Asthma
Conditions
Keywords
Asthma, Bronchospasm
Brief summary
A study to assess bronchospasm potentially induced by HFO MDI as compared with HFA MDI in participants with well controlled or partially controlled asthma
Detailed description
This is a phase 3b, multicentre, randomized, double-blind, single-dose crossover study comparing the safety and tolerability of HFO MDI with HFA MDI delivered in participants with well controlled or partially controlled asthma defined as an ACQ-5 score \< 1.5.Eligible participants are at least 18 years of age and no older than 45 years of age and are required to have asthma as defined by GINA guidelines (GINA 2022). Participants are required to be well controlled or partially controlled on their current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used. The primary objective is to assess the potential change in FEV1 induced by HFO MDI as compared with HFA MDI in participants with asthma. This study will be conducted at approximately 5 sites in the US and will randomize approximately 52 adult participants to achieve 46 completers. The study will be conducted for a maximal 37 days and will comprise: * A screening period approximately 14 (±2) days prior to first dosing * Two treatment periods of 1 day each, with a 3 to 12-day washout period between the 2 treatment periods * A final safety follow-up visit via telephone contact 3 to 7 days after the final dose administration in Treatment Period 2 Single dose study treatment will be administered via MDI device as 4 inhalations: * Treatment A: HFO propellant only MDI; 4 inhalations per dose - test formulation * Treatment B: HFA propellant only MDI; 4 inhalations per dose - reference formulation
Interventions
DRUGHFA MDI
* Dose formulation: MDI * Unit dose strength(s): Reference (propellant only) * Dosage Level: 4 inhalations, single dose * Route of administration: Oral inhalation * Participants will receive treatment A in 1 or 2 possible sequences AB or BA
DRUGHFO MDI
* Dose formulation: MDI * Unit dose strength(s): Experimental (propellant only) * Dosage Level: 4 inhalations, single dose * Route of administration: Oral inhalation * Participants will receive treatment A in 1 or 2 possible sequences AB or BA
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This study is double blinded with regard to treatment (MDI administered with 2 different propellants \[Treatment A or B\]), ie, the sponsor, the investigator, all clinical staff involved in the clinical study, the participants, and the study monitor will remain blinded, unless safety concerns or a regulatory requirement necessitate unblinding.
Intervention model description
The purpose of this study is to assess bronchospasm potentially induced by hydrofluoroolefin (HFO) metered dose inhaler (MDI) as compared with hydrofluoroalkane (HFA) MDI in participants with asthma, well controlled or partially controlled on treatment for asthma, including, low-dose inhaled corticosteroid (ICS) daily or low-dose ICS/formoterol as needed (not approved in the US), or short-acting beta2-agonists (SABA) as needed, or low-dose ICS whenever SABA as needed is used. Study details include: * The study duration will be up to 37 days. * The treatment duration will be 1 day for each treatment period. * The visit frequency will be approximately every 1 week.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Age 1. Male and female participant must be 18 to 45 years of age inclusive, at the time of signing the informed consent form (ICF). Type of Participant and Disease Characteristics 2. Participants who have a documented history of physician-diagnosed asthma ≥ 12 months prior to Visit 1, according to GINA guidelines (GINA 2022). 3. Participants who are well controlled or partially controlled on their current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used (low-dose ICS as defined by GINA 2022 in Table 4), for 4 weeks prior to screening. 4. ACQ-5 total score \< 1.5 at Visit 1. 5. A pre-bronchodilator FEV1 \> 60% predicted normal value at Visit 1. 6. Demonstrate acceptable MDI administration technique. Sex and Contraceptive/Barrier Requirements 7. Females must be not of childbearing potential, or should be using a form of highly effective birth control as defined below: * Female participants Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women included in this study will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the postmenopausal range. * Female participants of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. At enrolment, women of childbearing potential who are sexually active with a non-sterilized male partner should be stable on their chosen method of highly effective birth control, as defined below, and willing to remain on the birth control until at least 14 days after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together. All women of childbearing potential must have a negative serum pregnancy test result at Visit 1. * Highly effective birth control methods are listed below: * Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study intervention, and withdrawal are not acceptable methods of contraception. * Contraceptive subdermal implant * Intrauterine device or intrauterine system * Oral contraceptive (combined or progesterone only) * Injectable progestogen * Contraceptive vaginal ring * Percutaneous contraceptive patches * Male partner sterilization with documentation of azoospermia prior to the female participant's entry into the study, and this male is the sole partner for that participant. The documentation on male sterility can come from the site personnel's review of participant's medical records, medical examination and/or semen analysis or medical history interview provided by her or her partner. * Bilateral tubal ligation Informed Consent 8 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion criteria
* Medical Conditions 1. Life-threatening asthma defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s). 2. Current smokers, former smokers with \> 10 pack-years history, or former smokers who stopped smoking \< 6 months prior to Visit 1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana). 3. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (e.g., active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, COPD, and uncontrolled severe asthma). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the participant at risk through participation, or that could affect the safety/tolerability analysis. 4. Any respiratory infection or asthma exacerbation treated with systemic corticosteroids and/or additional ICS treatment in the 8 weeks prior to Visit 1 and throughout the screening period. 5. Hospitalization for asthma within 1 year prior to Visit 1. 6. Admission to intensive care unit or mechanical ventilation due to asthma exacerbation. 7. Known history of drug or alcohol abuse within 12 months of Visit 1. Prior/Concomitant Therapy 8. Do not meet the stable dosing period prior to Visit 1 (see Table 5) or unable to abstain from protocol-defined prohibited medications during screening and treatment periods (see Table 6 and Table 7). 9. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, e.g., vector, lipid nanoparticle) ≤ 7 days prior to Visit 1 (from last vaccination or booster dose). Prior/Concurrent Clinical Study Experience 10 Participation in another clinical study with an investigational product administered within 30 days or 5 half-lives (whichever is longer). 11 Participants with a known hypersensitivity to HFO or HFA or any of the excipients of the product. 12 Previously randomized into a study with an HFO-containing MDI. Diagnostic Assessments 13 Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urinalysis, vital signs, or electrocardiogram (ECG), which in the opinion of the investigator, may put the participant at risk because of his/her participation in the study. Note: Participants with ECG QT interval corrected for heart rate using Fridericia's formula (QTcF) \> 480 msec will be excluded. Participants with high degree atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who are not treated with pacemaker will also be excluded. Other Exclusions 14 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 15 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. 16 Previous enrolment or randomisation in the present study. 17 For women only - currently pregnant (confirmed with positive pregnancy test), breast feeding, or planned pregnancy during the study or women of childbearing potential not using acceptable contraception measures. 18 Study investigators, sub-investigators, coordinators, and their employees or immediate family members.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | 30 minutes prior to dosing and at 5, 15, and 30 minutes post-dose | The change from baseline (30 minutes pre-dose) in normalized FEV1 AUC0-15 min postdose induced by Treatment HFO was compared with Treatment HFA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Bronchospasm Events | 30 minutes prior to dosing and at 5 and 15 minutes post-dose | The potential of Treatment HFO to induce bronchospasm was compared with Treatment HFA. The number of participants with bronchospasm events post-dose (5 or 15 minutes post-dose) from baseline (30 minutes pre-dose) for each treatment is presented. An event of bronchospasm is defined as a reduction in FEV1 of \>15% from baseline (i.e. the FEV1 value obtained within 30 minutes prior to study intervention administration) at 5 or 15 minutes post-dose, with associated symptoms of wheezing, shortness of breath, or cough. |
| Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | From screening (Day - 14) to the last dose (day 8) + 7 days | The number of AEs, SAEs, and AESIs for Treatment HFO and Treatment HFA are presented. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDavid Miller, MD
Northeast Medical Research Associates, Inc.
PRINCIPAL_INVESTIGATORCraig LaForce, MD
North Carolina Clinical Research
PRINCIPAL_INVESTIGATORAllen T Funkhouser, MC
EPIMRD Inc.
PRINCIPAL_INVESTIGATORJeffrey Tillinghast, MD
The Clinical Research Center, LLC.
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence HFO-HFA HFO propellant only metered-dose inhaler (4 inhalations per dose - test formulation) then HFA propellant only metered-dose inhaler (4 inhalations per dose - reference formulation) | 26 |
| Sequence HFA-HFO HFA propellant only metered-dose inhaler (4 inhalations per dose - reference formulation) then HFO propellant only metered-dose inhaler (4 inhalations per dose - test formulation) | 26 |
| Total | 52 |
Baseline characteristics
| Characteristic | Sequence HFO-HFA | Sequence HFA-HFO | Total |
|---|---|---|---|
| Age, Continuous | 33.8 Years STANDARD_DEVIATION 9.78 | 30.9 Years STANDARD_DEVIATION 7.86 | 32.4 Years STANDARD_DEVIATION 8.9 |
| Age, Customized 18-45 | 26 Participants | 26 Participants | 52 Participants |
| Age, Customized Missing | 0 Participants | 0 Participants | 0 Participants |
| Country USA | 26 Participants | 26 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 19 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Female | 17 Participants | 19 Participants | 36 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 52 |
| other Total, other adverse events | 2 / 52 | 2 / 52 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 |
Outcome results
Primary
Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose
The change from baseline (30 minutes pre-dose) in normalized FEV1 AUC0-15 min postdose induced by Treatment HFO was compared with Treatment HFA.
Time frame: 30 minutes prior to dosing and at 5, 15, and 30 minutes post-dose
Population: Primary Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment HFO | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Baseline FEV1 (30 minutes pre-dose) | 2.969 Litres | Standard Deviation 0.666 |
| Treatment HFO | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Normalized FEV1 AUC0-15 min | 2.955 Litres | Standard Deviation 0.6577 |
| Treatment HFO | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Change from baseline in normalized FEV1 AUC0-15 min post-dose | -0.014 Litres | Standard Deviation 0.0794 |
| Treatment HFA | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Baseline FEV1 (30 minutes pre-dose) | 2.970 Litres | Standard Deviation 0.6463 |
| Treatment HFA | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Normalized FEV1 AUC0-15 min | 2.965 Litres | Standard Deviation 0.6474 |
| Treatment HFA | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve From 0 to 15 Minutes (AUC0-15 Min) Post-dose | Change from baseline in normalized FEV1 AUC0-15 min post-dose | -0.004 Litres | Standard Deviation 0.0565 |
95% CI: [-0.037, 0.018]Mixed Models Analysis
Secondary
Number of Participants With Bronchospasm Events
The potential of Treatment HFO to induce bronchospasm was compared with Treatment HFA. The number of participants with bronchospasm events post-dose (5 or 15 minutes post-dose) from baseline (30 minutes pre-dose) for each treatment is presented. An event of bronchospasm is defined as a reduction in FEV1 of \>15% from baseline (i.e. the FEV1 value obtained within 30 minutes prior to study intervention administration) at 5 or 15 minutes post-dose, with associated symptoms of wheezing, shortness of breath, or cough.
Time frame: 30 minutes prior to dosing and at 5 and 15 minutes post-dose
Population: Safety Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment HFO | Number of Participants With Bronchospasm Events | 0 Participants |
| Treatment HFA | Number of Participants With Bronchospasm Events | 0 Participants |
Secondary
Safety and Tolerability Evaluated in Terms of Adverse Events (AEs)
The number of AEs, SAEs, and AESIs for Treatment HFO and Treatment HFA are presented.
Time frame: Includes AEs with a start date on or after the date of treatment during treatment period 1, up to (and including) 7 days after the last dose date
Population: Safety Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any SAE with outcome death | 0 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any possibly related AE | 1 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Serious AE (SAE) | 0 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any possibly related SAE | 0 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE leading to discontinuation of investigational product | 0 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE of special interest | 0 Events |
| Treatment HFO | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE | 2 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE of special interest | 0 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE | 4 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Serious AE (SAE) | 0 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any SAE with outcome death | 0 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any AE leading to discontinuation of investigational product | 0 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any possibly related AE | 0 Events |
| Treatment HFA | Safety and Tolerability Evaluated in Terms of Adverse Events (AEs) | Any possibly related SAE | 0 Events |