Asthma
Conditions
Keywords
QAB149, asthma, indacaterol salts (acetate, maleate, and xinafoate), orally inhaled indacaterol salts, persistent asthma
Brief summary
This study assessed the efficacy, safety, and pharmacokinetics of indacaterol salts (maleate, xinafoate and acetate) in patients with asthma.
Interventions
DRUGIndacaterol maleate 400 μg
Indacaterol maleate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.
DRUGIndacaterol acetate 400 μg
Indacaterol acetate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.
DRUGIndacaterol xinafoate 400 μg
Indacaterol xinafoate 400 μg was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler. The dose refers to 400 μg of free base indacaterol.
DRUGPlacebo to indacaterol
Placebo to indacaterol was provided in powder filled capsules with the Concept1 single-dose dry-powder inhaler.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Non-smoker male and female adult patients aged 18-75 years inclusive, who have signed an informed consent form prior to initiation of any study-related procedure, including any adjustments to asthma medication prior to screening. * Patients with asthma, receiving daily treatment with inhaled corticosteroid. * Patients with a forced expiratory volume in 1 second (FEV1) during screening of ≥ 50% of the predicted normal value for the patient. * Body mass index (BMI) must be within the range 18-32 kg/m\^2 (inclusive). * Able to communicate well with the investigator and comply with the requirements of the study.
Exclusion criteria
* A urine cotinine level greater than the local laboratory lowest level of quantification (LOQ of 500 ng/ml or lower). * Patients who have had a severe asthma attack/exacerbation requiring hospitalization in the 6 months prior to screening. * Patients who have had an emergency room visit for an asthma attack/exacerbation within 6 weeks prior to screening or any time between screening and pre-dose on day 1 of the study. * Patients who have had a respiratory tract infection within 4 weeks prior to screening or any time between screening and pre-dose on day 1 of the study. * Patients who require the use of ≥ 8 inhalations per day of the short-acting β2-agonist salbutamol/albuterol (100 μg/90 μg salbutamol/albuterol metered dose inhaler \[MDI\] or equivalent dose of a dry-powder inhaler \[DPI\]) on any 2 consecutive days from screening to randomization. * Patients diagnosed with chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (2008). * Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation. Previous participation in a study with either the investigational or comparator drugs does not exclude a patient from participation in this study. * Significant illness. * History of being immunocompromised, including a positive human immunodeficiency virus (HIV) test result (ELISA and Western blot). * A positive hepatitis B surface antigen (HBsAg) or hepatitis C test result. * Patients who are considered vulnerable as per ICH GCP guidelines. * Patients with a history of hypersensitivity to indacaterol or to similar drugs including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof. * Treatments for asthma and allied conditions: * The following treatments should not be used unless they have been stabilized prior to screening: antihistamines, inhaled nasal cromolyn, inhaled nasal corticosteroids, and maintenance immunotherapy. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | Baseline to the end of each treatment period (Day 7) | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and at the end of each treatment period. The analysis included period baseline FEV1 as covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | Baseline to Day 1 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and on Day 1. The analysis included period baseline FEV1 as covariate. |
| Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 1 and Day 7 | FEV1 was measured with spirometry conducted according to internationally accepted standards at 5, 15, and 30 minutes; 1 hour, 1 hour 30 minutes; and 2, 4, and 12 hours post-dose on Day 1 and Day 7. |
| Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | Baseline to the end of each treatment period (Day 7) | Patients recorded use of rescue medication (salbutamol/albuterol multi-dose inhaler) as the number of puffs taken in respective preceding 12 hours morning and evening in a diary. Patient with any use of rescue medication (any number of puffs \> 0) was included to calculate endpoint. |
| Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period | End of each treatment period (Day 7) | Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Area under the concentration-time curve up to 24 hours (AUC\[0-24 hours\]) was calculated from concentration-time data and recorded sampling times using non-compartmental methods. |
| Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period | End of each treatment period (Day 7) | Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Maximum (peak) plasma drug concentration after drug administration (Cmax) was calculated from concentration-time data and recorded sampling times using non-compartmental methods. |
Countries
France, Germany, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population The entire study population included all 4 treatment groups who received the 3 salt forms of indacaterol 400 µg (maleate, acetate, and xinafoate) and placebo to indacaterol in 4 different sequences. The dose refers to 400 μg of free base indacaterol. Patients received each treatment for 7 days via the Concept1 single-dose dry-powder inhaler. There was a washout period of at least 7 days between each treatment period. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 | Subject withdrew consent | 0 | 0 | 1 | 0 |
| Treatment Period 4 | Adverse Event | 0 | 0 | 0 | 1 |
| Treatment Period 4 | Subject withdrew consent | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age Continuous | 50 years STANDARD_DEVIATION 12.3 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 30 | 4 / 29 | 7 / 29 | 5 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 | 0 / 29 | 0 / 29 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7)
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and at the end of each treatment period. The analysis included period baseline FEV1 as covariate.
Time frame: Baseline to the end of each treatment period (Day 7)
Population: Efficacy analysis set: All randomized subjects that received at least 1 dose of study drug and had a baseline and at least 1 post-baseline measurement of FEV1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Indacaterol Maleate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | 0.186 Liters |
| Indacaterol Acetate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | 0.190 Liters |
| Indacaterol Xinafoate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | 0.194 Liters |
| Placebo to Indacaterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of Each Treatment Period (Day 7) | -0.021 Liters |
Secondary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at Baseline and on Day 1. The analysis included period baseline FEV1 as covariate.
Time frame: Baseline to Day 1
Population: Efficacy analysis set: All randomized subjects that received at least 1 dose of study drug and had a baseline and at least 1 post-baseline measurement of FEV1.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Indacaterol Maleate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | 0.161 Liters |
| Indacaterol Acetate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | 0.185 Liters |
| Indacaterol Xinafoate 400 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | 0.205 Liters |
| Placebo to Indacaterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 1 | 0.008 Liters |
Secondary
Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period
Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Area under the concentration-time curve up to 24 hours (AUC\[0-24 hours\]) was calculated from concentration-time data and recorded sampling times using non-compartmental methods.
Time frame: End of each treatment period (Day 7)
Population: Pharmacokinetic analysis set: All subjects with evaluable pharmacokinetic parameter data. Number of subjects varied due to missing values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate 400 μg | Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period | 5159 pg * hr/mL | Geometric Coefficient of Variation 27.9 |
| Indacaterol Acetate 400 μg | Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period | 5434 pg * hr/mL | Geometric Coefficient of Variation 30.7 |
| Indacaterol Xinafoate 400 μg | Indacaterol Exposure (AUC[0-24 Hours]) at the End of Each 7 Day Treatment Period | 5170 pg * hr/mL | Geometric Coefficient of Variation 24.2 |
Secondary
Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period
Venous blood samples for pharmacokinetic evaluation were collected at 15 and 30 minutes; and 1, 2, 4, 12, and 24 hours post-dose at the end of each 7 day treatment period and were analyzed using a LC-MS/MS assay. Maximum (peak) plasma drug concentration after drug administration (Cmax) was calculated from concentration-time data and recorded sampling times using non-compartmental methods.
Time frame: End of each treatment period (Day 7)
Population: Pharmacokinetic analysis set: All subjects with evaluable pharmacokinetic parameter data. Number of subjects varied due to missing values.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol Maleate 400 μg | Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period | 720 pg/mL | Geometric Coefficient of Variation 35.5 |
| Indacaterol Acetate 400 μg | Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period | 753 pg/mL | Geometric Coefficient of Variation 40.6 |
| Indacaterol Xinafoate 400 μg | Indacaterol Exposure (Cmax) at the End of Each 7 Day Treatment Period | 664 pg/mL | Geometric Coefficient of Variation 26.4 |
Secondary
Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period
Patients recorded use of rescue medication (salbutamol/albuterol multi-dose inhaler) as the number of puffs taken in respective preceding 12 hours morning and evening in a diary. Patient with any use of rescue medication (any number of puffs \> 0) was included to calculate endpoint.
Time frame: Baseline to the end of each treatment period (Day 7)
Population: Efficacy analysis set: All randomized subjects that received at least 1 dose of study drug and had a baseline and at least 1 post-baseline measurement of FEV1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Indacaterol Maleate 400 μg | Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | 21 Percentage of participants |
| Indacaterol Acetate 400 μg | Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | 10 Percentage of participants |
| Indacaterol Xinafoate 400 μg | Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | 17 Percentage of participants |
| Placebo to Indacaterol | Percentage of Patients Using Rescue Medication During Each 7 Day Treatment Period | 21 Percentage of participants |
Secondary
Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7
FEV1 was measured with spirometry conducted according to internationally accepted standards at 5, 15, and 30 minutes; 1 hour, 1 hour 30 minutes; and 2, 4, and 12 hours post-dose on Day 1 and Day 7.
Time frame: Day 1 and Day 7
Population: Efficacy analysis set: All randomized subjects that received at least 1 dose of study drug and had a baseline and at least 1 post-baseline measurement of FEV1.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Indacaterol Maleate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 1, N=29, 30, 29, 29 | 4.00 Hours |
| Indacaterol Maleate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 7, N=28, 29, 28, 29 | 3.00 Hours |
| Indacaterol Acetate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 7, N=28, 29, 28, 29 | 2.50 Hours |
| Indacaterol Acetate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 1, N=29, 30, 29, 29 | 2.13 Hours |
| Indacaterol Xinafoate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 1, N=29, 30, 29, 29 | 1.50 Hours |
| Indacaterol Xinafoate 400 μg | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 7, N=28, 29, 28, 29 | 3.00 Hours |
| Placebo to Indacaterol | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 1, N=29, 30, 29, 29 | 2.25 Hours |
| Placebo to Indacaterol | Time to Peak Forced Expiratory Volume in 1 Second (FEV1) on Day 1 and Day 7 | Day 7, N=28, 29, 28, 29 | 12.38 Hours |