AstraZeneca Clinical Trials Website

Study to Evaluate Tezepelumab on Airway Inflammation in Adults with Uncontrolled Asthma (CASCADE) (CASCADE)

Recruitment Status:
Completed

Sponsor:
AstraZeneca

Collaborator:

Amgen

Information Provided by (Responsible Party):
AstraZeneca

ClinicalTrials.gov Identifier:
NCT03688074

Verification:
Verified 01 February 2022 by AstraZeneca

History of Changes:
ClinicalTrials.gov

Purpose

A phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled asthma.

Official Title:	A Phase 2, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in Adults with Inadequately Controlled Asthma on Inhaled Corticosteroids and at least one additional asthma controller (CASCADE)
Study Type:	Interventional
Overall Recruitment Status:	Completed
Study Start Date:	02 November 2018
Study Start Date Type:	Actual
Primary Completion Date:	16 November 2020
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Primary Purpose: Treatment Masking Description: Double-blind Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.

Condition	Intervention	Phase
Asthma Bronchial Diseases Respiratory Tract Diseases Lung Diseases, Obstructive Lung Diseases Respiratory Hypersensitivity Hypersensitivity, Immediate Hypersensitivity Immune System Diseases	Biological/Vaccine: Tezepelumab Other: Placebo	Phase 2

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Gender Based:	No
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:
- Subject must be 18 to 75 years of age.
- Documented physician-diagnosed asthma for at least 12 months.
- Subjects who have received a physician- prescribed asthma controller medication with medium or high dose ICS for at least 12 months; must be stable for at least 3 months prior to screening visit.
- At least one additional maintenance asthma controller medication is required according to standard practice of care and must be documented for at least 3 months.
-At enrolment, the subject must have a predicted normal value for the morning pre-bronchodilator FEV1>50% and more than 1L.
- Evidence of asthma as documented by reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 months prior to screening, or during the screening period prior to randomization.
- ACQ-6 score ≥ 1.5 during the screening period prior to randomization.

Principal Exclusion Criteria:
- Any clinically important pulmonary disease other than asthma.
- History of cancer.
- Hospitalization or required OCS for asthma exacerbation within 6 weeks of enrolment or >3 exacerbations requiring OCS or hospitalization in the year prior to visit 1 or who had been intubated or admitted to ICU for asthma exacerbation in the year prior to enrolment.
- History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalized <2 weeks before visit 1 or during the run-in period.
- Current smokers or subjects with smoking history ≥10 pack-yrs, including e-cigarettes. Former smokers with a smoking history of <10 pack-yrs must have stopped for at least 6 months prior to visit 1, including e-cigarette use.
- History of chronic alcohol or drug abuse within 12 months prior to visit 1.
-Tuberculosis requiring treatment within 12 months prior to visit 1.
- History of known immunodeficiency disorder including a positive HIV test at visit 1, or the subject is taking antiretroviral medications as determined by medical history and/or subject's verbal report.
- History of anaphylaxis or documented immune complex disease (type III hypersensitivity reactions) following any biologic therapy
Subject randomized in a previous Tezepelumab study or in a current study with another investigational product.
-Pregnant, breastfeeding or lactating women.

Contacts

Contact: AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Sponsors and Collaborators

AstraZeneca

Amgen

Investigators

Principal Investigator:

Chris Brightling

University of Leicester, United Kingdom

Locations

Country	Location	Facility	Status
Canada , AB	Research Site	Calgary, AB, Canada, T2N 4Z6	Completed
Canada , BC	Research Site	Vancouver, BC, Canada, V5Z 1M9	Completed
United States of America , TX	Research Site	Galveston, TX, United States of America, 77555	Completed
United States of America , MA	Research Site	Boston, MA, United States of America, 02115	Completed
United States of America , PA	Research Site	Pittsburgh, PA, United States of America, 15213	Completed
Germany	Research Site	Frankfurt, Germany, 60596	Completed
Germany	Research Site	Frankfurt/Main, Germany, 60389	Completed
Germany	Research Site	Grosshansdorf, Germany, 22927	Completed
Germany	Research Site	Landsberg, Germany, 86899	Completed
United Kingdom	Research Site	Cambridge, United Kingdom, CB2 0QQ	Completed
United Kingdom	Research Site	Headington, United Kingdom, OX3 9DU	Completed
United Kingdom	Research Site	Leicester, United Kingdom, LE3 9QP	Completed
United Kingdom	Research Site	Liverpool, United Kingdom, L7 8XP	Withdrawn
United Kingdom	Research Site	London, United Kingdom, W1G 8HU	Completed
United Kingdom	Research Site	Nottingham, United Kingdom, NG5 1PB	Completed
United Kingdom	Research Site	Wythenshawe, United Kingdom, M23 9QZ	Completed
United States of America , CO	Research Site	Denver, CO, United States of America, 80206	Completed
United States of America , CT	Research Site	New Haven, CT, United States of America, 06510	Completed
Canada , QC	Research Site	Montreal, QC, Canada, H4A 3J1	Completed
Canada , QC	Research Site	Quebec, QC, Canada, G1V 4G5	Completed
Denmark	Research Site	Aarhus N, Denmark, 8200	Completed
Denmark	Research Site	Ålborg, Denmark, 9000	Completed
Denmark	Research Site	Hvidovre, Denmark, 2650	Completed
Denmark	Research Site	København NV, Denmark, 2400	Completed
Denmark	Research Site	Naestved, Denmark, 4700	Completed
Denmark	Research Site	Odense C, Denmark, 5000	Completed
Denmark	Research Site	Vejle, Denmark, 7100	Completed
Canada , ON	Research Site	Hamilton, ON, Canada, L8N 3Z5	Completed
Canada , ON	Research Site	Ottawa, ON, Canada, K1H 8L6	Completed

	File name	Description
	Statistical Analysis Plan (SAP)	Statistical Analysis Plan (SAP)
	CSP	CSP

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
116 subjects randomized to Tezepelumab 210 mg Q4W or Placebo in 1:1 treatment allocation. All randomized subjects were treated.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study randomized subjects across the spectrum of T2 status. Randomization was stratified by screening blood eosinophil level (<150 , 150 - <300, >=300 cells/µL).

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Participant Flow: Overall Study

	Teze 210 mg Q4W	Placebo
STARTED	59	57
COMPLETED	58	56
NOT COMPLETED	1	1
Adverse Event	0	1
Other	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Full Analysis Set - Include all subjects randomised to study treatment who received at least one dose of IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Baseline Measures

	Teze 210 mg Q4W	Placebo	Total
Number of Participants [units: Participants]	59	57	116
Age Continuous ^[1] [units: Years] Mean ± Standard Deviation	50.4 ± 12.7	50.4 ± 13.9	50.4 ± 13.2
Age Categorical ^[2] [units: Participants]
<=18 years	0	0	0
Between 18 and 65 years	51	49	100
>=65 years	8	8	16
Sex: Female, Male ^[3] [units: Participants]
Female	39	26	65
Male	20	31	51
Race/Ethnicity, Customized ^[4] [units: Participants]
White	54	55	109
Black or African American	2	1	3
Asian	2	1	3
Other (includes Native Hawaiian or Other Pacific Islander and American Indian or Alaska Native)	1	0	1
Race/Ethnicity, Customized ^[5] [units: Participants]
Hispanic or Latino	0	0	0
Not Hispanic or Latino	59	57	116

Outcome Measures

1. Primary Outcome Measure: Airway submucosal inflammatory cells ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Primary
Measure Name	Airway submucosal inflammatory cells ratio change from baseline to EOT.
Measure Description	The change from baseline to end of treatment (EOT) expressed as a ratio i.e. (EOT/baseline) in numbers of each of the airway submucosal inflammatory cells, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	54	56
Airway submucosal inflammatory cells ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)
Eosinophils	0.11 (0.06 to 0.21)	0.75 (0.41 to 1.38)
Neutrophils	1.11 (0.88 to 1.39)	0.81 (0.66 to 1.01)
T cells CD3+	0.91 (0.78 to 1.07)	0.81 (0.70 to 0.95)
T cells CD4+	0.96 (0.82 to 1.14)	0.81 (0.70 to 0.95)
Mast cells Tryptase+	0.84 (0.70 to 1.02)	1.01 (0.84 to 1.22)
Mast cells Chymase+	1.07 (0.76 to 1.52)	0.90 (0.65 to 1.26)

Statistical Analysis 1 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	<0.001
Other^[5]	0.15
90% Confidence Interval	( 0.06 to 0.35 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter : Eosinophils (cells/mm^2)

Statistical Analysis 2 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.106
Other^[5]	1.36
90% Confidence Interval	( 0.99 to 1.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Neutrophils (cells/mm^2)

Statistical Analysis 3 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.389
Other^[5]	1.12
90% Confidence Interval	( 0.90 to 1.40 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: T cells CD3+ (cells/mm^2)

Statistical Analysis 4 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.216
Other^[5]	1.18
90% Confidence Interval	( 0.94 to 1.48 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: T cells CD4+ (cells/mm^2)

Statistical Analysis 5 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.260
Other^[5]	0.83
90% Confidence Interval	( 0.64 to 1.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Mast cells Tryptase+ (cells/mm^2)

Statistical Analysis 6 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.546
Other^[5]	1.19
90% Confidence Interval	( 0.74 to 1.92 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Mast cells Chymase+ (cells/mm^2)

2. Secondary Outcome Measure: Reticular basement membrane (RBM) thickness ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Secondary
Measure Name	Reticular basement membrane (RBM) thickness ratio change from baseline to EOT.
Measure Description	The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in RBM thickness, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects randomised to study treatment who completed at least 20 weeks of study treatment and had a baseline assessment and an EOT assessment not greater than 8 weeks after date of last dose of IP.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	42	40
Reticular basement membrane (RBM) thickness ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)	0.87 (0.79 to 0.95)	0.90 (0.81 to 0.99)

No statistical analysis provided for Reticular basement membrane (RBM) thickness ratio change from baseline to EOT.

3. Secondary Outcome Measure: Percent (%) airway epithelial integrity ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Secondary
Measure Name	Percent (%) airway epithelial integrity ratio change from baseline to EOT.
Measure Description	The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in % airway epithelial, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	54	56
Percent (%) airway epithelial integrity ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)
Intact epithelium	0.87 (0.61 to 1.23)	0.84 (0.59 to 1.19)
Damaged epithelium	1.01 (0.92 to 1.12)	0.95 (0.86 to 1.04)
Denuded epithelium	1.05 (0.83 to 1.31)	1.34 (1.07 to 1.68)

No statistical analysis provided for Percent (%) airway epithelial integrity ratio change from baseline to EOT.

Serious Adverse Events

Time Frame	From first dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Placebo subcutaneous injection
Teze 210 mg Q4W	Tezepelumab subcutaneous injection

Serious Adverse Events

Placebo

Teze 210 mg Q4W

Total, serious adverse events

# participants affected / at risk

7/57 (12.28%)

3/59 (5.08%)

Cardiac disorders

Myocarditis¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Gastrointestinal disorders

Hiatus hernia¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Meningioma¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Pancreatic carcinoma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Renal and urinary disorders

Urinary retention¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 23.1

Other Adverse Events

Time Frame	From first dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Placebo	Placebo subcutaneous injection
Teze 210 mg Q4W	Tezepelumab subcutaneous injection

Other Adverse Events

Placebo

Teze 210 mg Q4W

Total, other (not including serious) adverse events

# participants affected / at risk

45/57 (78.95%)

48/59 (81.36%)

Eye disorders

Dry eye¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/57 (0.00%)

5/59 (8.47%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

3/57 (5.26%)

2/59 (3.39%)

# events

General disorders and administration site conditions

Influenza like illness¹,^†

# participants affected / at risk

3/57 (5.26%)

3/59 (5.08%)

# events

General disorders and administration site conditions

Injection site erythema¹,^†

# participants affected / at risk

2/57 (3.51%)

5/59 (8.47%)

# events

General disorders and administration site conditions

Injection site granuloma¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

General disorders and administration site conditions

Injection site pruritus¹,^†

# participants affected / at risk

1/57 (1.75%)

4/59 (6.78%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Candida infection¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Chronic sinusitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Infections and infestations

Conjunctivitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Infections and infestations

Lower respiratory tract infection bacterial¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

21/57 (36.84%)

22/59 (37.29%)

# events

Infections and infestations

Oral candidiasis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Infections and infestations

Rhinitis¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Infections and infestations

Tonsillitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

4/57 (7.02%)

3/59 (5.08%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

2/57 (3.51%)

3/59 (5.08%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

10/57 (17.54%)

11/59 (18.64%)

# events

Injury, poisoning and procedural complications

Post procedural fever¹,^†

# participants affected / at risk

2/57 (3.51%)

4/59 (6.78%)

# events

Injury, poisoning and procedural complications

Procedural pain¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

3/57 (5.26%)

3/59 (5.08%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Musculoskeletal and connective tissue disorders

Bursitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

1/57 (1.75%)

3/59 (5.08%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

8/57 (14.04%)

6/59 (10.17%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

4/57 (7.02%)

6/59 (10.17%)

# events

Respiratory, thoracic and mediastinal disorders

Dysphonia¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal congestion¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

2/57 (3.51%)

6/59 (10.17%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 23.1

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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Globall Clinical Head
Organization:	AstraZeneca
Phone	+1 877-240-9479
E-mail:	[email protected]

Purpose

A phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled asthma.

Official Title:	A Phase 2, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in Adults with Inadequately Controlled Asthma on Inhaled Corticosteroids and at least one additional asthma controller (CASCADE)
Study Type:	Interventional
Overall Recruitment Status:	Completed
Study Start Date:	02 November 2018
Study Start Date Type:	Actual
Primary Completion Date:	16 November 2020
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Primary Purpose: Treatment Masking Description: Double-blind Model Description: Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.

Condition	Intervention	Phase
Asthma Bronchial Diseases Respiratory Tract Diseases Lung Diseases, Obstructive Lung Diseases Respiratory Hypersensitivity Hypersensitivity, Immediate Hypersensitivity Immune System Diseases	Biological/Vaccine: Tezepelumab Other: Placebo	Phase 2

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Gender Based:	No
Accepts Healthy Volunteers:	No

Criteria

Contacts

Contact: AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Sponsors and Collaborators

AstraZeneca

Amgen

Investigators

Principal Investigator:

Chris Brightling

University of Leicester, United Kingdom

Locations

Country	Location	Facility	Status
Canada , AB	Research Site	Calgary, AB, Canada, T2N 4Z6	Completed
Canada , BC	Research Site	Vancouver, BC, Canada, V5Z 1M9	Completed
United States of America , TX	Research Site	Galveston, TX, United States of America, 77555	Completed
United States of America , MA	Research Site	Boston, MA, United States of America, 02115	Completed
United States of America , PA	Research Site	Pittsburgh, PA, United States of America, 15213	Completed
Germany	Research Site	Frankfurt, Germany, 60596	Completed
Germany	Research Site	Frankfurt/Main, Germany, 60389	Completed
Germany	Research Site	Grosshansdorf, Germany, 22927	Completed
Germany	Research Site	Landsberg, Germany, 86899	Completed
United Kingdom	Research Site	Cambridge, United Kingdom, CB2 0QQ	Completed
United Kingdom	Research Site	Headington, United Kingdom, OX3 9DU	Completed
United Kingdom	Research Site	Leicester, United Kingdom, LE3 9QP	Completed
United Kingdom	Research Site	Liverpool, United Kingdom, L7 8XP	Withdrawn
United Kingdom	Research Site	London, United Kingdom, W1G 8HU	Completed
United Kingdom	Research Site	Nottingham, United Kingdom, NG5 1PB	Completed
United Kingdom	Research Site	Wythenshawe, United Kingdom, M23 9QZ	Completed
United States of America , CO	Research Site	Denver, CO, United States of America, 80206	Completed
United States of America , CT	Research Site	New Haven, CT, United States of America, 06510	Completed
Canada , QC	Research Site	Montreal, QC, Canada, H4A 3J1	Completed
Canada , QC	Research Site	Quebec, QC, Canada, G1V 4G5	Completed
Denmark	Research Site	Aarhus N, Denmark, 8200	Completed
Denmark	Research Site	Ålborg, Denmark, 9000	Completed
Denmark	Research Site	Hvidovre, Denmark, 2650	Completed
Denmark	Research Site	København NV, Denmark, 2400	Completed
Denmark	Research Site	Naestved, Denmark, 4700	Completed
Denmark	Research Site	Odense C, Denmark, 5000	Completed
Denmark	Research Site	Vejle, Denmark, 7100	Completed
Canada , ON	Research Site	Hamilton, ON, Canada, L8N 3Z5	Completed
Canada , ON	Research Site	Ottawa, ON, Canada, K1H 8L6	Completed

Oversight

Is IND/IDE protocol:	Yes
IND/IDE Grantor:	CDER
IND/IDE Number:	103031
IND/IDE Serial Number:	0124
Has Expanded Access:	Unknown
U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Product Exported From U.S.:	Yes

More Information

Statistical Analysis Plan (SAP)

CSP

No publications provided

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT03688074
Other Study ID Numbers:	D5180C00013

Keywords provided by AstraZeneca

Asthma

Uncontrolled asthma

Severe uncontrolled asthma

Additional Relevant MeSH terms:

Asthma	Bronchial Diseases
Respiratory Tract Diseases	Lung Diseases, Obstructive
Lung Diseases	Respiratory Hypersensitivity
Hypersensitivity, Immediate	Hypersensitivity
Immune System Diseases

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
116 subjects randomized to Tezepelumab 210 mg Q4W or Placebo in 1:1 treatment allocation. All randomized subjects were treated.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study randomized subjects across the spectrum of T2 status. Randomization was stratified by screening blood eosinophil level (<150 , 150 - <300, >=300 cells/µL).

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Participant Flow: Overall Study

	Teze 210 mg Q4W	Placebo
STARTED	59	57
COMPLETED	58	56
NOT COMPLETED	1	1
Adverse Event	0	1
Other	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Full Analysis Set - Include all subjects randomised to study treatment who received at least one dose of IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Baseline Measures

	Teze 210 mg Q4W	Placebo	Total
Number of Participants [units: Participants]	59	57	116
Age Continuous ^[1] [units: Years] Mean ± Standard Deviation	50.4 ± 12.7	50.4 ± 13.9	50.4 ± 13.2
Age Categorical ^[2] [units: Participants]
<=18 years	0	0	0
Between 18 and 65 years	51	49	100
>=65 years	8	8	16
Sex: Female, Male ^[3] [units: Participants]
Female	39	26	65
Male	20	31	51
Race/Ethnicity, Customized ^[4] [units: Participants]
White	54	55	109
Black or African American	2	1	3
Asian	2	1	3
Other (includes Native Hawaiian or Other Pacific Islander and American Indian or Alaska Native)	1	0	1
Race/Ethnicity, Customized ^[5] [units: Participants]
Hispanic or Latino	0	0	0
Not Hispanic or Latino	59	57	116

Outcome Measures

1. Primary Outcome Measure: Airway submucosal inflammatory cells ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Primary
Measure Name	Airway submucosal inflammatory cells ratio change from baseline to EOT.
Measure Description	The change from baseline to end of treatment (EOT) expressed as a ratio i.e. (EOT/baseline) in numbers of each of the airway submucosal inflammatory cells, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	54	56
Airway submucosal inflammatory cells ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)
Eosinophils	0.11 (0.06 to 0.21)	0.75 (0.41 to 1.38)
Neutrophils	1.11 (0.88 to 1.39)	0.81 (0.66 to 1.01)
T cells CD3+	0.91 (0.78 to 1.07)	0.81 (0.70 to 0.95)
T cells CD4+	0.96 (0.82 to 1.14)	0.81 (0.70 to 0.95)
Mast cells Tryptase+	0.84 (0.70 to 1.02)	1.01 (0.84 to 1.22)
Mast cells Chymase+	1.07 (0.76 to 1.52)	0.90 (0.65 to 1.26)

Statistical Analysis 1 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	<0.001
Other^[5]	0.15
90% Confidence Interval	( 0.06 to 0.35 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter : Eosinophils (cells/mm^2)

Statistical Analysis 2 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.106
Other^[5]	1.36
90% Confidence Interval	( 0.99 to 1.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Neutrophils (cells/mm^2)

Statistical Analysis 3 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.389
Other^[5]	1.12
90% Confidence Interval	( 0.90 to 1.40 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: T cells CD3+ (cells/mm^2)

Statistical Analysis 4 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.216
Other^[5]	1.18
90% Confidence Interval	( 0.94 to 1.48 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: T cells CD4+ (cells/mm^2)

Statistical Analysis 5 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.260
Other^[5]	0.83
90% Confidence Interval	( 0.64 to 1.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Mast cells Tryptase+ (cells/mm^2)

Statistical Analysis 6 for Airway submucosal inflammatory cells ratio change from baseline to EOT.

Groups^[1]	All groups
Method^[3]	ANCOVA
P-Value^[4]	0.546
Other^[5]	1.19
90% Confidence Interval	( 0.74 to 1.92 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p-values were reported. No adjustment of multiplicity was performed.
[5]	Other relevant estimation information:
	Parameter: Mast cells Chymase+ (cells/mm^2)

2. Secondary Outcome Measure: Reticular basement membrane (RBM) thickness ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Secondary
Measure Name	Reticular basement membrane (RBM) thickness ratio change from baseline to EOT.
Measure Description	The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in RBM thickness, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects randomised to study treatment who completed at least 20 weeks of study treatment and had a baseline assessment and an EOT assessment not greater than 8 weeks after date of last dose of IP.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	42	40
Reticular basement membrane (RBM) thickness ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)	0.87 (0.79 to 0.95)	0.90 (0.81 to 0.99)

No statistical analysis provided for Reticular basement membrane (RBM) thickness ratio change from baseline to EOT.

3. Secondary Outcome Measure: Percent (%) airway epithelial integrity ratio change from baseline to EOT. [ Time Frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). ]

Measure Type	Secondary
Measure Name	Percent (%) airway epithelial integrity ratio change from baseline to EOT.
Measure Description	The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in % airway epithelial, determined by microscopic evaluation of bronchoscopic biopsies.
Time Frame	First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.

Reporting Groups

	Description
Teze 210 mg Q4W	Tezepelumab subcutaneous injection
Placebo	Placebo subcutaneous injection

Measured Values

	Teze 210 mg Q4W	Placebo
Number of Participants Analyzed [units:participants]	54	56
Percent (%) airway epithelial integrity ratio change from baseline to EOT. [units: Ratio] Geometric Least Squares Mean (90% Confidence Interval)
Intact epithelium	0.87 (0.61 to 1.23)	0.84 (0.59 to 1.19)
Damaged epithelium	1.01 (0.92 to 1.12)	0.95 (0.86 to 1.04)
Denuded epithelium	1.05 (0.83 to 1.31)	1.34 (1.07 to 1.68)

No statistical analysis provided for Percent (%) airway epithelial integrity ratio change from baseline to EOT.

Serious Adverse Events

Time Frame	From first dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Additional Description	No text entered.

Reporting Groups

	Description
Placebo	Placebo subcutaneous injection
Teze 210 mg Q4W	Tezepelumab subcutaneous injection

Serious Adverse Events

Placebo

Teze 210 mg Q4W

Total, serious adverse events

# participants affected / at risk

7/57 (12.28%)

3/59 (5.08%)

Cardiac disorders

Myocarditis¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Gastrointestinal disorders

Hiatus hernia¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Meningioma¹,^†

# participants affected / at risk

0/57 (0.00%)

1/59 (1.69%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Pancreatic carcinoma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Squamous cell carcinoma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Renal and urinary disorders

Urinary retention¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Asthma¹,^†

# participants affected / at risk

1/57 (1.75%)

0/59 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 23.1

Other Adverse Events

Time Frame	From first dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Placebo	Placebo subcutaneous injection
Teze 210 mg Q4W	Tezepelumab subcutaneous injection

Other Adverse Events

Placebo

Teze 210 mg Q4W

Total, other (not including serious) adverse events

# participants affected / at risk

45/57 (78.95%)

48/59 (81.36%)

Eye disorders

Dry eye¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/57 (0.00%)

5/59 (8.47%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

3/57 (5.26%)

2/59 (3.39%)

# events

General disorders and administration site conditions

Influenza like illness¹,^†

# participants affected / at risk

3/57 (5.26%)

3/59 (5.08%)

# events

General disorders and administration site conditions

Injection site erythema¹,^†

# participants affected / at risk

2/57 (3.51%)

5/59 (8.47%)

# events

General disorders and administration site conditions

Injection site granuloma¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

General disorders and administration site conditions

Injection site pruritus¹,^†

# participants affected / at risk

1/57 (1.75%)

4/59 (6.78%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

General disorders and administration site conditions

Pyrexia¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Candida infection¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Chronic sinusitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Infections and infestations

Conjunctivitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Gastroenteritis¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Infections and infestations

Lower respiratory tract infection bacterial¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

21/57 (36.84%)

22/59 (37.29%)

# events

Infections and infestations

Oral candidiasis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Infections and infestations

Rhinitis¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Infections and infestations

Sinusitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Infections and infestations

Tonsillitis¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

4/57 (7.02%)

3/59 (5.08%)

# events

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

2/57 (3.51%)

3/59 (5.08%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

0/57 (0.00%)

2/59 (3.39%)

# events

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

1/57 (1.75%)

2/59 (3.39%)

# events

Injury, poisoning and procedural complications

Post procedural complication¹,^†

# participants affected / at risk

10/57 (17.54%)

11/59 (18.64%)

# events

Injury, poisoning and procedural complications

Post procedural fever¹,^†

# participants affected / at risk

2/57 (3.51%)

4/59 (6.78%)

# events

Injury, poisoning and procedural complications

Procedural pain¹,^†

# participants affected / at risk

0/57 (0.00%)

3/59 (5.08%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

3/57 (5.26%)

3/59 (5.08%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Musculoskeletal and connective tissue disorders

Bursitis¹,^†

# participants affected / at risk

2/57 (3.51%)

0/59 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Musculoskeletal and connective tissue disorders

Myalgia¹,^†

# participants affected / at risk

1/57 (1.75%)

3/59 (5.08%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

8/57 (14.04%)

6/59 (10.17%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

4/57 (7.02%)

6/59 (10.17%)

# events

Respiratory, thoracic and mediastinal disorders

Dysphonia¹,^†

# participants affected / at risk

2/57 (3.51%)

2/59 (3.39%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal congestion¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

2/57 (3.51%)

6/59 (10.17%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

2/57 (3.51%)

1/59 (1.69%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 23.1

Primary Outcome Measures:

The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies. [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ] [ Designated as safety issue: ]
The change from baseline in number of airway submucosal inflammatory cells/mm2 of bronchoscopic biopsies.

Secondary Outcome Measures:

The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ] [ Designated as safety issue: ]
The change in reticular basement membrane (RBM) thickness from baseline, determined by microscopic evaluation of bronchoscopic biopsies
The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ] [ Designated as safety issue: ]
The change in % airway epithelial integrity from baseline determined by microscopic evaluation of bronchoscopic biopsies
The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies [ Time Frame: Baseline, End of Treatment (EoT). The EoT will be performed at Week 28 for the majority of subjects but may be performed at later timepoints for some subjects (Week 32, etc.) due to up to 6 additional doses added during the Covid-19 pandemic. ] [ Designated as safety issue: ]
The change in number of airway submucosal inflammatory cells per mm2 from baseline, across the spectrum of T2 status, determined by microscopic evaluation of bronchoscopic biopsies

Other Pre-specified Outcome Measures:

[ Time Frame: ] [ Designated as safety issue: ]

Arms	Assigned Interventions
Experimental: Tezepelumab Tezepelumab subcutaneous injection	Biological/Vaccine: Tezepelumab Tezepelumab subcutaneous injection
Placebo Comparator: Placebo Placebo subcutaneous injection	Other: Placebo Placebo subcutaneous injection

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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Globall Clinical Head
Organization:	AstraZeneca
Phone	+1 877-240-9479
E-mail:	[email protected]