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A randomized, double-blind, parallel group, multi-center study to evaluate the long-term safety of salbutamol rescue medication when administered via metered dose inhalers containing the propellant HFA-152a or reference HFA-134a
Inclusion Criteria:
1. Participant must be 12 years of age or older at the time of signing the informed consent or written informed consent is obtained from each study participant’s legal guardian Type of Participant and Disease Characteristics
2. Asthma for ≥ 6 months, defined as: Documented history of asthma, as defined by GINA (GINA 2023) Receiving one of the following asthma treatments, at a stable dose, for at least 12 weeks prior to the screening visit, with treatment that is anticipated to remain stable for the duration of the study: Daily maintenance low to medium dose ICS (low to medium dose ICS defined as 100-500 µg/day fluticasone propionate or equivalent as defined in the 2023 GINA guidelines [GINA,2023]), plus SABA), which is anticipated to remain stable for the duration of the study. Daily maintenance low to medium dose ICS/LABA (low-dose ICS defined as 100-250 µg/day fluticasone propionate or equivalent as defined in the GINA guidelines plus SABA), which is anticipated to remain stable for the duration of the study.Subjects who utilize Symbicort (combination budesonide/formoterol) as reliever therapy, whether or not this is in addition to a SABA – are not eligible for screening. Subjects who utilize ICS/SABA combination therapy as reliever therapy, in addition to low to medium dose ICS or ICS/LABA as maintenance, are only eligible if they agree to discontinue their ICS/SABA inhaler for the duration of the study (screening through follow-up). The participant’s asthma symptoms must remain stable during the run-in period with marketed Ventolin HFA-134a formulation. Stable asthma is defined as:No more than 3 consecutive days where ≥8 inhalations/day of salbutamol were used. No severe asthma exacerbations (defined as requiring use of systemic corticosteroids tablets, suspension, or injection for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids).No clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment.
3. Severity of disease: Baseline pre-bronchodilator FEV1 ≥60% of predicted at screening. Participants who are unable to perform the pre-bronchodilator FEV1maneuvers at Visit 1 can, at the discretion of the investigator,attend the clinic once more after Visit 1 to attempt to perform the pre-bronchodilator FEV1 maneuvers again, as well as perform the post-bronchodilator FEV1 maneuvers for the assessment of reversibility (see Inclusion Criterion 5). This must be within 7 days of Visit 1. Participants must meet Inclusion Criteria 3 and 5 to be eligible for the study.Participants who provide a technically sound pre-bronchodilator FEV1 at Visit 1 which is not within the FEV1 inclusion limits cannot make another attempt. Should the participant successfully meet the requirements of Inclusion Criterion 3 at the second attempt then, provided that Inclusion Criterion 5 is met and all eligibility criteria assessed at Visit 1 were met, the participant may enter the run-in period. Should the participant not successfully meet the requirements of Inclusion Criterion 3 at the second attempt then they will not be considered eligible for further study participation NOTE: (please refer to the vendor manual for further details on performing spirometry assessments) 4. Asthma Control Status ACQ 6 score <1.5 during the screening period (score measured during randomization visit)
5. Reversibility of disease:Currently demonstrated as ≥ 12% and ≥ 200 mL reversibility of FEV1 within approximately 30 minutes of using an inhaled short acting beta-agonist. Spirometry will be performed after SABA is withheld for ≥4 hours and LABA containing medications are held ≥24 hours.Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria a) or b) are met:A. The participant performs technically acceptable post bronchodilator FEV1 manouvres which demonstrate ≥9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. B. Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of ≥12% and ≥200 mL. Should the subject successfully demonstrate airway reversibility (defined as ≥12% and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the run-in period. 6. Subjects should be able to withhold SABA for ≥4 hours and LABA-containing medications for ≥24 hours for the purpose of performing screening spirometry
7. Short Acting Beta-2-Agonist use:All subjects must be able to replace their current rescue inhalers with the marketed Ventolin HFA-134a formulation at Visit 2 for the run-in period and Visit 3 for use as directed for the duration of the study. The use of a spacer device with MDI or nebulized albuterol/salbutamol will not be allowed during the study with the exception of their use during reversibility at Screening.Smoking Status
8. Participants who are current non-smokers, who have not used any tobacco or vaping products within 12 months of the start of the study, and with a total pack year history of ≤10 pack Years Inhaler Proficiency
9. Demonstrates ability to use Salbutamol Test MDI device in a satisfactory and repeatable manner, as judged visually by the investigator or designee.Liver Criteria
10. Aspartate aminotransferase (AST) and Alanine transaminase (ALT) <2x upper limitof normal (ULN); alkaline phosphatase and bilirubin ≤1.5xULN (isolated bilirubin>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Clinical Laboratory Criteria
11. Serum potassium and blood glucose values within normal laboratory reference ranges.Sex 12. Male and female patients are eligible to participate.Female participants:A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:Is a woman of non-childbearing potential (WONCBP) as defined in [Section : Contraceptive and Barrier Guidance].ORIs a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section during the study intervention period and for at least 48 hours after the last dose of study intervention. The investigator should evaluate potential for contraceptive method failure (e.g., noncomlicance, recently initiated) in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as required by local regulations) within 7 days before the first dose of study intervention. See Section 8.3.6 Pregnancy Testing[If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.] Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.6.The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 days/weeks, after the last dose of study intervention: Refrain from donating fresh unwashed semenPlus either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception as detailed below Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person Informed Consent
13. 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.For paediatric participants, the investigator, or a person designated by the investigator, will obtain written informed consent from each study participant’s legal guardian (as defined in Section 10.1.3) and the participant’s assent, when applicable, before any study specific activity is performed. All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The participant capable of providing signed and dated written assent, signs and dates a written assent form (age-appropriate) and the parent/guardian signs and dates a written informed consent form (ICF) for study participation prior to the initiation of any study related activities. The informed consent is described in Section 10.1.3.
Compliance
14. Subjects must be able to comply with all the study requirements including clinic visit schedules and completion of eDiary.A legal guardian or primary caregiver must be available to help the study site personnel ensure follow-up and support the participant to attended assessment days according to the SoA (e.g., able to comply with scheduled visits, study procedures, and use of study intervention as directed).
1. Participant must be 12 years of age or older at the time of signing the informed consent or written informed consent is obtained from each study participant’s legal guardian Type of Participant and Disease Characteristics
2. Asthma for ≥ 6 months, defined as: Documented history of asthma, as defined by GINA (GINA 2023) Receiving one of the following asthma treatments, at a stable dose, for at least 12 weeks prior to the screening visit, with treatment that is anticipated to remain stable for the duration of the study: Daily maintenance low to medium dose ICS (low to medium dose ICS defined as 100-500 µg/day fluticasone propionate or equivalent as defined in the 2023 GINA guidelines [GINA,2023]), plus SABA), which is anticipated to remain stable for the duration of the study. Daily maintenance low to medium dose ICS/LABA (low-dose ICS defined as 100-250 µg/day fluticasone propionate or equivalent as defined in the GINA guidelines plus SABA), which is anticipated to remain stable for the duration of the study.Subjects who utilize Symbicort (combination budesonide/formoterol) as reliever therapy, whether or not this is in addition to a SABA – are not eligible for screening. Subjects who utilize ICS/SABA combination therapy as reliever therapy, in addition to low to medium dose ICS or ICS/LABA as maintenance, are only eligible if they agree to discontinue their ICS/SABA inhaler for the duration of the study (screening through follow-up). The participant’s asthma symptoms must remain stable during the run-in period with marketed Ventolin HFA-134a formulation. Stable asthma is defined as:No more than 3 consecutive days where ≥8 inhalations/day of salbutamol were used. No severe asthma exacerbations (defined as requiring use of systemic corticosteroids tablets, suspension, or injection for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids).No clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment.
3. Severity of disease: Baseline pre-bronchodilator FEV1 ≥60% of predicted at screening. Participants who are unable to perform the pre-bronchodilator FEV1maneuvers at Visit 1 can, at the discretion of the investigator,attend the clinic once more after Visit 1 to attempt to perform the pre-bronchodilator FEV1 maneuvers again, as well as perform the post-bronchodilator FEV1 maneuvers for the assessment of reversibility (see Inclusion Criterion 5). This must be within 7 days of Visit 1. Participants must meet Inclusion Criteria 3 and 5 to be eligible for the study.Participants who provide a technically sound pre-bronchodilator FEV1 at Visit 1 which is not within the FEV1 inclusion limits cannot make another attempt. Should the participant successfully meet the requirements of Inclusion Criterion 3 at the second attempt then, provided that Inclusion Criterion 5 is met and all eligibility criteria assessed at Visit 1 were met, the participant may enter the run-in period. Should the participant not successfully meet the requirements of Inclusion Criterion 3 at the second attempt then they will not be considered eligible for further study participation NOTE: (please refer to the vendor manual for further details on performing spirometry assessments) 4. Asthma Control Status ACQ 6 score <1.5 during the screening period (score measured during randomization visit)
5. Reversibility of disease:Currently demonstrated as ≥ 12% and ≥ 200 mL reversibility of FEV1 within approximately 30 minutes of using an inhaled short acting beta-agonist. Spirometry will be performed after SABA is withheld for ≥4 hours and LABA containing medications are held ≥24 hours.Note: If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria a) or b) are met:A. The participant performs technically acceptable post bronchodilator FEV1 manouvres which demonstrate ≥9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. B. Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of ≥12% and ≥200 mL. Should the subject successfully demonstrate airway reversibility (defined as ≥12% and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the run-in period. 6. Subjects should be able to withhold SABA for ≥4 hours and LABA-containing medications for ≥24 hours for the purpose of performing screening spirometry
7. Short Acting Beta-2-Agonist use:All subjects must be able to replace their current rescue inhalers with the marketed Ventolin HFA-134a formulation at Visit 2 for the run-in period and Visit 3 for use as directed for the duration of the study. The use of a spacer device with MDI or nebulized albuterol/salbutamol will not be allowed during the study with the exception of their use during reversibility at Screening.Smoking Status
8. Participants who are current non-smokers, who have not used any tobacco or vaping products within 12 months of the start of the study, and with a total pack year history of ≤10 pack Years Inhaler Proficiency
9. Demonstrates ability to use Salbutamol Test MDI device in a satisfactory and repeatable manner, as judged visually by the investigator or designee.Liver Criteria
10. Aspartate aminotransferase (AST) and Alanine transaminase (ALT) <2x upper limitof normal (ULN); alkaline phosphatase and bilirubin ≤1.5xULN (isolated bilirubin>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Clinical Laboratory Criteria
11. Serum potassium and blood glucose values within normal laboratory reference ranges.Sex 12. Male and female patients are eligible to participate.Female participants:A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:Is a woman of non-childbearing potential (WONCBP) as defined in [Section : Contraceptive and Barrier Guidance].ORIs a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section during the study intervention period and for at least 48 hours after the last dose of study intervention. The investigator should evaluate potential for contraceptive method failure (e.g., noncomlicance, recently initiated) in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as required by local regulations) within 7 days before the first dose of study intervention. See Section 8.3.6 Pregnancy Testing[If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.] Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.6.The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 days/weeks, after the last dose of study intervention: Refrain from donating fresh unwashed semenPlus either: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception as detailed below Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person Informed Consent
13. 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.For paediatric participants, the investigator, or a person designated by the investigator, will obtain written informed consent from each study participant’s legal guardian (as defined in Section 10.1.3) and the participant’s assent, when applicable, before any study specific activity is performed. All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The participant capable of providing signed and dated written assent, signs and dates a written assent form (age-appropriate) and the parent/guardian signs and dates a written informed consent form (ICF) for study participation prior to the initiation of any study related activities. The informed consent is described in Section 10.1.3.
Compliance
14. Subjects must be able to comply with all the study requirements including clinic visit schedules and completion of eDiary.A legal guardian or primary caregiver must be available to help the study site personnel ensure follow-up and support the participant to attended assessment days according to the SoA (e.g., able to comply with scheduled visits, study procedures, and use of study intervention as directed).
Exclusion Criteria:
1. A history of life-threatening asthma or asthma that is unstable in the opinion of the investigator.NOTE: Life-threatening asthma is defined as an asthma episode that required intubation/non-invasive positive pressure ventilation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years.
2. Other significant pulmonary diseases to include (but not limited to): pneumothorax, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory abnormalities other than asthma.
3. Respiratory Infection: Culture-documented or suspected bacterial or viral infectionof the upper or lower respiratory tract, sinus or middle ear that is not resolved within4 weeks of screening that led to a change in asthma management ORin the opinion of the Investigator, is expected to affect the participant’s asthma status OR the participant’s ability to participate in the study.
4. Asthma Exacerbation: Any severe asthma exacerbation requiring systemic corticosteroids within 6 months prior to screening. A severe exacerbation is defined asan exacerbation requiring: an asthma-related hospitalization or visit to the emergency department (ED) that leads to treatment with systemic (oral, intramuscular, or intravenous) corticosteroids, or (2) use of systemic corticosteroids (or an increase from a maintenance dose) for asthma, for at least 3 days. Participants must have had no more than 1 severe exacerbation during the prior 12 months.
5. Other concurrent Diseases/Abnormalities: A participant has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the participant at risk through study participation or would confound the interpretation of the study results if the condition/disease exacerbated during the study. (e.g. stroke or MI within 3 months, uncontrolled hypertension, congestive heart failure).
6. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Prior/Concomitant Therapy C8. Long-acting muscarinic antagonist (LAMA) during the 3 months prior to the start of the study.
9. Biologic/immunosuppressive therapies used for the treatment of respiratory diseases during the 6 months, or 5 half lives – whichever is longer - prior to start of the study
10. Participants undergoing de-sensitization therapy.
11. Current use of cholinesterase inhibitor medication (e.g. for myasthenia gravis)
12. Any other prescription or over the counter medication which would significantly affect the course of asthma, or interact with sympathomimetic amines, such as: anticonvulsants (barbiturates, hydantoins, carbamazepine); antidepressants; beta adrenergic blockers; phenothiazines; monoamine oxidase (MOA) inhibitors.
13. Administration of systemic, oral, or depot corticosteroids within 12 weeks of Visit 2 14. Drug Allergy: Known or suspected sensitivity to the constituents of VENTOLIN EVOHALER (e.g. salbutamol sulphate, HFA 134a, Oleic acid etc.). 5.2.4. Prior/Concurrent Clinical Study Experience
15. Exposure to more than four new chemical entities within 12 months prior to the first dosing day or participation in a clinical study within 30 days of study start, or 5 half-lives of study drug if that is longer. Relevant habits
16. Participants with a known or suspected history of alcohol or drug abuse.
17. A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, or geographic location which seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliance with study medication or procedures (i.e. completion of eDiary).
5.2.6. Diagnostic assessments
18. 12-Lead ECG abnormality: Significant abnormality in the 12-lead ECG performed at screening.
19. QT interval corrected for heart rate (QTc) >450 msec for males or QTc >470 msec for female participants and >480 in participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF).
1. A history of life-threatening asthma or asthma that is unstable in the opinion of the investigator.NOTE: Life-threatening asthma is defined as an asthma episode that required intubation/non-invasive positive pressure ventilation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years.
2. Other significant pulmonary diseases to include (but not limited to): pneumothorax, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory abnormalities other than asthma.
3. Respiratory Infection: Culture-documented or suspected bacterial or viral infectionof the upper or lower respiratory tract, sinus or middle ear that is not resolved within4 weeks of screening that led to a change in asthma management ORin the opinion of the Investigator, is expected to affect the participant’s asthma status OR the participant’s ability to participate in the study.
4. Asthma Exacerbation: Any severe asthma exacerbation requiring systemic corticosteroids within 6 months prior to screening. A severe exacerbation is defined asan exacerbation requiring: an asthma-related hospitalization or visit to the emergency department (ED) that leads to treatment with systemic (oral, intramuscular, or intravenous) corticosteroids, or (2) use of systemic corticosteroids (or an increase from a maintenance dose) for asthma, for at least 3 days. Participants must have had no more than 1 severe exacerbation during the prior 12 months.
5. Other concurrent Diseases/Abnormalities: A participant has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the participant at risk through study participation or would confound the interpretation of the study results if the condition/disease exacerbated during the study. (e.g. stroke or MI within 3 months, uncontrolled hypertension, congestive heart failure).
6. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Prior/Concomitant Therapy C8. Long-acting muscarinic antagonist (LAMA) during the 3 months prior to the start of the study.
9. Biologic/immunosuppressive therapies used for the treatment of respiratory diseases during the 6 months, or 5 half lives – whichever is longer - prior to start of the study
10. Participants undergoing de-sensitization therapy.
11. Current use of cholinesterase inhibitor medication (e.g. for myasthenia gravis)
12. Any other prescription or over the counter medication which would significantly affect the course of asthma, or interact with sympathomimetic amines, such as: anticonvulsants (barbiturates, hydantoins, carbamazepine); antidepressants; beta adrenergic blockers; phenothiazines; monoamine oxidase (MOA) inhibitors.
13. Administration of systemic, oral, or depot corticosteroids within 12 weeks of Visit 2 14. Drug Allergy: Known or suspected sensitivity to the constituents of VENTOLIN EVOHALER (e.g. salbutamol sulphate, HFA 134a, Oleic acid etc.). 5.2.4. Prior/Concurrent Clinical Study Experience
15. Exposure to more than four new chemical entities within 12 months prior to the first dosing day or participation in a clinical study within 30 days of study start, or 5 half-lives of study drug if that is longer. Relevant habits
16. Participants with a known or suspected history of alcohol or drug abuse.
17. A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, or geographic location which seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliance with study medication or procedures (i.e. completion of eDiary).
5.2.6. Diagnostic assessments
18. 12-Lead ECG abnormality: Significant abnormality in the 12-lead ECG performed at screening.
19. QT interval corrected for heart rate (QTc) >450 msec for males or QTc >470 msec for female participants and >480 in participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF).