ALTA - ALbuterol/Budesonide Treatment in Acute Airway Obstruction. A Randomized, Double-blind, 2-period, Cross-over Study Evaluating Efficacy and Safety of Repeated Doses of PT027 Compared to PT007 in Patients With Asthma and Acute Airway Obstruction Induced by Repeated Mannitol Challenges
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 190
- 试验地点
- 1
- 主要终点
- Part 1: Change From Mannitol Baseline Forced Expiratory Volume in the First Second (FEV1) Area Under the Curve (AUC [0-60 Min]) Post-mannitol Challenge 1 - Non-Inferiority Analysis
研究概览
简要总结
A study evaluating efficacy and safety of repeated doses of PT027 compared to PT007 in patients with asthma and acute airway obstruction induced by repeated mannitol challenges
详细描述
This is a multi-center, randomized, double-blind, 2-period, cross-over study evaluating efficacy and safety of repeated doses of PT027 (albuterol/budesonide pressurized metered dose inhaler (pMDI)) compared to PT007 (albuterol pMDI) in participants with asthma and acute airway obstruction induced by 2 mannitol challenges at least 8 hours apart.
It is a two-part study where Part 1 will enroll a small cohort of participants and will be used as a pilot study. The data obtained from Part 1 will be assessed by an internal AstraZeneca advisory board, and suggested changes may be made to Part 2 of the study.
The following is the sequence of study visits:
(i) Visit 1 (V1) screening (ii) Visit 2 (V2) 10 to 14 days after Visit 1 assessments; 1st dual challenge and treatment visit (iii) Visit 3 (V3) 10 to 14 days after Visit 2; 2nd dual challenge and treatment visit
At Visit 1, all participants will be subjected to a single mannitol challenge to establish a positive response (defined as a ≥15% decrease in forced expiratory volume in the first second [FEV1] from the 0 mg mannitol FEV1 value) and will receive 4 puffs of open-label PT007. At Visit 2, participants will be randomized to one of 2 treatment sequences, A/B or B/A, where treatments A and B are defined as:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants who have been diagnosed with asthma > 6 months before Visit 1 by a physician.
- •Participants must have been prescribed and using as-needed SABA as only asthma treatment for at least 4 weeks before screening visit.
- •Participants should have pre-bronchodilator FEV1 ≥ 1.5 L and FEV1 ≥ 60% to < 90% predicted normal at Visit
- •Participants should have a positive response to mannitol challenge performed at Visit 1 (a decrease in FEV1 by at least 15% [PD15] at ≤ 635 mg).
- •Participants should return to within 10% of baseline FEV1 (≥ 90% of baseline FEV1), within 1 hour after positive mannitol challenge and 4 inhalations of PT007, performed at Visit
- •Participants should be able to adhere to study procedures in the judgment of the Investigator.
- •Male or female.
- •Women of childbearing potential must have a negative urine pregnancy test at each study visit.
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.
- •Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
排除标准
- •Any evidence of clinically significant lung disease other than asthma.
- •If the participant has had any face-to-face unscheduled or urgent visit for asthma worsening within the last 4 weeks.
- •Any significant disease or disorder, or evidence of drug/substance abuse which in the Investigator's opinion would pose a risk to participant safety, interfere with the conduct of study, have an impact on the study results, or make it undesirable for the participant to participate in the study.
- •If participants have used Inhaled corticosteroids (ICS) within 1 month prior to enrolment.
- •If they have used immunosuppressive medication (including but not limited to methotrexate, troleandomycin, cyclosporine, azathioprine, systemic corticosteroids including regular treatment with oral corticosteroids or intramuscular long-acting depot corticosteroids, or any experimental anti-inflammatory therapy) within 3 months prior to enrolment (Visit 1) or plan on starting immunosuppressive medications during the study.
- •If they have used allergen-specific immunotherapy (desensitization) within 3 months prior to enrolment.
- •If they have used systemic corticosteroids (including oral and injected) within 3 months prior to enrolment.
- •If they have received any marketed or investigational biologic within 4 months or 5 half-lives prior to enrolment (whichever is longer) or received any investigational nonbiologic agent within 30 days or 5 half-lives prior to enrolment (whichever is longer).
- •Participants with a known hypersensitivity to beta2-agonists, ICS, mannitol, or any of the excipients of the product.
- •Any clinically significant abnormal findings in physical examination, vital signs, ECG (eg, participants with QTcF > 500 ms), hematology, clinical chemistry, or urinalysis, which in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete entire duration of the study.
- •If they are current smokers or participants with smoking history ≥ 10 pack years including the use of vaping products, such as electronic cigarettes, and water pipes. If they are former smokers with a smoking history of <10 pack years, including former vaping or water pipe users, smoking must have stopped for at least 6 months prior to Visit 1 to be eligible.
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and its affiliates and/or staff at the study site and their immediate relative(s)).
- •Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
- •Breast feeding, pregnancy or intention to become pregnant during the course of the study.
- •Previous randomization in the present study.
研究组 & 干预措施
Treatment A (PT027) [experimental], then Treatment B (PT007) [active comparator] Part 1 & 2
At Visit 2, participants will receive repeated oral inhalations of PT027 to treat acute airway obstruction induced by a repeated airway challenge, followed by a washout period of 10-14 days. At Visit 3, participants will receive repeated oral inhalations of PT007 to treat acute airway obstruction induced by a repeated airway challenge.
干预措施: PT027 (Combination Product)
Treatment A (PT027) [experimental], then Treatment B (PT007) [active comparator] Part 1 & 2
At Visit 2, participants will receive repeated oral inhalations of PT027 to treat acute airway obstruction induced by a repeated airway challenge, followed by a washout period of 10-14 days. At Visit 3, participants will receive repeated oral inhalations of PT007 to treat acute airway obstruction induced by a repeated airway challenge.
干预措施: PT007 (Combination Product)
Treatment B (PT007) [active comparator], then Treatment A (PT027) [experimental] Part 1 & 2
At Visit 2, participants will receive repeated oral inhalations of PT007 to treat acute airway obstruction induced by a repeated airway challenge, followed by a washout period of 10 to 14 days. At Visit 3, participants will receive repeated oral inhalations of PT027 to treat acute airway obstruction induced by a repeated airway challenge.
干预措施: PT027 (Combination Product)
Treatment B (PT007) [active comparator], then Treatment A (PT027) [experimental] Part 1 & 2
At Visit 2, participants will receive repeated oral inhalations of PT007 to treat acute airway obstruction induced by a repeated airway challenge, followed by a washout period of 10 to 14 days. At Visit 3, participants will receive repeated oral inhalations of PT027 to treat acute airway obstruction induced by a repeated airway challenge.
干预措施: PT007 (Combination Product)
结局指标
主要结局
Part 1: Change From Mannitol Baseline Forced Expiratory Volume in the First Second (FEV1) Area Under the Curve (AUC [0-60 Min]) Post-mannitol Challenge 1 - Non-Inferiority Analysis
时间窗: Up to 60 minutes post mannitol challenge 1
The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The primary efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on treatment estimand in the Per Protocol (PP) analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.
Part 1: Change From Mannitol Baseline FEV1 AUC (0-60 Min) Post-mannitol Challenge 1 - Superiority Analysis
时间窗: Up to 60 minutes post mannitol challenge 1
The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the randomized set (RS). Superiority was concluded if the 2-sided p-value was \< 0.05.
Part 2: Change From Mannitol Baseline FEV1 AUC (0-60 Min) Post-mannitol Challenge 1 - Non-Inferiority Analysis
时间窗: Up to 60 minutes post mannitol challenge 1
The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. The primary efficacy comparison of non-inferiority of PT027 versus PT007 evaluated the while-on-treatment estimand in the PP analysis set and was based on a 1-sided hypothesis testing approach with a non-inferiority margin of -150 mL.
Part 2: Change From Mannitol Baseline FEV1 AUC (0-60 Min) Post-mannitol Challenge 1 - Superiority Analysis
时间窗: Up to 60 minutes post mannitol challenge 1
The efficacy of repeated dosing of PT027 relative to PT007, on post-dose lung function, when used by participants with asthma on SABA as-needed treatment only who are experiencing acute airway obstruction induced by mannitol challenges was assessed. Mannitol baseline was defined as the FEV1 result where a positive response to mannitol was observed prior to dosing of study drug for challenge 1 in Visit 2 and in Visit 3 (time 0). A positive response was defined as a ≥ 15% decrease from the FEV1 determined after the 0 mg mannitol dose up to ≤ 635 mg cumulative mannitol dose. If non-inferiority was demonstrated, then comparisons were made to establish the superiority of PT027 versus PT007. The primary efficacy comparison of superiority was based on a 2-sided hypothesis testing approach in the modified randomized set (mRS). Superiority was concluded if the 2-sided p-value was \< 0.05.
次要结局
- Part 1: Change From Mannitol Baseline in FEV1 AUC (0-15 Min) Post-mannitol Challenge 1 - Non-Inferiority Analysis(Up to 15 minutes post mannitol challenge 1)
- Part 1: Change From Mannitol Baseline in FEV1 AUC (0-15 Min) Post-mannitol Challenge 1 - Superiority Analysis(Up to 15 minutes post mannitol challenge 1)
- Part 2: Change From Mannitol Baseline in FEV1 AUC (0-15 Min) Post-mannitol Challenge 1 - Non-Inferiority Analysis(Up to 15 minutes post mannitol challenge 1)
- Part 2: Change From Mannitol Baseline in FEV1 AUC (0-15 Min) Post-mannitol Challenge 1 - Superiority Analysis(Up to 15 minutes post mannitol challenge 1)
- Part 1: Change From Mannitol Baseline in FEV1 at 7 Hours Post-mannitol Challenge 1 - Non-Inferiority Analysis(At 7 hours post mannitol challenge 1)
- Part 1: Change From Mannitol Baseline in FEV1 at 7 Hours Post-mannitol Challenge 1 - Superiority Analysis(At 7 hours post mannitol challenge 1)
- Part 2: Change From Mannitol Baseline in FEV1 at 480 Minutes Post-mannitol Challenge 1 - Non-Inferiority Analysis(At 480 minutes post mannitol challenge 1)
- Part 2: Change From Mannitol Baseline in FEV1 at 480 Minutes Post-mannitol Challenge 1 - Superiority Analysis(At 480 minutes post mannitol challenge 1)
- Part 1: Time to Return to Baseline (-30 Min) FEV1 Post-mannitol Challenge 2 - Non-Inferiority Analysis(From baseline (30 minutes prior to mannitol challenge 1) up to 60 minutes post-mannitol challenge 2 (up to 550 minutes post-mannitol challenge 1))
- Part 1: Time to Return to Baseline (-30 Min) FEV1 Post-mannitol Challenge 2 - Superiority Analysis(From baseline (30 minutes prior to mannitol challenge 1) up to 60 minutes post-mannitol challenge 2 (up to 550 minutes post-mannitol challenge 1))
- Part 2: Time to Return to Baseline (-30 Min) FEV1 Post-mannitol Challenge 2, Pre-final Dose of Rescue/Reliever - Non-Inferiority Analysis(From baseline (30 minutes prior to mannitol challenge 1) up to 60 minutes post-mannitol challenge 2 (up to 550 minutes post-mannitol challenge 1))
- Part 2: Time to Return to Baseline (-30 Min) FEV1 Post-mannitol Challenge 2, Pre-final Dose of Rescue/Reliever - Superiority Analysis(From baseline (30 minutes prior to mannitol challenge 1) up to 60 minutes post-mannitol challenge 2 (up to 550 minutes post-mannitol challenge 1))
- Part 1: Peak Fall in FEV1 From Baseline (-30 Min) FEV1 to Post-mannitol Challenge 2, Pre-dose - Non-Inferiority Analysis(Baseline (30 minutes prior to mannitol challenge 1) and at 490 minutes post-mannitol challenge 1)
- Part 1: Peak Fall in FEV1 From Baseline (-30 Min) FEV1 to Post-mannitol Challenge 2, Pre-dose - Superiority Analysis(Baseline (30 minutes prior to mannitol challenge 1) and at 490 minutes post-mannitol challenge 1)
- Part 2: Peak Fall in FEV1 From Baseline (-30 Min) FEV1 to Post-mannitol Challenge 2, Pre-final Dose of Rescue/Reliever - Non-Inferiority Analysis(Baseline (30 minutes prior to mannitol challenge 1) and at 490 minutes post-mannitol challenge 1)
- Part 2: Peak Fall in FEV1 From Baseline (-30 Min) FEV1 to Post-mannitol Challenge 2, Pre-final Dose of Rescue/Reliever - Superiority Analysis(Baseline (30 minutes prior to mannitol challenge 1) and at 490 minutes post-mannitol challenge 1)
- Part 1: Peak Fall in FEV1 From 7 Hours to Post-mannitol Challenge 2, Pre-dose - Non-Inferiority Analysis(420 minutes post-mannitol challenge 1 and 430 minutes post-mannitol challenge 1)
- Part 1: Peak Fall in FEV1 From 7 Hours to Post-mannitol Challenge 2, Pre-dose - Superiority Analysis(420 minutes post-mannitol challenge 1 and 430 minutes post-mannitol challenge 1)
- Part 2: Peak Fall in FEV1 From 480 Minutes to Post-mannitol Challenge 2, Pre-final Dose of Rescue/Reliever - Superiority Analysis(480 minutes post-mannitol challenge 1 and 490 minutes post-mannitol challenge 1)
- Number of Participants With Adverse Events (AEs)(From Visit 1 until end of follow-up, up to 38 days)