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

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ClinicalTrials.gov Identifier: NCT03688074
Recruitment Status : Completed
First Posted : September 28, 2018
Results First Posted : February 21, 2022
Last Update Posted : February 21, 2022
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Interventions Biological: Tezepelumab
Other: Placebo
Enrollment 116
Recruitment Details 116 subjects randomized to Tezepelumab 210 mg Q4W or Placebo in 1:1 treatment allocation. All randomized subjects were treated.
Pre-assignment Details The study randomized subjects across the spectrum of T2 status. Randomization was stratified by screening blood eosinophil level (<150 , 150 - <300, >=300 cells/µL).
Arm/Group Title Teze 210 mg Q4W Placebo
Hide Arm/Group Description Tezepelumab subcutaneous injection Placebo subcutaneous injection
Period Title: Overall Study
Started 59 57
Completed 58 56
Not Completed 1 1
Reason Not Completed
Adverse Event             0             1
Other             1             0
Arm/Group Title Teze 210 mg Q4W Placebo Total
Hide Arm/Group Description Tezepelumab subcutaneous injection Placebo subcutaneous injection Total of all reporting groups
Overall Number of Baseline Participants 59 57 116
Hide Baseline Analysis Population Description
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.
Age, Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 59 participants 57 participants 116 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
51
  86.4%
49
  86.0%
100
  86.2%
>=65 years
8
  13.6%
8
  14.0%
16
  13.8%
[1]
Measure Description: 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.
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 59 participants 57 participants 116 participants
50.4  (12.7) 50.4  (13.9) 50.4  (13.2)
[1]
Measure Description: 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.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 59 participants 57 participants 116 participants
Female
39
  66.1%
26
  45.6%
65
  56.0%
Male
20
  33.9%
31
  54.4%
51
  44.0%
[1]
Measure Description: 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.
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 59 participants 57 participants 116 participants
White
54
  91.5%
55
  96.5%
109
  94.0%
Black or African American
2
   3.4%
1
   1.8%
3
   2.6%
Asian
2
   3.4%
1
   1.8%
3
   2.6%
Other (includes Native Hawaiian or Other Pacific Islander and American Indian or Alaska Native)
1
   1.7%
0
   0.0%
1
   0.9%
[1]
Measure Description: Race - 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.
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 59 participants 57 participants 116 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
59
 100.0%
57
 100.0%
116
 100.0%
[1]
Measure Description: Ethnicity - 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.
1.Primary Outcome
Title Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT.
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Teze 210 mg Q4W Placebo
Hide Arm/Group Description:
Tezepelumab subcutaneous injection
Placebo subcutaneous injection
Overall Number of Participants Analyzed 54 56
Geometric Least Squares Mean (90% Confidence Interval)
Unit of Measure: Ratio
Eosinophils Number Analyzed 48 participants 51 participants
0.11
(0.06 to 0.21)
0.75
(0.41 to 1.38)
Neutrophils Number Analyzed 48 participants 51 participants
1.11
(0.88 to 1.39)
0.81
(0.66 to 1.01)
T cells CD3+ Number Analyzed 48 participants 51 participants
0.91
(0.78 to 1.07)
0.81
(0.70 to 0.95)
T cells CD4+ Number Analyzed 48 participants 51 participants
0.96
(0.82 to 1.14)
0.81
(0.70 to 0.95)
Mast cells Tryptase+ Number Analyzed 48 participants 51 participants
0.84
(0.70 to 1.02)
1.01
(0.84 to 1.22)
Mast cells Chymase+ Number Analyzed 48 participants 51 participants
1.07
(0.76 to 1.52)
0.90
(0.65 to 1.26)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 0.15
Confidence Interval (2-Sided) 90%
0.06 to 0.35
Estimation Comments Parameter : Eosinophils (cells/mm^2)
Other Statistical Analysis 95% CI (0.05, 0.41)
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.106
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 1.36
Confidence Interval (2-Sided) 90%
0.99 to 1.86
Estimation Comments Parameter: Neutrophils (cells/mm^2)
Other Statistical Analysis 95% CI (0.94, 1.97)
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.389
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 1.12
Confidence Interval (2-Sided) 90%
0.90 to 1.40
Estimation Comments Parameter: T cells CD3+ (cells/mm^2)
Other Statistical Analysis 95% CI (0.86, 1.46)
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.216
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 1.18
Confidence Interval (2-Sided) 90%
0.94 to 1.48
Estimation Comments Parameter: T cells CD4+ (cells/mm^2)
Other Statistical Analysis 95% CI (0.90, 1.55)
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.260
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 0.83
Confidence Interval (2-Sided) 90%
0.64 to 1.09
Estimation Comments Parameter: Mast cells Tryptase+ (cells/mm^2)
Other Statistical Analysis 95% CI (0.61, 1.15)
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Teze 210 mg Q4W, Placebo
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.546
Comments Nominal p-values were reported. No adjustment of multiplicity was performed.
Method ANCOVA
Comments Model includes treatment+log transformed baseline value+stratification factor (screening eos count [<150, 150-<300, >=300 cells/uL])
Method of Estimation Estimation Parameter Ratio of Geometric LSMeans
Estimated Value 1.19
Confidence Interval (2-Sided) 90%
0.74 to 1.92
Estimation Comments Parameter: Mast cells Chymase+ (cells/mm^2)
Other Statistical Analysis 95% CI (0.67, 2.10)
2.Secondary Outcome
Title Reticular Basement Membrane (RBM) Thickness Ratio Change From Baseline to EOT.
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Teze 210 mg Q4W Placebo
Hide Arm/Group Description:
Tezepelumab subcutaneous injection
Placebo subcutaneous injection
Overall Number of Participants Analyzed 42 40
Geometric Least Squares Mean (90% Confidence Interval)
Unit of Measure: Ratio
0.87
(0.79 to 0.95)
0.90
(0.81 to 0.99)
3.Secondary Outcome
Title Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT.
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Teze 210 mg Q4W Placebo
Hide Arm/Group Description:
Tezepelumab subcutaneous injection
Placebo subcutaneous injection
Overall Number of Participants Analyzed 54 56
Geometric Least Squares Mean (90% Confidence Interval)
Unit of Measure: Ratio
Intact epithelium Number Analyzed 45 participants 46 participants
0.87
(0.61 to 1.23)
0.84
(0.59 to 1.19)
Damaged epithelium Number Analyzed 45 participants 46 participants
1.01
(0.92 to 1.12)
0.95
(0.86 to 1.04)
Denuded epithelium Number Analyzed 45 participants 46 participants
1.05
(0.83 to 1.31)
1.34
(1.07 to 1.68)
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).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Teze 210 mg Q4W
Hide Arm/Group Description Placebo subcutaneous injection Tezepelumab subcutaneous injection
All-Cause Mortality
Placebo Teze 210 mg Q4W
Affected / at Risk (%) Affected / at Risk (%)
Total   0/57 (0.00%)      0/59 (0.00%)    
Hide Serious Adverse Events
Placebo Teze 210 mg Q4W
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/57 (12.28%)      3/59 (5.08%)    
Cardiac disorders     
Myocarditis  1  1/57 (1.75%)  1 0/59 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  1/57 (1.75%)  1 0/59 (0.00%)  0
Gastrooesophageal reflux disease  1  0/57 (0.00%)  0 1/59 (1.69%)  1
Hiatus hernia  1  0/57 (0.00%)  0 1/59 (1.69%)  1
Infections and infestations     
Influenza  1  0/57 (0.00%)  0 1/59 (1.69%)  1
Injury, poisoning and procedural complications     
Post procedural complication  1  2/57 (3.51%)  2 0/59 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Meningioma  1  0/57 (0.00%)  0 1/59 (1.69%)  1
Pancreatic carcinoma  1  1/57 (1.75%)  1 0/59 (0.00%)  0
Squamous cell carcinoma  1  1/57 (1.75%)  1 0/59 (0.00%)  0
Renal and urinary disorders     
Urinary retention  1  1/57 (1.75%)  1 0/59 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/57 (1.75%)  1 0/59 (0.00%)  0
1
Term from vocabulary, MedDRA 23.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Placebo Teze 210 mg Q4W
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   45/57 (78.95%)      48/59 (81.36%)    
Eye disorders     
Dry eye  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Gastrointestinal disorders     
Diarrhoea  1  0/57 (0.00%)  0 5/59 (8.47%)  6
Nausea  1  2/57 (3.51%)  2 2/59 (3.39%)  2
Vomiting  1  3/57 (5.26%)  3 2/59 (3.39%)  2
General disorders     
Influenza like illness  1  3/57 (5.26%)  3 3/59 (5.08%)  3
Injection site erythema  1  2/57 (3.51%)  12 5/59 (8.47%)  14
Injection site granuloma  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Injection site pruritus  1  1/57 (1.75%)  1 4/59 (6.78%)  5
Oedema peripheral  1  0/57 (0.00%)  0 3/59 (5.08%)  3
Pyrexia  1  0/57 (0.00%)  0 3/59 (5.08%)  3
Infections and infestations     
Bronchitis  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Candida infection  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Chronic sinusitis  1  2/57 (3.51%)  2 0/59 (0.00%)  0
Conjunctivitis  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Gastroenteritis  1  2/57 (3.51%)  2 1/59 (1.69%)  1
Lower respiratory tract infection  1  1/57 (1.75%)  1 2/59 (3.39%)  2
Lower respiratory tract infection bacterial  1  2/57 (3.51%)  2 1/59 (1.69%)  1
Nasopharyngitis  1  21/57 (36.84%)  22 22/59 (37.29%)  28
Oral candidiasis  1  0/57 (0.00%)  0 2/59 (3.39%)  4
Pneumonia  1  1/57 (1.75%)  1 2/59 (3.39%)  2
Rhinitis  1  2/57 (3.51%)  2 1/59 (1.69%)  1
Sinusitis  1  2/57 (3.51%)  2 0/59 (0.00%)  0
Tonsillitis  1  0/57 (0.00%)  0 2/59 (3.39%)  2
Upper respiratory tract infection  1  4/57 (7.02%)  4 3/59 (5.08%)  3
Urinary tract infection  1  2/57 (3.51%)  5 3/59 (5.08%)  4
Injury, poisoning and procedural complications     
Contusion  1  0/57 (0.00%)  0 2/59 (3.39%)  5
Fall  1  1/57 (1.75%)  1 2/59 (3.39%)  4
Post procedural complication  1  10/57 (17.54%)  12 11/59 (18.64%)  11
Post procedural fever  1  2/57 (3.51%)  2 4/59 (6.78%)  4
Procedural pain  1  0/57 (0.00%)  0 3/59 (5.08%)  3
Musculoskeletal and connective tissue disorders     
Arthralgia  1  3/57 (5.26%)  4 3/59 (5.08%)  3
Back pain  1  2/57 (3.51%)  2 2/59 (3.39%)  2
Bursitis  1  2/57 (3.51%)  2 0/59 (0.00%)  0
Musculoskeletal chest pain  1  2/57 (3.51%)  3 1/59 (1.69%)  1
Myalgia  1  1/57 (1.75%)  1 3/59 (5.08%)  3
Nervous system disorders     
Headache  1  8/57 (14.04%)  8 6/59 (10.17%)  9
Respiratory, thoracic and mediastinal disorders     
Cough  1  4/57 (7.02%)  5 6/59 (10.17%)  9
Dysphonia  1  2/57 (3.51%)  2 2/59 (3.39%)  2
Nasal congestion  1  2/57 (3.51%)  2 1/59 (1.69%)  1
Oropharyngeal pain  1  2/57 (3.51%)  2 6/59 (10.17%)  6
Vascular disorders     
Hypertension  1  2/57 (3.51%)  2 1/59 (1.69%)  1
1
Term from vocabulary, MedDRA 23.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Globall Clinical Head
Organization: AstraZeneca
Phone: +1 877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03688074    
Other Study ID Numbers: D5180C00013
First Submitted: September 26, 2018
First Posted: September 28, 2018
Results First Submitted: November 12, 2021
Results First Posted: February 21, 2022
Last Update Posted: February 21, 2022