Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Two Orally Inhaled Indacaterol Salts in Adult Subjects With Asthma.

This is a randomized, double-blind, placebo-controlled, three-period cross-over study in asthma patients. The study will consist of a screening epoch, followed by a treatment epoch which consists of three treatment periods, and will conclude with an end of study epoch.

Each subject will be assigned to 1 of 6 treatment sequences and will sequentially receive the investigational products and placebo during the trial.

• Indacaterol maleate (Drug), also known as A: 150 μg via Concept1 device
• Indacaterol acetate (Drug), also known as B: 150 μg via Concept1 device
• Placebo (Drug), also known as C: Capsule containing no active ingredients delivered via Concept1 device

Primary outcomes

• Trough FEV1 [Day 14 of each of the three treatment periods]: FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of forced exhalation. Treatment differences in trough FEV1 after 14 days of treatment between indacaterol maleate 150 μg and placebo, between indacaterol acetate 150 μg and placebo and indacaterol maleate and indacaterol acetate

Secondary outcomes

• Pharmacokinetics AUC 0-24hours at Steady State [Day 14 of each of the three treatment periods]: AUC 0-24hours of plasma concentrations of indacaterol maleate and indacaterol acetate at steady state.The area under the concentrations-time curve (AUC0-24) was calculated with the measured data points from the time of administration up to 24 h after administration by the trapezoidal formula. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings
• The Maximum Concentration (Cmax) at Steady State (ss) [Day 14 of each of the three treatment periods]: Maximal plasma concentrations of indacaterol maleate and indacaterol acetate at steady state. The maximum concentration (Cmax) were obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration in the blood samplings.
• Time of Maximal Plasma Concentration (Tmax) at Steady State [Day 14 of each of the three treatment periods]: Time of maximal plasma concentration of indacaterol maleate and indacaterol acetate at steady state. Time to reach the maximum concentration after administration. In this analysis Tmax will be reported using blood samples taken on Days 14
• The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State [Day 14 of each of the three treatment periods]: The lowest plasma (or serum or blood) concentration observed during a dosing interval at steady state. Only summary statistics was provided.
• Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate [Day 14]: Relative bioavailability will be determined for AUC0-24h,ss and Cmax,ss comparing systemic exposure of indacaterol acetate and indacaterol maleate.
• Time to Peak FEV1 on Day 14 [Day 14 of each of the three treatment periods]: The differences in median time to peak FEV1 (h) between indacaterol maleate 150 µg and placebo
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints [Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1. Day 14, FEV1 was measured at 24hours post dose
• Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints [Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: The FEV1 percent predicted expresses FEV1 as a percentage of the "predicted values" for participants of similar characteristics (height, age, sex, and sometimes race and weight). A positive change from baseline in FEV1 % predicted indicates improvement in lung function. FEV1 % predicted was assessed at each post dose time point after 14 days
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) [Day 14 of each of the three treatment periods at at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function.
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) [Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: Forced Vital Capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed by spirometry at each post dose time point after 14 days. A positive change from baseline in FVC indicates improvement in lung function.
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC [Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: Bronchodilator effect of indacaterol salts compared to placebo in terms of FEV1/FVC at each post dose time point after 14 days. FEV1/FVC ratio is the percentage of the total FVC that is expelled from the lungs during the first second of forced exhalation.
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% [Day 14 of each of the three treatment periods at 5, 15, 30m, 1 2, 3, 4, 8, 12, 23hour.15min and 23hour.45min]: The Forced Expiratory Flow (FEF) 25%-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test and is measured using spirometry at each post dose time point after 14 days
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. [Pre-dose to 4 hours post-dose on Day 14 of each of the three treatment periods]: Standardized FEV1 AUC from pre-dose to 4 h post-dose. Evaluated the differences in standardized FEV1 AUC0-4h (L) after 14 days of treatment between indacaterol maleate 150 μg and placebo, and between indacaterol acetate 150 μg and placebo. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 0-4h)
• Rescue Medication Usage [14 days of treatment for each of the three treatment periods]: The mean daily number of puffs of rescue medication usage as reported by subjects via diary.
• Mean Overall Peak Expiratory Flow (PEF) [Days 8 through Day 14 of each of the three treatment periods]: A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits LS Mean of change from baseline in mean morning PEF is calculated with the ANOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates

Sex: All, ages: 18 Years to any

Key Inclusion Criteria:

* Male and female patients aged ≥ 18 and above
* Patients with a documented physician diagnosis of asthma for a period of at least 1 year prior to screening and who additionally meet the following criteria:

Patients receiving daily treatment with an inhaled corticosteroid up to the maximum dose per day (as indicated in the package leaflet), on a stable regimen for at least 4 weeks prior to screening.

* Pre-bronchodilator FEV1 ≥ 50 % and ≤ 90% of the predicted normal value for the patient during screening.
* Patients who demonstrate an increase in FEV1 of ≥ 12% and ≥ 200 mL after administration of 400 μg salbutamol/360 μg albuterol (or equivalent dose) at screening.
* Subjects must weigh at least 50 kg at screening to participate in the study, and must have a body mass index (BMI) within the range of 18 to 40 kg/m2.

Key Exclusion Criteria:

-Contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class, or any component thereof: Sympathomimetic amines / adrenoceptor agonist agents Lactose or any of the other excipients of the study drug (including patients with history of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption)

* Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of screening.
* Patients who have had a respiratory tract infection or asthma worsening within 4 weeks prior to screening.
* Patients with a history of chronic lung diseases other than asthma
* Patients who have a decline in PEF from the reference PEF (taken at screening) of ≥30% for 5 of 6 consecutive scheduled PEF readings (readings taken at morning and evening) during at least 3 days of screening epoch prior to randomization.
* Patients who require the use of ≥12 puffs / 24 hours of rescue medication for 48 hours (over two consecutive days) during screening prior to randomization.
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
* Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c > 9%) at screening.
* Current smokers (urine cotinine > than the laboratory's lowest level of quantification (LoQ of 500 ng/mL or lower)) and patients who have smoked or inhaled tobacco products within the 6 month period prior to screening, or who have a smoking history of greater than 10 pack years (Note: 1 pack is equivalent to 20 cigarettes. 10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).

Participant flow

Outcome results

• Trough FEV1 (Primary), Mean, Liters: Indacaterol Maleate 2.4173 +/- 0.78214; Indacaterol Acetate 2.3774 +/- 0.77679; Placebo 2.2191 +/- 0.72350 (p <0.001)
• Pharmacokinetics AUC 0-24hours at Steady State (Secondary), Mean, h*pg/mL: Indacaterol Maleate 150 µg 2300 +/- 732; Indacaterol Acetate 150 µg 2050 +/- 636
• The Maximum Concentration (Cmax) at Steady State (ss) (Secondary), Median, pg/mL: Indacaterol Maleate 150 µg 249 (126 to 443); Indacaterol Acetate 150 µg 224 (84.9 to 426)
• Time of Maximal Plasma Concentration (Tmax) at Steady State (Secondary), Median, h: Indacaterol Maleate 150 µg 0.250 (0.183 to 0.850); Indacaterol Acetate 150 µg 0.467 (0.183 to 1.00)
• The Lowest Plasma (or Serum or Blood) Concentration (Cmin) at Steady State (Secondary), Median, pg/mL: Indacaterol Maleate 150 µg 56 (14.5 to 126); Indacaterol Acetate 150 µg 52.3 (9.03 to 106)
• Relative Bioavailability (Frel) of Indacaterol Acetate and Indacaterol Maleate (Secondary), Mean, Ratio: Indacaterol Maleate / Indacaterol Acetate 0.912 +/- 0.201; Indacaterol Acetate 150 µg 0.910 +/- 0.242
• Time to Peak FEV1 on Day 14 (Secondary), Median, h: Indacaterol Maleate -0.02 (-0.83 to 0.33); Indacaterol Acetate -0.02 (-0.82 to 0.51); Placebo 0.00 (-0.50 to 0.73) (p 0.823)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Expiratory Volume in 1 Second (FEV1) at All Timepoints (Secondary), Least squares mean, Liter: Indacaterol Maleate 2.4795 (2.2575 to 2.7014); Indacaterol Acetate 2.4813 (2.2595 to 2.7031); Placebo 2.2617 (2.0398 to 2.4837) (p <0.001)
• Percent of Predicted Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1 (% Predicted) at All Timepoints (Secondary), Least squares mean, Percent of predicted: Indacaterol Maleate 78.2 (74.7 to 81.7); Indacaterol Acetate 78.2 (74.8 to 81.7); Placebo 71.1 (67.7 to 74.6) (p <.001)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by Forced Vital Capacity (FVC) (Secondary), Least squares mean, liter: Indacaterol Maleate 150 µg 3.5648 (3.2407 to 3.8890); Indacaterol Acetate 150 µg 3.5912 (3.2672 to 3.9152); Placebo 3.3783 (3.0541 to 3.7024) (p <0.001)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FVC (% Predicted) (Secondary), Least squares mean, Percentage of predicted FVC: Indacaterol Maleate 150 µg 90.4 (86.1 to 94.6); Indacaterol Acetate 150 µg 91.2 (86.9 to 95.4); Placebo 85.3 (81.1 to 89.6) (p <0.001)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEV1/FVC (Secondary), Least squares mean, Ratio: Indacaterol Maleate 0.6979 (0.6728 to 0.7230); Indacaterol Acetate 0.6952 (0.6701 to 0.7202); Placebo 0.6729 (0.6478 to 0.6981) (p <.001)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo Measured by FEF25-75% (Secondary), Least squares mean, Liters/second: Indacaterol Maleate 150 µg 1.6968 (1.4675 to 1.9261); Indacaterol Acetate 150 µg 1.6918 (1.4628 to 1.9208); Placebo 1.4962 (1.2668 to 1.7256) (p <0.001)
• Bronchodilator Effect of Indacaterol Salts Compared to Placebo in Standardized FEV1 AUC. (Secondary), Least squares mean, Liters: Indacaterol Maleate 150 µg 2.5179 +/- 0.11213; Indacaterol Acetate 150 µg 2.5151 +/- 0.11205; Placebo 2.2703 +/- 0.11213 (p <.001)
• Rescue Medication Usage (Secondary), Least squares mean, Puffs: Indacaterol Maleate 150 µg 1.01 +/- 0.228; Indacaterol Acetate 150 µg 1.01 +/- 0.227; Placebo 1.43 +/- 0.228 (p 0.009)
• Mean Overall Peak Expiratory Flow (PEF) (Secondary), Least squares mean, Liters/min: Indacaterol Maleate 150 µg 409.7 +/- 15.06; Indacaterol Acetate 150 µg 407.6 +/- 15.05; Placebo 376.8 +/- 15.06 (p <0.001)

Adverse events

Time frame: until 30 days after the last Investigational Product (IP) administration

Serious adverse events by term

Other adverse events by term

• Results publication: Miller D, Vaidya S, Jauernig J, Ethell B, Wagner K, Radhakrishnan R, Tillmann HC. Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients. Respir Res. 2020 Sep 23;21(1):248. doi: 10.1186/s12931-020-01501-1. PMID 32967685

• Statistical Analysis Plan (PDF, 2018-04-16)
• Study Protocol (PDF, 2017-02-27)