Asthma
Conditions
Keywords
Asthma, patients, lung function
Brief summary
The purpose of this study is to evaluate the pharmacokinetics and pharmacodynamics of single doses of three different dry powder inhalation formulations of AZD3199 administered via Single Inhalation Device (SID) compared to AZD3199 administered via Turbuhaler™ Inhaler and compared to placebo in patients with persistent asthma.
Interventions
DRUGAZD3199
Inhaled via single inhaler device (SID)
OTHERAZD3199 Placebo
Inhaled via Turbuhaler inhaler and SID
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of signed and dated written informed consent prior to any study specific procedures * Men or women, age ≥ 18 years. Women must be of non-childbearing potential or stable on a highly effective contraceptive method for at least 3 months prior to Visit 1 and be willing to continue on the chosen contraceptive method throughout the study. * Be a non-smoker or ex-smoker who has stopped smoking for \>6 months prior to study start * A history of asthma for at least 6 months. * Body Mass Index (BMI) 19-30 kg/m2
Exclusion criteria
* Significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the result of the study, or the patient's ability to participate in the study * History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to β2-agonists in general or to AZD3199 and/or excipients * Prolonged QTcF \> 450 msec or shortened QTcF \<340 msec * History of alcohol/drug abuse or excessive intake of alcohol as judged by the Investigator * Pregnancy or lactation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Emax: Maximum Value of FEV1 for Every Treatment Visits | 0-24 hrs | Peak effect (Emax) within 0-24 hours of FEV1, for treatment visits 2 to 7. |
| E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 22-26 hrs. | Trough effect (E22-26h) will be computed from the repeated measurements collected after each single dose during 22-26 hours of FEV1 from visit 2 to 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 0 - 24 hrs | Average effect over 0-24 hours of FEV1 (E0-24h), for treatment visits 2 to 7. |
| Emax: Maximum Value of Pulse for Every Treatment Visits | 0 - 4 hrs. | Peak effect (Emax) within 0-4 hours of pulse, for treatment visits 2 to 7. |
| E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 0 - 4 hrs. | Average effect (E0-4h) of Pulse, for treatment visits 2 to 7. |
| tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 0 - 24 hrs. | Time to peak effect (tEmax), within 0-24 hours of FEV1, for treatment visits 2 to 7. |
| AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits. | Area under the plasma concentration-time curve from zero to infinity (AUC), for AZD3199 doses |
| Tmax:Time to Maximum Plasma Concentration | 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits. | Time to maximum plasma concentration (tmax), for AZD3199 doses |
| t1/2 :Terminal Half-life | 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits. | Terminal half-life (t1/2),for AZD3199 doses |
| Cmax: Maximum Plasma Concentration | 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits. | Maximum plasma concentration (Cmax) for AZD3199 doses |
| E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | FEV1 at 5 min | Onset of effect (E5min), observed at 5 min. FEV1 for treatment visits 2 to 7. |
Countries
Sweden
Participant flow
Recruitment details
A total of 39 patients were enrolled at 3 centres in Sweden. Of these, 26 patients were randomised to receive a treatment sequence consisting of 6 different treatments in random order. The number of patients randomised was well balanced across all the treatment periods. In total, 25 patients completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Baseline Total Total number of patients randomised and treated in the study. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Baseline Total |
|---|---|
| Age Continuous All | 36.5 Years STANDARD_DEVIATION 11.29 |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 24 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 26 | 9 / 25 | 7 / 25 | 7 / 25 | 14 / 25 | 6 / 25 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Primary
E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit
Trough effect (E22-26h) will be computed from the repeated measurements collected after each single dose during 22-26 hours of FEV1 from visit 2 to 7.
Time frame: 22-26 hrs.
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.448 Liters | Standard Deviation 0.709 |
| Arm 2 - AZD3199 880 μg | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.453 Liters | Standard Deviation 0.739 |
| Arm 3 - AZD3199 800 μg | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.495 Liters | Standard Deviation 0.73 |
| Arm 4 - AZD3199 300 μg | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.448 Liters | Standard Deviation 0.732 |
| Arm 5 - AZD3199 1200 μg | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.569 Liters | Standard Deviation 0.761 |
| Arm 6 - Placebo | E22-26h: The Average of the FEV1 Values Between 22 and 26 h for Every Treatment Visit | 3.310 Liters | Standard Deviation 0.723 |
Primary
Emax: Maximum Value of FEV1 for Every Treatment Visits
Peak effect (Emax) within 0-24 hours of FEV1, for treatment visits 2 to 7.
Time frame: 0-24 hrs
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.788 Liters | Standard Deviation 0.782 |
| Arm 2 - AZD3199 880 μg | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.784 Liters | Standard Deviation 0.724 |
| Arm 3 - AZD3199 800 μg | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.756 Liters | Standard Deviation 0.733 |
| Arm 4 - AZD3199 300 μg | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.763 Liters | Standard Deviation 0.744 |
| Arm 5 - AZD3199 1200 μg | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.847 Liters | Standard Deviation 0.781 |
| Arm 6 - Placebo | Emax: Maximum Value of FEV1 for Every Treatment Visits | 3.498 Liters | Standard Deviation 0.676 |
Secondary
AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC),
Area under the plasma concentration-time curve from zero to infinity (AUC), for AZD3199 doses
Time frame: 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits.
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 21.83501 nmol*h/L | Standard Deviation 10.43729 |
| Arm 2 - AZD3199 880 μg | AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 20.21716 nmol*h/L | Standard Deviation 10.19966 |
| Arm 3 - AZD3199 800 μg | AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 22.80110 nmol*h/L | Standard Deviation 11.71379 |
| Arm 4 - AZD3199 300 μg | AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 10.25880 nmol*h/L | Standard Deviation 4.886541 |
| Arm 5 - AZD3199 1200 μg | AUC: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC), | 37.48982 nmol*h/L | Standard Deviation 13.11484 |
Secondary
Cmax: Maximum Plasma Concentration
Maximum plasma concentration (Cmax) for AZD3199 doses
Time frame: 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits.
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | Cmax: Maximum Plasma Concentration | 6.93846 nmol/L | Standard Deviation 2.497151 |
| Arm 2 - AZD3199 880 μg | Cmax: Maximum Plasma Concentration | 5.81240 nmol/L | Standard Deviation 2.497151 |
| Arm 3 - AZD3199 800 μg | Cmax: Maximum Plasma Concentration | 6.29560 nmol/L | Standard Deviation 2.82791 |
| Arm 4 - AZD3199 300 μg | Cmax: Maximum Plasma Concentration | 3.01836 nmol/L | Standard Deviation 1.294151 |
| Arm 5 - AZD3199 1200 μg | Cmax: Maximum Plasma Concentration | 13.54120 nmol/L | Standard Deviation 4.337208 |
Secondary
E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit
Average effect over 0-24 hours of FEV1 (E0-24h), for treatment visits 2 to 7.
Time frame: 0 - 24 hrs
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.489 Liters | Standard Deviation 0.71 |
| Arm 2 - AZD3199 880 μg | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.526 Liters | Standard Deviation 0.737 |
| Arm 3 - AZD3199 800 μg | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.537 Liters | Standard Deviation 0.729 |
| Arm 4 - AZD3199 300 μg | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.493 Liters | Standard Deviation 0.707 |
| Arm 5 - AZD3199 1200 μg | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.636 Liters | Standard Deviation 0.776 |
| Arm 6 - Placebo | E0-24h: The Average of the FEV1 Values Between 0 and 24 h for Every Treatment Visit | 3.287 Liters | Standard Deviation 0.671 |
Secondary
E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit
Average effect (E0-4h) of Pulse, for treatment visits 2 to 7.
Time frame: 0 - 4 hrs.
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 59.85 Beats/min | Standard Deviation 9.13 |
| Arm 2 - AZD3199 880 μg | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 59.13 Beats/min | Standard Deviation 8.83 |
| Arm 3 - AZD3199 800 μg | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 59.07 Beats/min | Standard Deviation 8.38 |
| Arm 4 - AZD3199 300 μg | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 58.77 Beats/min | Standard Deviation 8.66 |
| Arm 5 - AZD3199 1200 μg | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 59.73 Beats/min | Standard Deviation 9.63 |
| Arm 6 - Placebo | E0-4h: The Average of the Pulse Values Between 0 and 4 h for Every Treatment Visit | 58.66 Beats/min | Standard Deviation 10.4 |
Secondary
E5min: The Value of FEV1 at 5 Min for Every Treatment Visit.
Onset of effect (E5min), observed at 5 min. FEV1 for treatment visits 2 to 7.
Time frame: FEV1 at 5 min
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.406 Liters | Standard Deviation 0.743 |
| Arm 2 - AZD3199 880 μg | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.449 Liters | Standard Deviation 0.663 |
| Arm 3 - AZD3199 800 μg | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.496 Liters | Standard Deviation 0.692 |
| Arm 4 - AZD3199 300 μg | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.489 Liters | Standard Deviation 0.653 |
| Arm 5 - AZD3199 1200 μg | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.486 Liters | Standard Deviation 0.723 |
| Arm 6 - Placebo | E5min: The Value of FEV1 at 5 Min for Every Treatment Visit. | 3.188 Liters | Standard Deviation 0.586 |
Secondary
Emax: Maximum Value of Pulse for Every Treatment Visits
Peak effect (Emax) within 0-4 hours of pulse, for treatment visits 2 to 7.
Time frame: 0 - 4 hrs.
Population: PD analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | Emax: Maximum Value of Pulse for Every Treatment Visits | 66.15 Beats/min | Standard Deviation 11.1 |
| Arm 2 - AZD3199 880 μg | Emax: Maximum Value of Pulse for Every Treatment Visits | 64.36 Beats/min | Standard Deviation 10.1 |
| Arm 3 - AZD3199 800 μg | Emax: Maximum Value of Pulse for Every Treatment Visits | 64.24 Beats/min | Standard Deviation 9.27 |
| Arm 4 - AZD3199 300 μg | Emax: Maximum Value of Pulse for Every Treatment Visits | 64.84 Beats/min | Standard Deviation 10.18 |
| Arm 5 - AZD3199 1200 μg | Emax: Maximum Value of Pulse for Every Treatment Visits | 66.20 Beats/min | Standard Deviation 12.38 |
| Arm 6 - Placebo | Emax: Maximum Value of Pulse for Every Treatment Visits | 64.12 Beats/min | Standard Deviation 11.22 |
Secondary
t1/2 :Terminal Half-life
Terminal half-life (t1/2),for AZD3199 doses
Time frame: 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits.
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - AZD3199 1400 μg | t1/2 :Terminal Half-life | 80.97301 Hours | Standard Deviation 24.65131 |
| Arm 2 - AZD3199 880 μg | t1/2 :Terminal Half-life | 79.24210 Hours | Standard Deviation 22.07879 |
| Arm 3 - AZD3199 800 μg | t1/2 :Terminal Half-life | 103.7279 Hours | Standard Deviation 113.8432 |
| Arm 4 - AZD3199 300 μg | t1/2 :Terminal Half-life | 77.46496 Hours | Standard Deviation 47.17895 |
| Arm 5 - AZD3199 1200 μg | t1/2 :Terminal Half-life | 88.99700 Hours | Standard Deviation 46.23237 |
Secondary
tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit
Time to peak effect (tEmax), within 0-24 hours of FEV1, for treatment visits 2 to 7.
Time frame: 0 - 24 hrs.
Population: PD analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 - AZD3199 1400 μg | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 2.000 Hours |
| Arm 2 - AZD3199 880 μg | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 2.000 Hours |
| Arm 3 - AZD3199 800 μg | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 2.000 Hours |
| Arm 4 - AZD3199 300 μg | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 1.000 Hours |
| Arm 5 - AZD3199 1200 μg | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 4.000 Hours |
| Arm 6 - Placebo | tEmax: Time to Maximum Value of FEV1 for Every Treatment Visit | 10.000 Hours |
Secondary
Tmax:Time to Maximum Plasma Concentration
Time to maximum plasma concentration (tmax), for AZD3199 doses
Time frame: 0 - 120 hrs for first two treatment visit 2 and 3 and 0 - 48 hrs for other treatment visits.
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 - AZD3199 1400 μg | Tmax:Time to Maximum Plasma Concentration | 0.47000 Hours |
| Arm 2 - AZD3199 880 μg | Tmax:Time to Maximum Plasma Concentration | 0.48000 Hours |
| Arm 3 - AZD3199 800 μg | Tmax:Time to Maximum Plasma Concentration | 0.52000 Hours |
| Arm 4 - AZD3199 300 μg | Tmax:Time to Maximum Plasma Concentration | 0.52000 Hours |
| Arm 5 - AZD3199 1200 μg | Tmax:Time to Maximum Plasma Concentration | 0.48000 Hours |