Asthma
Conditions
Keywords
MEDI3506, lung function, IL-33, inflammation
Brief summary
Study D9181C00001 is a Phase II, randomised, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy, safety, pharmacokinetics (PK) and immunogenicity of MEDI3506 in adult participants with uncontrolled moderate to severe asthma on standard of care (SOC). Up to approximately 80 sites globally will participate in this study. Approximately 228 participants will be randomized to 3 treatment groups in a 1:1:1 ratio to receive MEDI3506 dose 1, MEDI3506 dose 2, or placebo.
Interventions
BIOLOGICALMEDI3506
Participants will receive multiple doses of MEDI3506 at dose level 1 or dose level 2
DRUGPlacebo
Participants will receive multiple doses of placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Aged 18 to \< 65 years of age * Physician-diagnosed asthma of early onset, defined as development of asthma before the age of 25 years. * History of ≥ 1 asthma exacerbation in previous 24 months * Treated with medium to high dose ICS defined as total daily dose of \> 250 g fluticasone dry powder or equivalent, for at least 12 months and on a stable dose for ≥ 3 months. * Stable LABA therapy for ≥ 3 months. * An ACQ-6 score ≥ 1.5. * Morning pre-BD FEV1 ≥ 40% predicted normal and \> 1 L. * Morning pre-BD FEV1 \< 85% predicted normal. * Participants with documented evidence of asthma as demonstrated by either: * BD reversibility, within 12 months, or at screening, or * Positive methacholine challenge test within 12 months. * Bodyweight ≥ 40 kg and BMI \< 40 kg/m2. * For female participants, a negative pregnancy test. * Abide by contraception requirements for males and females * Provide informed consent
Exclusion criteria
* Participants with a positive diagnostic nucleic acid test for SARS-CoV-2. * Participants with a significant COVID-19 illness within 6 months of enrolment: * Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis B, hepatitis C, or HIV. * Evidence of active or latent TB: * An LVEF \< 45% measured by echocardiogram during screening. * A family history of heart failure. * Current smokers or recent ex-smokers i.e., have quit e cigarettes or other inhaled tobacco products ≤ 6 months prior to SV1. * Ex-smokers with a total smoking history of \> 10 pack years. * As judged by the investigator, any evidence of any active medical or psychiatric condition or other reason (prior to randomisation) that in the investigator's opinion makes it undesirable for the participant to participate in the study. * Any clinically important pulmonary disease other than asthma. * Any other clinically relevant abnormal findings on physical examination or laboratory testing, that in the opinion of the investigator or medical monitor might compromise the safety of the participant in the study or interfere with evaluation of the study intervention. * A known history of severe reaction to any medication including biologic agents or human gamma globulin therapy. * History of, or a reason to believe, a participant has a history of, drug or alcohol abuse within the past 2 years. * Current diagnosis of cancer. * History of cancer, except if treated with apparent success with curative therapy (response duration of \> 5 years). * History of allogeneic bone marrow transplant. * A helminth parasitic infection diagnosed within 6 months prior to SV4 (randomisation) that has not been treated, or has not responded to SOC therapy. * An asthma exacerbation within 8 weeks. * Receiving any prohibited concomitant medications or therapies as specified in the protocol: Known history of allergy or reaction to any component of the study intervention formulation, including hereditary fructose intolerance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline and week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Baseline and weeks 8 and 16 | 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. |
| Serum Concentrations of Tozorakimab | Pharmacokinetic (PK) samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, 20, and 24 | Tozorakimab serum concentrations were measured using a validated assay method. |
| Number of Participants With Anti-drug Antibodies (ADAs) | Blood samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, and 24 | 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. |
| Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score | Baseline and week 16 | 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. |
| Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16 | Baseline and week 16 | 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. |
| Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16 | Baseline and week 16 | 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. |
| Asthma CompEx Annualised Event Rate | Baseline to week 16 | 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. |
| Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath | Baseline and week 16 | 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. |
| Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | Baseline and week 16 | 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. |
| Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16 | Baseline and week 16 | 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. |
| Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16 | Baseline to week 16 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline and week 16 | 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). |
| Eosinophil Count | Baseline and Week 16 | The eosinophil count at baseline and week 16 are presented. Baseline was defined as the last measurement prior to first injection of IP. |
Countries
Argentina, Germany, Hungary, Poland, South Africa, United Kingdom, United States
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| Tozorakimab Dose A Participants were randomised to receive tozorakimab Dose A by subcutaneous (SC) injection. | 77 |
| Tozorakimab Dose B Participants were randomised to receive tozorakimab Dose B by SC injection. | 77 |
| Placebo Participants were randomised to receive placebo by SC injection. | 81 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Tozorakimab Dose A | Tozorakimab Dose B | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 42.1 years STANDARD_DEVIATION 11.97 | 43.1 years STANDARD_DEVIATION 12.37 | 48.3 years STANDARD_DEVIATION 10.41 | 44.5 years STANDARD_DEVIATION 11.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 24 Participants | 33 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 53 Participants | 48 Participants | 152 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 8 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 71 Participants | 67 Participants | 72 Participants | 210 Participants |
| Sex: Female, Male Female | 53 Participants | 54 Participants | 43 Participants | 150 Participants |
| Sex: Female, Male Male | 24 Participants | 23 Participants | 38 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 77 | 0 / 81 |
| other Total, other adverse events | 25 / 77 | 20 / 77 | 20 / 81 |
| serious Total, serious adverse events | 1 / 77 | 4 / 77 | 2 / 81 |
Outcome results
Primary
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
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tozorakimab Dose A | 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 | 0.148 litres | Standard Error 0.047 |
| Tozorakimab Dose B | 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 | 0.116 litres | Standard Error 0.048 |
| Placebo | 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 | 0.112 litres | Standard Error 0.046 |
p-value: 0.26780% CI: [-0.038, 0.111]MMRM
p-value: 0.47380% CI: [-0.071, 0.079]MMRM
Secondary
Asthma CompEx Annualised Event Rate
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
Population: The ITT population included participants who were randomised and received any study intervention.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tozorakimab Dose A | Asthma CompEx Annualised Event Rate | 0.86 events per participant-treatment year |
| Tozorakimab Dose B | Asthma CompEx Annualised Event Rate | 0.69 events per participant-treatment year |
| Placebo | Asthma CompEx Annualised Event Rate | 0.99 events per participant-treatment year |
p-value: 0.34680% CI: [0.56, 1.36]Negative binomial regression
p-value: 0.16680% CI: [0.43, 1.12]Negative binomial regression
Secondary
Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tozorakimab Dose A | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Total Score | -10.133 score on a scale | Standard Error 1.815 |
| Tozorakimab Dose A | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Activity Total Score | -10.340 score on a scale | Standard Error 2.477 |
| Tozorakimab Dose A | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Impacts Total Score | -8.237 score on a scale | Standard Error 1.75 |
| Tozorakimab Dose A | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Symptoms Total Score | -15.290 score on a scale | Standard Error 2.828 |
| Tozorakimab Dose B | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Total Score | -11.366 score on a scale | Standard Error 1.838 |
| Tozorakimab Dose B | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Activity Total Score | -11.706 score on a scale | Standard Error 2.507 |
| Tozorakimab Dose B | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Symptoms Total Score | -19.130 score on a scale | Standard Error 2.873 |
| Tozorakimab Dose B | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Impacts Total Score | -8.509 score on a scale | Standard Error 1.774 |
| Placebo | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Total Score | -9.470 score on a scale | Standard Error 1.75 |
| Placebo | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Impacts Total Score | -6.816 score on a scale | Standard Error 1.689 |
| Placebo | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Symptoms Total Score | -15.981 score on a scale | Standard Error 2.726 |
| Placebo | Change From Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores | SGRQ Activity Total Score | -10.342 score on a scale | Standard Error 2.39 |
p-value: 0.580% CI: [-3.825, 3.828]MMRM
p-value: 0.32480% CI: [-5.198, 2.47]MMRM
p-value: 0.24880% CI: [-4.103, 1.26]MMRM
p-value: 0.2180% CI: [-4.383, 0.996]MMRM
p-value: 0.4280% CI: [-3.715, 5.096]MMRM
p-value: 0.18180% CI: [-7.579, 1.28]MMRM
p-value: 0.3880% CI: [-3.454, 2.129]MMRM
p-value: 0.19280% CI: [-4.694, 0.903]MMRM
Secondary
Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tozorakimab Dose A | Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score | -0.925 score on a scale | Standard Error 0.117 |
| Tozorakimab Dose B | Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score | -0.942 score on a scale | Standard Error 0.117 |
| Placebo | Change From Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score | -0.895 score on a scale | Standard Error 0.112 |
p-value: 0.41680% CI: [-0.215, 0.154]MMRM
p-value: 0.37180% CI: [-0.231, 0.137]MMRM
Secondary
Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tozorakimab Dose A | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 8 | -0.062 litres | Standard Error 0.067 |
| Tozorakimab Dose A | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 16 | -0.064 litres | Standard Error 0.067 |
| Tozorakimab Dose B | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 8 | 0.008 litres | Standard Error 0.068 |
| Tozorakimab Dose B | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 16 | -0.050 litres | Standard Error 0.068 |
| Placebo | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 8 | -0.050 litres | Standard Error 0.06 |
| Placebo | Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic | Week 16 | -0.026 litres | Standard Error 0.06 |
p-value: 0.37280% CI: [-0.122, 0.072]MMRM
p-value: 0.43780% CI: [-0.11, 0.086]MMRM
p-value: 0.22180% CI: [-0.039, 0.157]MMRM
p-value: 0.30880% CI: [-0.136, 0.06]MMRM
Secondary
Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tozorakimab Dose A | Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16 | 17 Participants |
| Tozorakimab Dose B | Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16 | 18 Participants |
| Placebo | Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16 | 21 Participants |
p-value: 0.57580% CI: [0.5, 1.31]Chi-squared
p-value: 0.67980% CI: [0.53, 1.38]Chi-squared
Secondary
Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tozorakimab Dose A | Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16 | 53 Participants |
| Tozorakimab Dose B | Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16 | 56 Participants |
| Placebo | Number of Participants With a Decrease in ACQ-6 Score ≥ 0.5 From Baseline to Week 16 | 53 Participants |
p-value: 0.61280% CI: [0.76, 1.9]Chi-squared
p-value: 0.34880% CI: [0.88, 2.25]Chi-squared
Secondary
Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with evaluable SGRQ scores were included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tozorakimab Dose A | Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16 | 50 Participants |
| Tozorakimab Dose B | Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16 | 53 Participants |
| Placebo | Number of Participants With a Decrease in SGRQ Total Score of ≥ 4 Points From Baseline to Week 16 | 54 Participants |
p-value: 0.82880% CI: [0.59, 1.46]Chi-squared
p-value: 0.8480% CI: [0.68, 1.7]Chi-squared
Secondary
Number of Participants With Anti-drug Antibodies (ADAs)
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
Population: The as-treated population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA+ | 3 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | Both baseline and post-baseline positive | 0 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA- | 0 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | ADA prevalence | 3 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | ADA transiently positive | 0 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | ADA persistently positive | 3 Participants |
| Tozorakimab Dose A | Number of Participants With Anti-drug Antibodies (ADAs) | Treatment-induced ADA+ | 3 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA- | 1 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | ADA prevalence | 3 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA+ | 2 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | Treatment-induced ADA+ | 2 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | Both baseline and post-baseline positive | 1 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | ADA persistently positive | 1 Participants |
| Tozorakimab Dose B | Number of Participants With Anti-drug Antibodies (ADAs) | ADA transiently positive | 1 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | Both baseline and post-baseline positive | 0 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA+ | 1 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | ADA transiently positive | 1 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | ADA persistently positive | 0 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | TE-ADA- | 0 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | Treatment-induced ADA+ | 1 Participants |
| Placebo | Number of Participants With Anti-drug Antibodies (ADAs) | ADA prevalence | 1 Participants |
Secondary
Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16
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
Population: The ITT population included participant who were randomised and received any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tozorakimab Dose A | Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16 | 19 Participants |
| Tozorakimab Dose B | Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16 | 15 Participants |
| Placebo | Number of Participants With at Least One Asthma CompEx Event From Baseline to Week 16 | 15 Participants |
p-value: 0.23980% CI: [0.8, 2]Regression, Cox
p-value: 0.46180% CI: [0.6, 1.7]Regression, Cox
Secondary
Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Tozorakimab Dose A | Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath | -17.429 percent change |
| Tozorakimab Dose B | Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath | -16.500 percent change |
| Placebo | Percent Change From Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath | -5.007 percent change |
p-value: 0.02980% CI: [0.791, 0.956]MMRM
p-value: 0.0480% CI: [0.8, 0.966]MMRM
Secondary
Serum Concentrations of Tozorakimab
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
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 12 | 2673.94 µg/L | Geometric Coefficient of Variation 121.08 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Pre-dose | NA µg/L | — |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 16 | 2742.93 µg/L | Geometric Coefficient of Variation 128.83 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 4 | 2165.82 µg/L | Geometric Coefficient of Variation 180.17 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 20 | 356.56 µg/L | Geometric Coefficient of Variation 177.25 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 1 | 8939.24 µg/L | Geometric Coefficient of Variation 367.31 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 24 | 80.36 µg/L | Geometric Coefficient of Variation 170.34 |
| Tozorakimab Dose A | Serum Concentrations of Tozorakimab | Week 8 | 2680.07 µg/L | Geometric Coefficient of Variation 113.59 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 24 | 146.67 µg/L | Geometric Coefficient of Variation 214.16 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Pre-dose | NA µg/L | — |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 1 | 18374.15 µg/L | Geometric Coefficient of Variation 239.89 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 4 | 4102.04 µg/L | Geometric Coefficient of Variation 168.6 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 12 | 4646.57 µg/L | Geometric Coefficient of Variation 153.62 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 16 | 5007.93 µg/L | Geometric Coefficient of Variation 117.76 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 20 | 761.75 µg/L | Geometric Coefficient of Variation 152.78 |
| Tozorakimab Dose B | Serum Concentrations of Tozorakimab | Week 8 | 4476.11 µg/L | Geometric Coefficient of Variation 109.27 |
Other Pre-specified
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
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
Population: 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 | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Tozorakimab Dose A | 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 | 1 Exacerbation in Last 12 Months | 0.188 litres | Standard Error 0.065 |
| Tozorakimab Dose A | 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 | ≥ 2 Exacerbations in Last 12 Months | 0.059 litres | Standard Error 0.067 |
| Tozorakimab Dose B | 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 | 1 Exacerbation in Last 12 Months | 0.042 litres | Standard Error 0.07 |
| Tozorakimab Dose B | 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 | ≥ 2 Exacerbations in Last 12 Months | 0.194 litres | Standard Error 0.065 |
| Placebo | 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 | 1 Exacerbation in Last 12 Months | 0.165 litres | Standard Error 0.062 |
| Placebo | 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 | ≥ 2 Exacerbations in Last 12 Months | -0.018 litres | Standard Error 0.069 |
Comparison: 1 Exacerbation in Last 12 Monthsp-value: 0.38580% CI: [-0.078, 0.124]MMRM
Comparison: 1 Exacerbation in Last 12 Monthsp-value: 0.0680% CI: [-0.224, -0.022]MMRM
Comparison: ≥ 2 Exacerbation in Last 12 Monthsp-value: 0.18680% CI: [-0.034, 0.187]MMRM
Comparison: ≥ 2 Exacerbation in Last 12 Monthsp-value: 0.00780% CI: [0.102, 0.322]MMRM
Other Pre-specified
Eosinophil Count
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
Population: The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Tozorakimab Dose A | Eosinophil Count | Week 16 | 0.122 10^9 cells/L | Geometric Coefficient of Variation 82.9 |
| Tozorakimab Dose A | Eosinophil Count | Baseline | 0.187 10^9 cells/L | Geometric Coefficient of Variation 80.4 |
| Tozorakimab Dose B | Eosinophil Count | Baseline | 0.200 10^9 cells/L | Geometric Coefficient of Variation 88.4 |
| Tozorakimab Dose B | Eosinophil Count | Week 16 | 0.136 10^9 cells/L | Geometric Coefficient of Variation 77.6 |
| Placebo | Eosinophil Count | Baseline | 0.178 10^9 cells/L | Geometric Coefficient of Variation 83.3 |
| Placebo | Eosinophil Count | Week 16 | 0.185 10^9 cells/L | Geometric Coefficient of Variation 93.2 |
Comparison: 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.p-value: <0.00180% CI: [0.559, 0.71]MMRM
Comparison: 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.p-value: <0.00180% CI: [0.599, 0.76]MMRM