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Study to Assess the Efficacy and Safety of MEDI3506 in Adults With Uncontrolled Moderate-to-severe Asthma (FRONTIER-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04570657
Recruitment Status : Completed
First Posted : September 30, 2020
Results First Posted : January 30, 2024
Last Update Posted : January 30, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Asthma
Interventions Biological: MEDI3506
Drug: Placebo
Enrollment 250
Recruitment Details Participants were enrolled and randomised in 52 study centres in 7 countries including Argentina, Germany, Hungary, Poland, South Africa, the United Kingdom, and the United States from 17 September 2020. The last participant completed their last study visit on 06 February 2023.
Pre-assignment Details Adult participants with uncontrolled moderate to severe asthma were randomised in a 1:1:1 ratio to receive tozorakimab (MEDI3506) Dose A (lower dose), tozorakimab Dose B (higher dose), or placebo. Of the 478 participants screened, 250 were enrolled, and of these, 15 were excluded from analysis due to invalidity of data (see limitations and caveats for further details).
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection. Participants were randomised to receive tozorakimab Dose B by SC injection. Participants were randomised to receive placebo by SC injection.
Period Title: Overall Study
Started 77 77 81
Intent to Treat (ITT) Population 77 77 81
As-treated Population 77 77 81
Pharmacokinetic (PK) Population 75 77 0
Completed 76 74 77
Not Completed 1 3 4
Reason Not Completed
Adverse Event             0             0             1
Lost to Follow-up             0             0             1
Physician Decision             0             1             0
Withdrawal by Subject             1             2             2
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo Total
Hide Arm/Group Description Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection. Participants were randomised to receive tozorakimab Dose B by SC injection. Participants were randomised to receive placebo by SC injection. Total of all reporting groups
Overall Number of Baseline Participants 77 77 81 235
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 77 participants 77 participants 81 participants 235 participants
42.1  (11.97) 43.1  (12.37) 48.3  (10.41) 44.5  (11.87)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 77 participants 81 participants 235 participants
Female
53
  68.8%
54
  70.1%
43
  53.1%
150
  63.8%
Male
24
  31.2%
23
  29.9%
38
  46.9%
85
  36.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 77 participants 81 participants 235 participants
Hispanic or Latino
26
  33.8%
24
  31.2%
33
  40.7%
83
  35.3%
Not Hispanic or Latino
51
  66.2%
53
  68.8%
48
  59.3%
152
  64.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 77 participants 81 participants 235 participants
Asian
0
   0.0%
0
   0.0%
1
   1.2%
1
   0.4%
Black or African American
4
   5.2%
8
  10.4%
7
   8.6%
19
   8.1%
White
71
  92.2%
67
  87.0%
72
  88.9%
210
  89.4%
Other
2
   2.6%
2
   2.6%
1
   1.2%
5
   2.1%
1.Primary Outcome
Title Change From Baseline to Week 16 in Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in the First Second (FEV1) as Measured in the Study Clinic
Hide Description

In-clinic spirometry measurements were taken prior to the administration of bronchodilators. Baseline was the last measurement prior to first injection of investigational product (IP).

The least squares (LS) means, LS mean differences and 80% confidence intervals (CIs), and one-sided p-value results were based on a mixed model repeated measures (MMRM). The model included fixed effects for baseline, background medication, geographic region, baseline inhaled corticosteroids (ICS) total daily dose, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 76 77 81
Least Squares Mean (Standard Error)
Unit of Measure: litres
0.148  (0.047) 0.116  (0.048) 0.112  (0.046)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.267
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.036
Confidence Interval (2-Sided) 80%
-0.038 to 0.111
Estimation Comments Tozorakimab Dose A - Placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.473
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.004
Confidence Interval (2-Sided) 80%
-0.071 to 0.079
Estimation Comments Tozorakimab Dose B - Placebo
2.Secondary Outcome
Title Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic
Hide Description

In-clinic spirometry measurements were taken following the use of bronchodilators. Bronchodilatation was induced using albuterol (90 µg metered dose), salbutamol (100 µg metered dose), or levalbuterol (45 µg metered dose), and measurements were taken after up to a maximum of 4 inhalations. Baseline was the last measurement prior to first injection of IP.

The LS means, LS mean differences and 80% CIs, and one-sided p-value results were based on MMRM. The model included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements.
Time Frame Baseline and weeks 8 and 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 24 25 35
Least Squares Mean (Standard Error)
Unit of Measure: litres
Week 8 -0.062  (0.067) 0.008  (0.068) -0.050  (0.060)
Week 16 -0.064  (0.067) -0.050  (0.068) -0.026  (0.060)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.437
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.012
Confidence Interval (2-Sided) 80%
-0.110 to 0.086
Estimation Comments Week 8: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.221
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.059
Confidence Interval (2-Sided) 80%
-0.039 to 0.157
Estimation Comments Week 8: Tozorakimab Dose B - Placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.308
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.038
Confidence Interval (2-Sided) 80%
-0.136 to 0.060
Estimation Comments Week 16: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.372
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.025
Confidence Interval (2-Sided) 80%
-0.122 to 0.072
Estimation Comments Week 16: Tozorakimab Dose B - Placebo
3.Secondary Outcome
Title Serum Concentrations of Tozorakimab
Hide Description Tozorakimab serum concentrations were measured using a validated assay method.
Time Frame Pharmacokinetic (PK) samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
The PK population included participants who received at least one dose of tozorakimab and had at least one detectable serum concentration measurement post-first dose of study intervention. Participants with data available at each time point are presented.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Overall Number of Participants Analyzed 75 77
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: µg/L
Pre-dose Number Analyzed 74 participants 77 participants
NA [1] 
(NA%)
NA [1] 
(NA%)
Week 1 Number Analyzed 74 participants 76 participants
8939.24
(367.31%)
18374.15
(239.89%)
Week 4 Number Analyzed 72 participants 72 participants
2165.82
(180.17%)
4102.04
(168.60%)
Week 8 Number Analyzed 74 participants 70 participants
2680.07
(113.59%)
4476.11
(109.27%)
Week 12 Number Analyzed 74 participants 75 participants
2673.94
(121.08%)
4646.57
(153.62%)
Week 16 Number Analyzed 71 participants 72 participants
2742.93
(128.83%)
5007.93
(117.76%)
Week 20 Number Analyzed 75 participants 72 participants
356.56
(177.25%)
761.75
(152.78%)
Week 24 Number Analyzed 74 participants 72 participants
80.36
(170.34%)
146.67
(214.16%)
[1]
Geometric mean (CV%) could not be calculated due to too many samples with tozorakimab concentrations below the limit of quantification.
4.Secondary Outcome
Title Number of Participants With Anti-drug Antibodies (ADAs)
Hide Description ADA prevalence is the number of participants ADA positive (ADA+) at baseline and/or post-baseline. Treatment-emergent ADA+ (TE-ADA +) positive is defined as being either of treatment-induced ADA+ (ADA negative [ADA-] at baseline and at least one post-baseline ADA+) and treatment-boosted ADA+ (ADA+ at baseline and baseline titre is boosted by ≥ 4-fold increase at ≥ 1 post-baseline time point). Treatment-emergent ADA- (TE-ADA-) is defined as ADA+ but not fulfilling the definition of TE-ADA+. ADA persistently positive is defined as ADA- at baseline and ADA+ at ≥ 2 post-baseline assessment with ≥ 16 weeks between first and last positive assessments, or ADA+ at the last post-baseline assessment. ADA transiently positive is defined as ADA- at baseline, having at least one post-baseline ADA+ assessment and not fulfilling the conditions of ADA persistently positive. Baseline is defined as the last ADA assessment prior to first injection of IP.
Time Frame Blood samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
The as-treated population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 77 77 81
Measure Type: Count of Participants
Unit of Measure: Participants
ADA prevalence Number Analyzed 77 participants 77 participants 81 participants
3
   3.9%
3
   3.9%
1
   1.2%
TE-ADA+ Number Analyzed 75 participants 77 participants 81 participants
3
   4.0%
2
   2.6%
1
   1.2%
Treatment-induced ADA+ Number Analyzed 75 participants 77 participants 81 participants
3
   4.0%
2
   2.6%
1
   1.2%
TE-ADA- Number Analyzed 75 participants 77 participants 81 participants
0
   0.0%
1
   1.3%
0
   0.0%
Both baseline and post-baseline positive Number Analyzed 74 participants 77 participants 81 participants
0
   0.0%
1
   1.3%
0
   0.0%
ADA persistently positive Number Analyzed 74 participants 77 participants 81 participants
3
   4.1%
1
   1.3%
0
   0.0%
ADA transiently positive Number Analyzed 74 participants 77 participants 81 participants
0
   0.0%
1
   1.3%
1
   1.2%
5.Secondary Outcome
Title Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score
Hide Description In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma. Results were based on an MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. A negative change from baseline indicates an improvement in asthma control.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 76 77 81
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-0.925  (0.117) -0.942  (0.117) -0.895  (0.112)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.416
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.030
Confidence Interval (2-Sided) 80%
-0.215 to 0.154
Estimation Comments Tozorakimab Dose A - Placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.371
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.047
Confidence Interval (2-Sided) 80%
-0.231 to 0.137
Estimation Comments Tozorakimab Dose B - Placebo
6.Secondary Outcome
Title Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16
Hide Description In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma. A decrease in ACQ-6 score baseline indicates an improvement in asthma control, and individual changes of at least 0.5 are considered clinically meaningful.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with evaluable ACQ-6 scores were included in the analysis.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 73 74 77
Measure Type: Count of Participants
Unit of Measure: Participants
53
  72.6%
56
  75.7%
53
  68.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.612
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.20
Confidence Interval (2-Sided) 80%
0.76 to 1.90
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.348
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.41
Confidence Interval (2-Sided) 80%
0.88 to 2.25
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16
Hide Description In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with evaluable ACQ-6 scores were included in the analysis.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 73 74 77
Measure Type: Count of Participants
Unit of Measure: Participants
17
  23.3%
18
  24.3%
21
  27.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.575
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.81
Confidence Interval (2-Sided) 80%
0.50 to 1.31
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.679
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.86
Confidence Interval (2-Sided) 80%
0.53 to 1.38
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores
Hide Description The SGRQ is a 50-item patient-reported outcome instrument to measure the health status of participants with airway obstruction diseases, giving a total score and 3 domain scores (symptoms, activity, and impacts). The total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 the best possible health status. Each domain score ranges from 0 to 100, with higher scores indicating greater impairment. A negative change from baseline indicates an improvement in impairments. Results were based on an MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 76 77 80
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
SGRQ Activity Total Score -10.340  (2.477) -11.706  (2.507) -10.342  (2.390)
SGRQ Impacts Total Score -8.237  (1.750) -8.509  (1.774) -6.816  (1.689)
SGRQ Symptoms Total Score -15.290  (2.828) -19.130  (2.873) -15.981  (2.726)
SGRQ Total Score -10.133  (1.815) -11.366  (1.838) -9.470  (1.750)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.500
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.002
Confidence Interval (2-Sided) 80%
-3.825 to 3.828
Estimation Comments SGRQ Activity Total Score: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.324
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -1.364
Confidence Interval (2-Sided) 80%
-5.198 to 2.470
Estimation Comments SGRQ Activity Total Score: Tozorakimab Dose B - Placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.248
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -1.421
Confidence Interval (2-Sided) 80%
-4.103 to 1.260
Estimation Comments SGRQ Impacts Total Score: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.210
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -1.694
Confidence Interval (2-Sided) 80%
-4.383 to 0.996
Estimation Comments SGRQ Impacts Total Score: Tozorakimab Dose B - Placebo
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.420
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.691
Confidence Interval (2-Sided) 80%
-3.715 to 5.096
Estimation Comments SGRQ Symptoms Total Score: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.181
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -3.150
Confidence Interval (2-Sided) 80%
-7.579 to 1.280
Estimation Comments SGRQ Symptoms Total Score: Tozorakimab Dose B - Placebo
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.380
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.663
Confidence Interval (2-Sided) 80%
-3.454 to 2.129
Estimation Comments SGRQ Total Score: Tozorakimab Dose A - Placebo
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.192
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -1.896
Confidence Interval (2-Sided) 80%
-4.694 to 0.903
Estimation Comments SGRQ Total Score: Tozorakimab Dose B - Placebo
9.Secondary Outcome
Title Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16
Hide Description The SGRQ is a 50-item patient-reported outcome instrument to measure the health status of participants with airway obstruction diseases, giving a total score and 3 domain scores (symptoms, activity, and impacts). The total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 the best possible health status. A decrease in the SGRQ total score indicates an improvement in overall impairment.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with evaluable SGRQ scores were included in the analysis.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 73 74 77
Measure Type: Count of Participants
Unit of Measure: Participants
50
  68.5%
53
  71.6%
54
  70.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.828
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.93
Confidence Interval (2-Sided) 80%
0.59 to 1.46
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.840
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.07
Confidence Interval (2-Sided) 80%
0.68 to 1.70
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16
Hide Description Asthma CompEx is a combination of exacerbations of asthma and diary events (i.e., a combination of electronic diary [eDiary] variables). eDiary events are defined by criteria using morning/evening diary variables of PEF, symptoms, and use of rescue medication. A participant was considered to have a CompEx event if they had one or both of an asthma exacerbation or diary event. For participants who did not experience an on-treatment CompEx event, date of censoring was the minimum between the date of last dose + 28 days, and the last day of eDiary recording during the on-treatment period.
Time Frame Baseline to week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participant who were randomised and received any study intervention.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 77 77 81
Measure Type: Count of Participants
Unit of Measure: Participants
19
  24.7%
15
  19.5%
15
  18.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.239
Comments One-sided p-value
Method Regression, Cox
Comments Cox regression model with treatment group, background medication, geographic region, and ICS total daily dose as covariates.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.3
Confidence Interval (2-Sided) 80%
0.8 to 2.0
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.461
Comments One-sided p-value
Method Regression, Cox
Comments Cox regression model with treatment group, background medication, geographic region, and ICS total daily dose as covariates.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.0
Confidence Interval (2-Sided) 80%
0.6 to 1.7
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Asthma CompEx Annualised Event Rate
Hide Description

The annualised rate of asthma CompEx events was calculated as the total number of asthma CompEx events / (date of last dose of IP + 28 - date of first dose of IP - recovery time + 1) / 365.25.

The rates, rate ratios, and one-sided p-values were estimated from a negative binomial regression, with the log(follow up time) included as an offset term. The dependent variable will be the number of CompEx events during the on-treatment period (i.e., from baseline to last dose date +28 days), and the model will include treatment group, background medication, geographic region and baseline ICS total daily dose as covariates.
Time Frame Baseline to week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 77 77 81
Measure Type: Number
Number (80% Confidence Interval)
Unit of Measure: events per participant-treatment year
0.86
(0.58 to 1.28)
0.69
(0.44 to 1.07)
0.99
(0.68 to 1.44)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.346
Comments One-sided p-value
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.87
Confidence Interval (2-Sided) 80%
0.56 to 1.36
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.166
Comments One-sided p-value
Method Negative binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.70
Confidence Interval (2-Sided) 80%
0.43 to 1.12
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath
Hide Description A standardised single-breath FeNO test was performed to evaluate airway inflammation. Results were based on MMRM on log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model were then back transformed. The model included fixed effects for baseline (in log), background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within subject were considered as repeated measurements.
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 74 77 81
Geometric Least Squares Mean (80% Confidence Interval)
Unit of Measure: percent change
-17.429
(-23.423 to -10.965)
-16.500
(-22.548 to -9.981)
-5.007
(-11.612 to 2.091)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.029
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS mean ratio
Estimated Value 0.869
Confidence Interval (2-Sided) 80%
0.791 to 0.956
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.040
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS mean ratio
Estimated Value 0.879
Confidence Interval (2-Sided) 80%
0.800 to 0.966
Estimation Comments [Not Specified]
13.Other Pre-specified Outcome
Title Change From Baseline to Week 16 in Pre-BD FEV1 as Measured in the Study Clinic: Analysis Per Number of Exacerbations in Last 12 Months
Hide Description

In-clinic spirometry measurements were taken prior to the administration of bronchodilators. Baseline was the last measurement prior to first injection of IP.

The LS means, LS mean differences and 80% CIs, and one-sided p-value results were based on MMRM. The model included fixed effects for baseline, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. Analysis is presented by the number of asthma exacerbations experienced within the 12 months prior to baseline (1 or ≥ 2 exacerbations in the previous 12 months).
Time Frame Baseline and week 16
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the ITT population with 1 or ≥ 2 exacerbations in the previous 12 months are included in the analysis. The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 45 47 52
Least Squares Mean (Standard Error)
Unit of Measure: litres
1 Exacerbation in Last 12 Months Number Analyzed 45 participants 47 participants 52 participants
0.188  (0.065) 0.042  (0.070) 0.165  (0.062)
≥ 2 Exacerbations in Last 12 Months Number Analyzed 31 participants 30 participants 29 participants
0.059  (0.067) 0.194  (0.065) -0.018  (0.069)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments 1 Exacerbation in Last 12 Months
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.385
Comments One-sided p-value; alpha = 0.1
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.023
Confidence Interval (2-Sided) 80%
-0.078 to 0.124
Estimation Comments Tozorakimab Dose A - Placebo
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments 1 Exacerbation in Last 12 Months
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.060
Comments One-sided p-value; alpha = 0.1
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -0.123
Confidence Interval (2-Sided) 80%
-0.224 to -0.022
Estimation Comments Tozorakimab Dose B - Placebo
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments ≥ 2 Exacerbation in Last 12 Months
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.186
Comments One-sided p-value; alpha = 0.1
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean Difference
Estimated Value 0.077
Confidence Interval (2-Sided) 80%
-0.034 to 0.187
Estimation Comments Tozorakimab Dose A - Placebo
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments ≥ 2 Exacerbation in Last 12 Months
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments One-sided p-value; alpha = 0.1
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 0.212
Confidence Interval (2-Sided) 80%
0.102 to 0.322
Estimation Comments Tozorakimab Dose B - Placebo
14.Other Pre-specified Outcome
Title Eosinophil Count
Hide Description The eosinophil count at baseline and week 16 are presented. Baseline was defined as the last measurement prior to first injection of IP.
Time Frame Baseline and Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description:
Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection.
Participants were randomised to receive tozorakimab Dose B by SC injection.
Participants were randomised to receive placebo by SC injection.
Overall Number of Participants Analyzed 77 77 81
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: 10^9 cells/L
Baseline Number Analyzed 77 participants 77 participants 81 participants
0.187
(80.4%)
0.200
(88.4%)
0.178
(83.3%)
Week 16 Number Analyzed 65 participants 70 participants 73 participants
0.122
(82.9%)
0.136
(77.6%)
0.185
(93.2%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose A, Placebo
Comments Analysis at Week 16 based on MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 0.630
Confidence Interval (2-Sided) 80%
0.559 to 0.710
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tozorakimab Dose B, Placebo
Comments Analysis at Week 16 based on MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments One-sided p-value
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 0.675
Confidence Interval (2-Sided) 80%
0.599 to 0.760
Estimation Comments [Not Specified]
Time Frame Day 1 to Week 24 (up to 24 weeks)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tozorakimab Dose A Tozorakimab Dose B Placebo
Hide Arm/Group Description Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection. Participants were randomised to receive tozorakimab Dose B by SC injection. Participants were randomised to receive placebo by SC injection.
All-Cause Mortality
Tozorakimab Dose A Tozorakimab Dose B Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/77 (0.00%)      0/77 (0.00%)      0/81 (0.00%)    
Hide Serious Adverse Events
Tozorakimab Dose A Tozorakimab Dose B Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/77 (1.30%)      4/77 (5.19%)      2/81 (2.47%)    
Gastrointestinal disorders       
Acid peptic disease † 1  0/77 (0.00%)  0 1/77 (1.30%)  1 0/81 (0.00%)  0
Umbilical hernia † 1  0/77 (0.00%)  0 0/77 (0.00%)  0 1/81 (1.23%)  1
General disorders       
Asthenia † 1  0/77 (0.00%)  0 1/77 (1.30%)  1 0/81 (0.00%)  0
Infections and infestations       
Bronchitis † 1  0/77 (0.00%)  0 1/77 (1.30%)  1 0/81 (0.00%)  0
Clostridium difficile colitis † 1  0/77 (0.00%)  0 0/77 (0.00%)  0 1/81 (1.23%)  1
Injury, poisoning and procedural complications       
Clavicle fracture † 1  1/77 (1.30%)  1 0/77 (0.00%)  0 0/81 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Asthma † 1  0/77 (0.00%)  0 2/77 (2.60%)  2 0/81 (0.00%)  0
1
Term from vocabulary, MedDRA 25.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tozorakimab Dose A Tozorakimab Dose B Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   25/77 (32.47%)      20/77 (25.97%)      20/81 (24.69%)    
General disorders       
Injection site erythema † 1  4/77 (5.19%)  5 7/77 (9.09%)  15 2/81 (2.47%)  5
Injection site swelling † 1  0/77 (0.00%)  0 4/77 (5.19%)  5 1/81 (1.23%)  4
Injection site urticaria † 1  1/77 (1.30%)  1 4/77 (5.19%)  7 0/81 (0.00%)  0
Infections and infestations       
COVID-19 † 1  15/77 (19.48%)  17 10/77 (12.99%)  12 11/81 (13.58%)  12
Nasopharyngitis † 1  6/77 (7.79%)  6 5/77 (6.49%)  6 4/81 (4.94%)  5
Urinary tract infection † 1  4/77 (5.19%)  4 2/77 (2.60%)  2 3/81 (3.70%)  3
1
Term from vocabulary, MedDRA 25.1
†
Indicates events were collected by systematic assessment
15 participants enrolled at 1 study centre were excluded from the final analysis due to inability to confirm the validity of the data reported by the site. The exclusion of data from this site did not change the interpretation of the primary endpoint, or results in a significant change to the interpretation of any other endpoint.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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: Global Clinical Lead
Organization: AstraZeneca AB
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04570657    
Other Study ID Numbers: D9181C00001
140910 ( Other Identifier: FDA )
2020-000789-40 ( EudraCT Number )
First Submitted: August 7, 2020
First Posted: September 30, 2020
Results First Submitted: December 12, 2023
Results First Posted: January 30, 2024
Last Update Posted: January 30, 2024