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
|
- Study Details
- Tabular View
- Study Results
- Disclaimer
- How to Read a Study Record
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Asthma | Biological: MEDI3506 Drug: Placebo | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 250 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase II, Randomised, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of MEDI3506 in Adult Participants With Uncontrolled Moderate-to-severe Asthma |
| Actual Study Start Date : | September 17, 2020 |
| Actual Primary Completion Date : | December 12, 2022 |
| Actual Study Completion Date : | February 6, 2023 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: MEDI3506 Dose 1
Approximately 76 participants will be randomized to this arm to receive the higher dose of MEDI3506
|
Biological: MEDI3506
Participants will receive multiple doses of MEDI3506 at dose level 1 or dose level 2 |
|
Experimental: MEDI3506 Dose 2
Approximately 76 participants will be randomized to this arm to receive the lower dose of MEDI3506
|
Biological: MEDI3506
Participants will receive multiple doses of MEDI3506 at dose level 1 or dose level 2 |
|
Placebo Comparator: Placebo
Approximately 76 participants will be randomized to this arm. Participants in this group will receive the placebo.
|
Drug: Placebo
Participants will receive multiple doses of 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 [ Time Frame: 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.
- Change From Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
- Asthma CompEx Annualised Event Rate [ Time Frame: 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 [ Time Frame: 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 Pre-BD FEV1 as Measured in the Study Clinic: Analysis Per Number of Exacerbations in Last 12 Months [ Time Frame: 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 [ Time Frame: 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04570657
Show 65 study locations
Documents provided by AstraZeneca:
| Responsible Party: | AstraZeneca |
| ClinicalTrials.gov Identifier: | NCT04570657 |
| Other Study ID Numbers: |
D9181C00001 140910 ( Other Identifier: FDA ) 2020-000789-40 ( EudraCT Number ) |
| First Posted: | September 30, 2020 Key Record Dates |
| Results First Posted: | January 30, 2024 |
| Last Update Posted: | January 30, 2024 |
| Last Verified: | January 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) |
| Time Frame: | AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. |
| Access Criteria: | When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. |
| URL: | https://astrazenecagroup-dt.pharmacm.com/DT/Home |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
|
MEDI3506 lung function IL-33 inflammation |
|
Asthma Bronchial Diseases Respiratory Tract Diseases Lung Diseases, Obstructive Lung Diseases |
Respiratory Hypersensitivity Hypersensitivity, Immediate Hypersensitivity Immune System Diseases |