Mucociliary Clearance
Conditions
Brief summary
The primary objective of this study was to assess the effect of multiple doses of the HFA-152a propellant and the HFA-134a propellant on mucociliary clearance (MCC).
Detailed description
This clinical trial was a Phase I, single-centre, multiple-dose, randomised, open-label, controlled, 2-way cross-over study to assess the effect on MCC of the new HFA-152a propellant (5 inhalations BID for 8 days) versus the marketed HFA-134a propellant (5 inhalations BID for 8 days) in adult healthy volunteers by measuring the clearance from the lungs of inhaled radioaerosol. A total of 20 subjects were randomised into the study. Standard safety assessments was conducted during the Study, including safety blood and urine laboratory tests, vital signs, physical examinations, ECGs, spirometry, and observations of any adverse events (AE).
Interventions
OTHERPlacebo formulated with HFA-152a propellant via pMDI
5 inhalations BID (morning and evening) for 8 consecutive days, starting from the morning of Day 1 until the morning of Day 8
OTHERPlacebo formulated with HFA-134a propellant via pMDI
5 inhalations BID (morning and evening) for 8 consecutive days, starting from the morning of Day 1 until the morning of Day 8
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject's written informed consent obtained prior to any study-related procedure; 2. Healthy male and female subjects aged 18-55 years (inclusive); 3. Ability to understand the study procedures, the risks involved and ability to be trained to use the inhalers correctly; 4. Body Mass Index (BMI) between 18 and 30 kg/m2 (extremes inclusive); 5. Non-smokers or ex-smokers who smoked \< 5 pack-years and stopped smoking \> 5 years prior to screening; 6. Good physical and mental status at screening and before randomisation; 7. Vital signs within normal limits at screening; body temperature \< 37.5°C; 8. 12-lead digitised electrocardiogram (ECG) in triplicate considered as normal at screening; 9. Lung function measurements within normal limits at screening; 10. Female subjects fulfilling one of the following criteria: Women of non-childbearing potential (WONCBP). Women of childbearing potential (WOCBP) with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method preferably with low user dependency, from the signature of the informed consent form (ICF) and until the follow-up call. 11. Male subjects fulfilling one of the following criteria: Fertile male subjects with a pregnant or non-pregnant WOCBP partner: they must be willing to use male condom, from the signature of the ICF until the follow-up call.
Exclusion criteria
1. Participation in another clinical study with an investigational drug in the 3 months or five half-lives of that investigational drug (whichever is longer) preceding the administration of the study treatment; 2. Clinically relevant and uncontrolled respiratory, cardiac, hepatic, gastrointestinal, renal, endocrine, metabolic, neurologic, or psychiatric disorders ; 3. Clinically relevant abnormal laboratory values at screening; 4. Subjects with history of breathing problems (i.e. history of asthma including childhood asthma); 5. Positive serology test for human immunodeficiency virus (HIV) 1 or HIV2 serology at screening; 6. Positive results from the hepatitis serology, indicating acute or chronic hepatitis B or hepatitis C at screening; 7. Blood donation or blood loss (≥ 450 mL) during the 2 months prior to screening or randomisation; 8. Positive urine test for cotinine at screening or prior to randomisation; 9. Documented history of alcohol abuse within 12 months prior to screening, an average weekly alcohol intake of greater than 14 units, or a positive alcohol breath test at screening or prior to randomisation; 10. Documented history of drug abuse within 12 months prior to screening or a positive urine drug screen evaluated at screening or prior to randomisation; 11. Intake of non-permitted concomitant medications in the predefined period prior to screening or prior to randomisation; 12. Presence of any current infection, or previous infection that resolved less than 1 week prior to screening or to randomisation; 13. Known intolerance and/or hypersensitivity to any of the excipients contained in the formulation used in the study; 14. Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 2 weeks, or associated complications/symptoms which have not resolved within 2 weeks prior to screening or prior to randomisation; 15. Heavy caffeine drinker; 16. For females only: pregnant or lactating women; 17. The use of any kind of smoking electronic devices (e.g. e-cigarettes), within 6 months before screening or prior to randomisation; 18. Subjects for whom participation in this study will exceed a total radiation exposure of 5 mSv in the last 12-month period or 10 mSv in the last 5-year period; 19. Subjects with a total dosimetry value (including history of exposure through occupation) which contraindicates their participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 2 Hours (PPR2) on Day 8 | 2 hours post inhalation of radiolabelled particles | MCC rate was assessed by the percent particle retention at 2 hours (PPR2) after the inhalation of radiolabelled particles. Results are shown as adjusted mean (95% CI) for change from baseline in PPR2 (right whole lung) on Day 8, considering either HFA-152a and HFA-134a propellants. PPR2=Percent particle retention at 2 h after the inhalation of radiolabelled particles |
| Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 4 Hours (PPR4) on Day 8 | 4 hours post inhalation of radiolabelled particles | Mucociliary Clearance rate (MCC) rate, as assessed by the percent particle retention (PPR) (in right whole lung) at 4 h after the inhalation of radiolabelled particles (PPR4), on Day 8. Results are shown as adjusted mean (95% CI) for change from baseline in PPR4 (right whole lung) on Day 8, considering either HFA-152a and HFA-134a propellants. PPR4=Percent particle retention at 4 h after the inhalation of radiolabelled particles |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mucociliary Clearance -- AUC(0-4) -- Right Whole Lung Region | Post inhalation of radiolabelled particles; baseline and 4 h after inhalation of the radiotracer on Day 8. | The MCC variables AUC(0-4) was calculated for PPR parameter on the right whole lung region up to 4 h after inhalation of the radiotracer. Results are shown as change from baseline (Day -1) and Day 8, as mean and SD, in percent x hour. AUC(0-4)=Area under the tracheobronchial particle retention curve between 0 and 4 h. |
Countries
United Kingdom
Participant flow
Recruitment details
In total, 20 healthy male and female subjects 18-55y (inclusive) were enrolled according to the inclusion and exclusion criteria. They were randomised, to one of the two sequences with Test (\[T\], HFA-152a propellant) or Reference (\[R\], HFA-134a propellant), i.e. T-R sequence or R-T sequence, with 10 subjects per sequence. All the randomised subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| HFA-152a Followed by HFA-134a HFA-152a and HFA-134a propellant via pressurised metered-dose inhaler (pMDI):
Placebo formulated with HFA-152a propellant via pMDI: 5 inhalations BID (morning and evening) for 8 consecutive days, starting from the morning of Day 1 until the morning of Day 8.
In this study arm, HFA-152a was used during period 1 and HFA-134a was used during period 2. | 10 |
| HFA-134a Followed by HFA-152a HFA-134a and HFA-152a propellant via pressurised metered-dose inhaler (pMDI):
Placebo formulated with HFA-134a propellant via pMDI: 5 inhalations BID (morning and evening) for 8 consecutive days, starting from the morning of Day 1 until the morning of Day 8.
In this study arm, HFA-134a was used during period 1 and HFA-152a was used during period 2. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | HFA-152a Followed by HFA-134a | HFA-134a Followed by HFA-152a | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 20 Participants |
| Age, Continuous | 34.3 years STANDARD_DEVIATION 8.6 | 34.4 years STANDARD_DEVIATION 5.9 | 34.4 years STANDARD_DEVIATION 7.1 |
| Body Mass Index | 26.15 kg/m^2 STANDARD_DEVIATION 2.63 | 24.84 kg/m^2 STANDARD_DEVIATION 2.89 | 25.50 kg/m^2 STANDARD_DEVIATION 2.77 |
| FEV1/FVC | 0.803 Ratio STANDARD_DEVIATION 0.04 | 0.802 Ratio STANDARD_DEVIATION 0.037 | 0.803 Ratio STANDARD_DEVIATION 0.037 |
| FEV1 % of predicted normal value | 102.81 percent of predicted STANDARD_DEVIATION 9.38 | 102.60 percent of predicted STANDARD_DEVIATION 8.55 | 102.71 percent of predicted STANDARD_DEVIATION 8.74 |
| FVC actual value | 4.835 L STANDARD_DEVIATION 0.953 | 4.963 L STANDARD_DEVIATION 0.895 | 4.899 L STANDARD_DEVIATION 0.902 |
| Lung Function Parameter -- FEV1 (actual value) | 3.877 L STANDARD_DEVIATION 0.741 | 3.974 L STANDARD_DEVIATION 0.73 | 3.926 L STANDARD_DEVIATION 0.718 |
| Race/Ethnicity, Customized Black Or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 8 Participants | 17 Participants |
| Region of Enrollment United Kingdom | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
| Smoking status at screening Ex-smoker | 2 Participants | 1 Participants | 3 Participants |
| Smoking status at screening Non-smoker | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 5 / 20 | 7 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 2 Hours (PPR2) on Day 8
MCC rate was assessed by the percent particle retention at 2 hours (PPR2) after the inhalation of radiolabelled particles. Results are shown as adjusted mean (95% CI) for change from baseline in PPR2 (right whole lung) on Day 8, considering either HFA-152a and HFA-134a propellants. PPR2=Percent particle retention at 2 h after the inhalation of radiolabelled particles
Time frame: 2 hours post inhalation of radiolabelled particles
Population: The ITT analysis set, defined as all subjects who were randomised and received at least one dose of study treatment (analysed as randomised), included 20 subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Test Propellant | Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 2 Hours (PPR2) on Day 8 | 0.94 percent of particle retention |
| Reference Propellant | Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 2 Hours (PPR2) on Day 8 | -0.42 percent of particle retention |
p-value: 0.44295% CI: [-2.28, 4.99]ANCOVA
Primary
Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 4 Hours (PPR4) on Day 8
Mucociliary Clearance rate (MCC) rate, as assessed by the percent particle retention (PPR) (in right whole lung) at 4 h after the inhalation of radiolabelled particles (PPR4), on Day 8. Results are shown as adjusted mean (95% CI) for change from baseline in PPR4 (right whole lung) on Day 8, considering either HFA-152a and HFA-134a propellants. PPR4=Percent particle retention at 4 h after the inhalation of radiolabelled particles
Time frame: 4 hours post inhalation of radiolabelled particles
Population: The ITT analysis set, defined as all subjects who were randomised and received at least one dose of study treatment (analysed as randomised), included 20 subjects.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Test Propellant | Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 4 Hours (PPR4) on Day 8 | -0.58 percent of particle retention |
| Reference Propellant | Mucociliary Clearance Rate -- Right Whole Lung -- Percent Particle Retention at 4 Hours (PPR4) on Day 8 | -1.27 percent of particle retention |
p-value: 0.55395% CI: [-1.73, 3.12]ANCOVA
Other Pre-specified
Mucociliary Clearance -- AUC(0-4) -- Right Whole Lung Region
The MCC variables AUC(0-4) was calculated for PPR parameter on the right whole lung region up to 4 h after inhalation of the radiotracer. Results are shown as change from baseline (Day -1) and Day 8, as mean and SD, in percent x hour. AUC(0-4)=Area under the tracheobronchial particle retention curve between 0 and 4 h.
Time frame: Post inhalation of radiolabelled particles; baseline and 4 h after inhalation of the radiotracer on Day 8.
Population: The ITT analysis set, defined as all subjects who were randomised and received at least one dose of study treatment (analysed as randomised), included 20 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Propellant | Mucociliary Clearance -- AUC(0-4) -- Right Whole Lung Region | 1.093 Percent x h | Standard Deviation 5.345 |
| Reference Propellant | Mucociliary Clearance -- AUC(0-4) -- Right Whole Lung Region | -1.961 Percent x h | Standard Deviation 6.402 |