to ≤100% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and, no change or any increase.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
>=90% to <=100% reduction	40 54.1%	35 46.1%
>=75% to <90% reduction	5 6.8%	4 5.3%
>=50% to <75% reduction	10 13.5%	14 18.4%
>0% to <50% reduction	5 6.8%	9 11.8%
no change or any increase	14 18.9%	14 18.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tezepelumab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.434
	Comments
	Method	Proportional odds model
	Comments	Response variable: categorised % reduction from baseline in final OCS dose. Covariates in the model: treatment, region and daily OCS dose at baseline.
Method of Estimation	Estimation Parameter	Cumulative Odds Ratio
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Annualised Asthma Exacerbation Rate (AAER)
Description	The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 48 weeks.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Least Squares Mean (95% Confidence Interval) [Events per year]	1.38	2.00

3. Secondary Outcome

Title	Proportion of Subjects With 100% Reduction From Baseline in Daily OCS Dose at Week 48
Description	Proportion (expressed as a percentage) of subjects with 100% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Number [Percentage of participants]	54.1 73.1%	46.1 60.7%

4. Secondary Outcome

Title	Proportion of Subjects With Daily OCS Dose ≤5 mg at Week 48
Description	Proportion (expressed as a percentage) of subjects with daily OCS dose ≤5 mg at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Number [Percentage of participants]	71.6 96.8%	72.4 95.3%

5. Secondary Outcome

Title	Proportion of Subjects With ≥50% Reduction From Baseline in Daily OCS Dose at Week 48
Description	Proportion (expressed as a percentage) of subjects with ≥50% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Number [Percentage of participants]	74.3 100.4%	69.7 91.7%

6. Secondary Outcome

Title	Change From Baseline in Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in 1 Second (FEV1)
Description	Change from baseline in pre-BD FEV1 at Week 48. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	65	64
Least Squares Mean (Standard Error) [Litre]	0.21 (0.046)	-0.04 (0.046)

7. Secondary Outcome

Title	Change From Baseline in Weekly Mean Daily Asthma Symptom Score Via the Daily Asthma Symptom Diary
Description	Change from baseline in Asthma Symptom Diary score at Week 48. The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4, where 0 indicates no asthma symptoms.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	58	68
Least Squares Mean (Standard Error) [Score on a scale]	-0.36 (0.071)	-0.26 (0.068)

8. Secondary Outcome

Title	Change From Baseline in Weekly Mean Rescue Medication Use
Description	Change from baseline in weekly mean rescue medication use at Week 48. Daily rescue medication use is defined as: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of daytime inhaler puffs + 2 x [number of day nebulizer times]. Each timepoint is calculated as weekly means based on daily diary data.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	60	70
Least Squares Mean (Standard Error) [Weekly mean rescue medication use]	-0.85 (0.280)	-0.37 (0.268)

9. Secondary Outcome

Title	Change From Baseline in Weekly Mean Home Peak Expiratory Flow (PEF) (Morning and Evening)
Description	Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) at Week 48. Home PEF testing will be performed by the subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means using at least 4 of the 7 days of PEF data.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
morning PEF	13.29 (5.653)	-9.71 (5.435)
evening PEF	10.05 (5.980)	-11.37 (5.749)

10. Secondary Outcome

Title	Change From Baseline in Weekly Mean Number of Night-time Awakening Due to Asthma
Description	Change from baseline in weekly mean number (expressed as a percentage) of night time awakenings at Week 48. Night-time awakenings percentage defined as number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%. At least 4 out of 7 days of data is required to calculate a weekly mean.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	59	70
Least Squares Mean (Standard Error) [Percentage of nights with awakenings]	-15.71 (3.482)	-12.79 (3.317)

11. Secondary Outcome

Title	Change From Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score
Description	Change from baseline in ACQ-6 at Week 48. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	66	68
Least Squares Mean (Standard Error) [Score on a scale]	-0.87 (0.125)	-0.51 (0.123)

12. Secondary Outcome

Title	Change From Baseline in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(s)+12) Total Score
Description	Change from baseline in AQLQ(S)+12 as compared to placebo at Week 48. The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma subjects. The total score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment).
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	66	67
Least Squares Mean (Standard Error) [Score on a scale]	0.94 (0.124)	0.58 (0.123)

13. Secondary Outcome

Title	Change From Baseline in European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) Score
Description	Change from baseline in EQ-5D-5L at Week 48. The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no/slight/moderate/severe/extreme problems) that reflect increasing levels of difficulty. The EQ-5D-5L scores are converted into a single index-based value (Health State Valuation), using the UK population-based weights. The Helth State Valuation is scored between 0 to 1, where higher score indicates a better health state.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	62	58
Least Squares Mean (Standard Error) [Score on a scale]	0.07 (0.026)	0.00 (0.027)

14. Secondary Outcome

Title	Number of Participants With Asthma Specific Resource Utilizations
Description	Number of participants with asthma specific resource utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 48 weeks.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Hospitalisation	5 6.8%	10 13.2%
Emergency room visit	4 5.4%	7 9.2%
Unscheduled visit to specialist	29 39.2%	41 53.9%
Home visit	1 1.4%	2 2.6%
Telephone call	26 35.1%	43 56.6%
Ambulance transport	0 0%	1 1.3%

15. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire (WPAI+CIQ) Score
Description	Change from baseline in WPAI+CIQ score at Week 48. The WPAI+CIQ consists of 10 questions about how asthma and asthma related issues impact a subject's ability to work, attend classes, and perform regular daily activities. Work (Class) productivity loss is derived by sum of percentage of missed work (class hours) due to asthma and product of percentage of actual working hours (class) times degree of asthma affecting work (class) productivity while working. Percentage of missed work (class hours) due to asthma is calculated by number of hours missed work (class) due to asthma divided by total number of hours missed work (class) plus number of hours actually worked (in class). Activity impairment is the degree health affected regular activities (other than work or class) rated from 0 to 10, with 0 meaning no effect, divided by 10, and then expressed as a percentage.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

The work productivity loss is only applicable to subjects who were employed, which is a subset of the study population. The class productivity loss is only applicable to subjects attending school, which is a subset of the study population. No subject in Placebo arm has selected the option 'in school' on the WPAI+CIQ questionnaire at Week 48.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
Work productivity loss	-6.27 (25.30)	-9.66 (36.63)
Class productivity loss	-10.00 (0)
Activity impairment	-13.2 (29.3)	-7.8 (26.4)

16. Secondary Outcome

Title	Change From Baseline in FENO
Description	Change from baseline in fractional exhaled nitric oxide (FeNO) at week 48.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	58	57
Least Squares Mean (Standard Error) [ppb]	-11.71 (2.757)	-1.40 (2.774)

17. Secondary Outcome

Title	Change From Baseline in Peripheral Blood Eosinophils
Description	Change from baseline in blood eosinophil counts at week 48.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	63	67
Least Squares Mean (Standard Error) [cells/μL]	-83.79 (17.078)	33.38 (16.605)

18. Secondary Outcome

Title	Change From Baseline From Total Serum IgE
Description	Change from baseline in total serum IgE at week 48.
Time Frame	Baseline to Week 48

Outcome Measure Data

Analysis Population Description

Number of participants analysed presents the number of subjects with an observation at Week 48. All subjects from the Full Analysis Set with at least one change from baseline value at any post baseline visit contributes to the analyses.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	65	67
Least Squares Mean (Standard Error) [IU/mL]	-80.66 (36.253)	37.77 (35.621)

19. Secondary Outcome

Title	PK: Serum Trough Concentrations
Description	Serum trough concentrations at each scheduled visit.
Time Frame	Pre-dose samples at Baseline, Week 4, Week 12, Week 24, Week 40, Week 48, Week 60

Outcome Measure Data

Analysis Population Description

The placebo arm is not applicable since it is not the experimental product.

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	0
Baseline	0 (0)
Week 4	10.3298 (42.31)
Week 12	17.9626 (57.85)
Week 24	18.9210 (55.83)
Week 40	16.7095 (181.44)
Week 48	13.9224 (352.35)
Week 60	3.5591 (177.36)

20. Secondary Outcome

Title	Immunogenicity: Incidence of Anti-drug Antibodies (ADA)
Description	Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Treatment boosted ADA defined as baseline positive ADA that was boosted to a 4 fold or higher level following treatment. Treatment emergent ADA defined as sum of treatment induced ADA and treatment boosted ADA.
Time Frame	Baseline to Week 60

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tezepelumab	Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously	Placebo administered every 4 weeks subcutaneously
Measure Participants	74	76
ADA positive at baseline and/or post-baseline (ADA prevalence)	3 4.1%	2 2.6%
Any baseline ADA positive	2 2.7%	2 2.6%
Only baseline ADA positive	1 1.4%	1 1.3%
Any post-baseline ADA positive	2 2.7%	1 1.3%
Both baseline and at least one post-baseline ADA positive	1 1.4%	1 1.3%
Treatment-induced ADA positive	1 1.4%	0 0%
Treatment-boosted ADA positive	0 0%	0 0%
TE-ADA positive (ADA incidence)	1 1.4%	0 0%
ADA persistently positive	1 1.4%	1 1.3%
ADA transiently positive	1 1.4%	0 0%

Adverse Events

Time Frame	Baseline to Week 60
Arm/Group Title	Tezepelumab		Placebo
Arm/Group Description	Tezepelumab 210 mg administered every 4 weeks subcutaneously		Placebo administered every 4 weeks subcutaneously
All Cause Mortality
	Tezepelumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/74 (1.4%)		0/76 (0%)
Serious Adverse Events
	Tezepelumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/74 (16.2%)		16/76 (21.1%)
Cardiac disorders
Cardiac arrest	1/74 (1.4%)	1	0/76 (0%)	0
Cardiac failure	1/74 (1.4%)	1	0/76 (0%)	0
Supraventricular tachycardia	1/74 (1.4%)	2	0/76 (0%)	0
Gastrointestinal disorders
Inguinal hernia	1/74 (1.4%)	1	0/76 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	0/74 (0%)	0	1/76 (1.3%)	1
Infections and infestations
H1n1 influenza	0/74 (0%)	0	1/76 (1.3%)	1
Intervertebral discitis	1/74 (1.4%)	1	0/76 (0%)	0
Pneumonia	1/74 (1.4%)	1	2/76 (2.6%)	2
Septic shock	1/74 (1.4%)	1	0/76 (0%)	0
Injury, poisoning and procedural complications
Incisional hernia	1/74 (1.4%)	1	0/76 (0%)	0
Road traffic accident	0/74 (0%)	0	1/76 (1.3%)	1
Spinal compression fracture	0/74 (0%)	0	1/76 (1.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/74 (1.4%)	1	0/76 (0%)	0
Arthritis	0/74 (0%)	0	1/76 (1.3%)	1
Muscle spasms	0/74 (0%)	0	1/76 (1.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive breast carcinoma	1/74 (1.4%)	1	0/76 (0%)	0
Nervous system disorders
Headache	0/74 (0%)	0	1/76 (1.3%)	1
Migraine	0/74 (0%)	0	1/76 (1.3%)	1
Renal and urinary disorders
Acute kidney injury	1/74 (1.4%)	1	0/76 (0%)	0
Nephrolithiasis	1/74 (1.4%)	1	0/76 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	4/74 (5.4%)	6	8/76 (10.5%)	11
Bronchial secretion retention	0/74 (0%)	0	1/76 (1.3%)	1
Nasal polyps	0/74 (0%)	0	1/76 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Tezepelumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/74 (47.3%)		48/76 (63.2%)
Eye disorders
Cataract	1/74 (1.4%)	1	3/76 (3.9%)	3
General disorders
Influenza like illness	0/74 (0%)	0	5/76 (6.6%)	5
Infections and infestations
Bronchitis	4/74 (5.4%)	4	3/76 (3.9%)	3
Bronchitis bacterial	6/74 (8.1%)	14	7/76 (9.2%)	10
Nasopharyngitis	12/74 (16.2%)	14	19/76 (25%)	29
Oral candidiasis	4/74 (5.4%)	4	4/76 (5.3%)	5
Sinusitis	1/74 (1.4%)	1	5/76 (6.6%)	6
Upper respiratory tract infection	9/74 (12.2%)	9	8/76 (10.5%)	8
Injury, poisoning and procedural complications
Fall	3/74 (4.1%)	3	1/76 (1.3%)	1
Musculoskeletal and connective tissue disorders
Myalgia	4/74 (5.4%)	5	1/76 (1.3%)	2
Nervous system disorders
Headache	3/74 (4.1%)	3	8/76 (10.5%)	9
Respiratory, thoracic and mediastinal disorders
Asthma	6/74 (8.1%)	7	8/76 (10.5%)	15
Nasal polyps	0/74 (0%)	0	4/76 (5.3%)	6
Vascular disorders
Hypertension	2/74 (2.7%)	2	6/76 (7.9%)	6

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.