Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, cycle ergometry, exercise testing, spirometry, cardiovascular, salbutamol, indacaterol, chronic obstructive pulmonary disease
Brief summary
This study investigated the effect of exercise and high-dose salbutamol on the maximum heart rate in patients with chronic obstructive pulmonary disease (COPD) receiving therapeutic doses of indacaterol, salmeterol and placebo.
Interventions
DRUGIndacaterol
Single dose of indacaterol 300μg capsule via Concept 1 inhaler device at approximately the same time in the morning (i.e. between 8am and 9am).
DRUGPlacebo
Single dose indacaterol matching placebo via Concept 1 device
DRUGSalmeterol
Single dose salmeterol 50μg via the Diskus dry powder inhaler (DPI) in part 1 of the study. Morning single inhalational dose and an evening single inhalation dose of salmeterol 50μg via the Diskus DPI in part 2 of the study.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients between 40 and 75 years of age diagnosed with chronic obstructive pulmonary disease (COPD). Female patients must be surgically sterilized, postmenopausal or using a double-barrier method of contraception. * Body mass index (BMI) must be within the range of 18 to 32.
Exclusion criteria
* Participation in any clinical investigation with experimental drug therapy within four weeks prior to dosing or longer as required by local regulation. * Donation or loss of 400 mL or more of blood within two months prior to dosing. * Significant illness (other than respiratory) within two weeks prior to dosing. * A past medical history of, or a family history (grandparents, parents and siblings) of a prolonged QT-interval syndrome or a prolonged QT-interval at screening. * Any clinically significant medical abnormalities (excluding COPD) limiting ability to perform standardized exercise protocol on cycle ergometer will exclude the patient. For example, arthritis. * History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). * A known hypersensitivity to the study drug or drugs similar to the study drug. * History of immunocompromise, including a positive HIV, Hepatitis B or C test result. * History of drug or alcohol abuse within the 12 months prior to dosing * Any conditions that in the opinion of the investigator may compromise patient safety, interfere with evaluations, or preclude the completion of the trial. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study | 24-hours post-dose on Day 1 (of each treatment) | The percentage of patients with an increase of more than 10 beats per minute (bpm) in their heart rate following treatment with indacaterol and salmeterol compared to treatment with placebo was determined. |
| Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 24 hours post dose on Day 1 | The percentage of patients with an increase of \>= 10 beats per minute (bpm) in their heart rate (HR) following treatment with indacaterol and salmeterol compared to treatment with placebo over 24 hours in Part 2 was determined. * 0-12 hours: post first dose measurements up to second dose * 12-24 hours: post second dose measurement up to and including the 24 hour measurement * 0-24 hours: all post dose measurements up to and including the 24 hour measurement |
| Maximum Heart Rate During Exercise in Part 1 | 2 hour post-dose on Day 1 | Maximum heart rate was generally taken from the continuous ECG monitoring. Analysis based on mixed effects analysis using model with treatment and period as fixed effects and subject as random effect. |
| Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 24 hours post dose on Day 1 | Maximum HR (0-12 hours): maximum (max) of post dose measurement up to second administration. Maximum HR (12-24 hours): max of the post second administration of salbutamol measurements. Maximum HR (0-24 hours): max of all post dose measurements up to and including the 24 hour measurement. Mixed effects analysis model used period baseline HR as the covariate. The maximum HR for 0-24 hours (h) is the maximum of the maximum HR for the two 12h periods and thus the average (LS means) of the maximum HRs for 0-24h will be equal to or greater than the average of the maximum for the two periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Heart Rate During Exercise in Part 1 | 1.5 hour post dose to max heart rate during exercise | Change in heart rate is calculated from the 1.5 hour post dose to the maximum heart rate during exercise. Analysis of covariance included treatment and period as fixed effects, subject as random effect and 1.5 hour pre-exercise/post dose heart rate as a covariate. |
| Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 23 hours 30 minutes and 24 hours post-dose at Day 1 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hours 30 minutes and 24 hours post morning dose FEV1 measurements. Analysis of covariance included pre-dose FEV1 as covariate. |
Countries
Belgium
Participant flow
Pre-assignment details
The study was double blind with regard to the administration of indacaterol and placebo and open label with regard to salmeterol. The study had 2 parts. Each Part of the study consisted of 3 treatment periods separated by a minimum of 7 days. The two parts of the study were separated by a minimum of 7 days.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Sequence A, Part 2: Sequence A Part 1: Sequence 'A' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device.
Part 2: Sequence 'A' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 4 |
| Part 1 : Sequence B, Part 2: Sequence B Part 1: Sequence 'B' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI.
Part 2: Sequence 'B' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 5 |
| Part 1: Sequence C, Part 2: Sequence C Part 1: Sequence 'C' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus DPI. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device.
Part 2: Sequence 'C' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device . In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 4 |
| Part 1; Sequence D, Part 2: Sequence D Part 1: Sequence 'D' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI.
Part 2: Sequence 'D' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 5 |
| Part 1: Sequence E, Part 2: Sequence E Part 1: Sequence 'E' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device.
Part 2: Sequence 'E' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 4 |
| Part 1: Sequence F, Part 2: Sequence F Part 1: Sequence 'F' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device.
Part 2: Sequence 'F' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals. | 5 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1: Period 1 | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 1: Period 1 | Protocol Deviation | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 1: Period 3 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 2: Period 1 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2: Period 3 | Abnormal test procedure | 1 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1: Sequence A, Part 2: Sequence A | Part 1 : Sequence B, Part 2: Sequence B | Part 1: Sequence C, Part 2: Sequence C | Part 1; Sequence D, Part 2: Sequence D | Part 1: Sequence E, Part 2: Sequence E | Part 1: Sequence F, Part 2: Sequence F | Total |
|---|---|---|---|---|---|---|---|
| Age Continuous | 59.0 years STANDARD_DEVIATION 9.2 | 63.0 years STANDARD_DEVIATION 7.58 | 58.5 years STANDARD_DEVIATION 5.07 | 58.4 years STANDARD_DEVIATION 5.18 | 60.5 years STANDARD_DEVIATION 5.8 | 61.6 years STANDARD_DEVIATION 5.86 | 60.3 years STANDARD_DEVIATION 6.17 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 5 Participants | 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 | 4 / 25 | 4 / 26 | 8 / 23 | 8 / 24 | 6 / 23 |
| serious Total, serious adverse events | 1 / 26 | 0 / 25 | 1 / 26 | 0 / 23 | 0 / 24 | 0 / 23 |
Outcome results
Primary
Maximum Heart Rate During Exercise in Part 1
Maximum heart rate was generally taken from the continuous ECG monitoring. Analysis based on mixed effects analysis using model with treatment and period as fixed effects and subject as random effect.
Time frame: 2 hour post-dose on Day 1
Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Indacaterol 300μg | Maximum Heart Rate During Exercise in Part 1 | 133.13 Beats per minute (bpm) |
| Part 1 : Salmeterol 50μg | Maximum Heart Rate During Exercise in Part 1 | 131.18 Beats per minute (bpm) |
| Part 1: Placebo | Maximum Heart Rate During Exercise in Part 1 | 129.96 Beats per minute (bpm) |
Primary
Maximum Heart Rate (HR) During Salbutamol Administration in Part 2
Maximum HR (0-12 hours): maximum (max) of post dose measurement up to second administration. Maximum HR (12-24 hours): max of the post second administration of salbutamol measurements. Maximum HR (0-24 hours): max of all post dose measurements up to and including the 24 hour measurement. Mixed effects analysis model used period baseline HR as the covariate. The maximum HR for 0-24 hours (h) is the maximum of the maximum HR for the two 12h periods and thus the average (LS means) of the maximum HRs for 0-24h will be equal to or greater than the average of the maximum for the two periods.
Time frame: 24 hours post dose on Day 1
Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization. ECG monitoring was not performed successfully for three subjects in Part 2 during the afternoon monitoring. These subjects were therefore excluded from the analysis of heart rate.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Part 1: Indacaterol 300μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 12 hours (N= 23, 24, 23) | 98.026 Beats per minute (bpm) |
| Part 1: Indacaterol 300μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 24 hours (N= 23, 24, 23) | 102.501 Beats per minute (bpm) |
| Part 1: Indacaterol 300μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 12 - 24 hours (N= 20, 21, 20) | 97.179 Beats per minute (bpm) |
| Part 1 : Salmeterol 50μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 24 hours (N= 23, 24, 23) | 102.303 Beats per minute (bpm) |
| Part 1 : Salmeterol 50μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 12 hours (N= 23, 24, 23) | 98.087 Beats per minute (bpm) |
| Part 1 : Salmeterol 50μg | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 12 - 24 hours (N= 20, 21, 20) | 99.954 Beats per minute (bpm) |
| Part 1: Placebo | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 24 hours (N= 23, 24, 23) | 103.951 Beats per minute (bpm) |
| Part 1: Placebo | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 12 - 24 hours (N= 20, 21, 20) | 97.786 Beats per minute (bpm) |
| Part 1: Placebo | Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 | 0 - 12 hours (N= 23, 24, 23) | 97.960 Beats per minute (bpm) |
Primary
Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study
The percentage of patients with an increase of more than 10 beats per minute (bpm) in their heart rate following treatment with indacaterol and salmeterol compared to treatment with placebo was determined.
Time frame: 24-hours post-dose on Day 1 (of each treatment)
Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Indacaterol 300μg | Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study | 20.00 Percentage of participants |
| Part 1 : Salmeterol 50μg | Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study | 16.0 Percentage of participants |
Primary
Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study
The percentage of patients with an increase of \>= 10 beats per minute (bpm) in their heart rate (HR) following treatment with indacaterol and salmeterol compared to treatment with placebo over 24 hours in Part 2 was determined. * 0-12 hours: post first dose measurements up to second dose * 12-24 hours: post second dose measurement up to and including the 24 hour measurement * 0-24 hours: all post dose measurements up to and including the 24 hour measurement
Time frame: 24 hours post dose on Day 1
Population: Safety population. ECG monitoring was not performed successfully for three subjects in Part 2 during the afternoon monitoring. These subjects were therefore excluded from the analysis of heart rate. In a patient where data for the second 12 hour period is missing, 0-24 is not reported; hence the discrepancy of 4 and 3 subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Indacaterol 300μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 0 - 12 hours (N= 23,23) | 17.39 Percentage of participants |
| Part 1: Indacaterol 300μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 12 - 24 hours (N= 20, 20) | 10.00 Percentage of participants |
| Part 1: Indacaterol 300μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 0 - 24 hours (N= 23, 23) | 13.04 Percentage of participants |
| Part 1 : Salmeterol 50μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 0 - 12 hours (N= 23,23) | 17.39 Percentage of participants |
| Part 1 : Salmeterol 50μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 12 - 24 hours (N= 20, 20) | 25.00 Percentage of participants |
| Part 1 : Salmeterol 50μg | Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study | 0 - 24 hours (N= 23, 23) | 17.39 Percentage of participants |
Secondary
Change in Heart Rate During Exercise in Part 1
Change in heart rate is calculated from the 1.5 hour post dose to the maximum heart rate during exercise. Analysis of covariance included treatment and period as fixed effects, subject as random effect and 1.5 hour pre-exercise/post dose heart rate as a covariate.
Time frame: 1.5 hour post dose to max heart rate during exercise
Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Indacaterol 300μg | Change in Heart Rate During Exercise in Part 1 | 66.246 Beats per minute (bpm) |
| Part 1 : Salmeterol 50μg | Change in Heart Rate During Exercise in Part 1 | 64.265 Beats per minute (bpm) |
| Part 1: Placebo | Change in Heart Rate During Exercise in Part 1 | 63.058 Beats per minute (bpm) |
Secondary
Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hours 30 minutes and 24 hours post morning dose FEV1 measurements. Analysis of covariance included pre-dose FEV1 as covariate.
Time frame: 23 hours 30 minutes and 24 hours post-dose at Day 1
Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Indacaterol 300μg | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.72 Liters |
| Part 1 : Salmeterol 50μg | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.59 Liters |
| Part 1: Placebo | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.56 Liters |
| Part 2:Indacaterol 300μg Morning/Placebo Evening | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.75 Liters |
| Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.68 Liters |
| Part 2:Placebo Morning/Placebo Evening | Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2 | 1.54 Liters |