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

Phase 2

Completed

Conditions: Asthma

Interventions: Drug: Placebo
Biological: MEDI3506

Registration Number: NCT04570657

Lead Sponsor: AstraZeneca

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 250

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Approximately 76 participants will be randomized to this arm. Participants in this group will receive the placebo.
MEDI3506 Dose 2	MEDI3506	Approximately 76 participants will be randomized to this arm to receive the lower dose of MEDI3506
MEDI3506 Dose 1	MEDI3506	Approximately 76 participants will be randomized to this arm to receive the higher dose of MEDI3506

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.