Safety of Indacaterol in Patients (≥ 12 Years) With Moderate to Severe Persistent Asthma

Novartis Pharmaceuticals805 enrolled

Overview

This study was designed to assess the safety of indacaterol (300 µg and 600 µg (2 x 300 μg capsules) once daily \[od\]), compared with salmeterol (50 μg twice a day \[b.i.d.\]), over 26 weeks, in patients with moderate to severe persistent asthma.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

805

Conditions

Asthma

Interventions

Indacaterol 300 μgDRUG

Indacaterol was supplied as powder filled capsules together with a single dose dry powder inhaler (SDDPI).

Salmeterol 50 μgDRUG

Salmeterol was supplied as powder filled capsules together with the manufacturer's proprietary dry powder inhalation device.

Placebo to indacaterolDRUG

Placebo to indacaterol was supplied as powder filled capsules together with a single dose dry powder inhaler (SDDPI).

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male and female patients aged ≥ 12 years (or ≥ 18 years depending upon regulatory and/or Institutional Review Board/Independent Ethics Committee/Research Ethics Board \[IRB/IEC/REB\] approval) who have signed an informed consent form. 2. Patients with moderate to severe persistent asthma, diagnosed according to the Global Initiative for Asthma (GINA) guidelines (Updated 2006) and who additionally meet the following criteria: * Patients who have used treatment with a bronchodilator, either regularly or on-demand, and who had used a daily dose of at least 100 μg beclomethasone dipropionate (or equivalent) for at least 1 month prior to screening. * Patients whose forced expiratory volume in 1 second (FEV1) is ≥ 50% of the predicted normal value. * Patients with documented (in the previous 6 months) or who demonstrate (prior to randomization) a ≥ 12% and at least 200 ml increase in FEV1, after inhaling 200 μg salbutamol. Exclusion Criteria: 1. Pregnant or nursing (lactating) women and women of child-bearing potential UNLESS they meet pre-specified definitions of post-menopausal or are using pre-specified acceptable methods of contraception. 2. Patients who have used tobacco products within the 12 month period prior to screening, or who have a smoking history of greater than 10 pack years. 3. Patients who suffer from chronic obstructive pulmonary disease (COPD) as diagnosed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (2006). 4. Patients who have had emergency room treatment for an acute asthma attack in the 6 weeks prior to screening or who have been hospitalized for an acute asthma attack in the 6 months prior to screening, or at any time between screening and Week 1. 5. Patients with diabetes Type I or those with uncontrolled diabetes Type II including patients with a history of blood glucose levels consistently outside the normal range or glycosylated hemoglobin (HbA1C) \> 8.0% measured at screening. 6. Patients who, in the judgment of the investigator or the responsible Novartis personnel, have a clinically significant condition or a clinically relevant laboratory abnormality that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study. 7. Patients with a history of long QT syndrome, or whose QTc interval (Bazett's formula) is prolonged to \> 450 ms (males) or \> 470 ms (females). 8. Certain medications for asthma and allied conditions such as long-acting bronchodilators must not be used prior to screening and for a pre-specified minimum washout period. Other protocol-defined inclusion/exclusion criteria applied to the study.

Locations (126)

Outcomes

Primary Outcomes

Percentage of Patients With at Least 1 Adverse Event During the 26 Weeks of the Study

Adverse events include asthma exacerbations. An asthma exacerbation was defined as a worsening of asthma as judged clinically significant by the physician, requiring treatment with rescue oral or intravenous (IV) corticosteroids. Asthma worsening that required treatment with inhaled or nebulized short-acting β2-agonists or an increase in inhaled corticosteroids only was not considered an asthma exacerbation.

Time frame: Baseline (Day 1) to end of study (Week 26)

Systolic Blood Pressure 1 Hour Post-dose at Day 1

Systolic blood pressure measurements (in millimeters of mercury, mmHg) were made 1 hour post-dose after the patient had rested in the sitting position for at least 10 minutes. Measurements were made using an inflatable cuff around the upper arm. The analysis included baseline systolic blood pressure and forced expiratory volume in 1 second (FEV1) pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Day 1

Systolic Blood Pressure 1 Hour Post-dose at Week 12

Systolic blood pressure measurements (in millimeters of mercury, mmHg) were made 1 hour post-dose after the patient had rested in the sitting position for at least 10 minutes. Measurements were made using an inflatable cuff around the upper arm. The analysis included baseline systolic blood pressure and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Week 12

Diastolic Blood Pressure 1 Hour Post-dose at Day 1

Diastolic blood pressure measurements (in millimeters of mercury, mmHg) were made 1 hour post-dose after the patient had rested in the sitting position for at least 10 minutes. Measurements were made using an inflatable cuff around the upper arm. Phase V Korotkoff sounds were used for determination of diastolic pressure. The analysis included baseline diastolic blood pressure and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Day 1

Data from ClinicalTrials.gov

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Placebo to salmeterol was supplied as powder filled capsules together with the manufacturer's proprietary dry powder inhalation device.

Novartis Investigator Site

Glendale, Arizona, United States

Novartis Investigator Site

Phoenix, Arizona, United States

Novartis Investigator Site

Encinitas, California, United States

Novartis Investigator Site

Huntington Beach, California, United States

Novartis Investigator Site

Long Beach, California, United States

Novartis Investigator Site

Long Beach, California, United States

Novartis Investigator Site

Los Angeles, California, United States

Novartis Investigator Site x 2 sites

Oakland, California, United States

Novartis Investigator Site

Orange, California, United States

Novartis Investigator Site

Palmdale, California, United States

...and 116 more locations

Diastolic Blood Pressure 1 Hour Post-dose at Week 12

Time frame: Week 12

Corrected QT (QTc) Interval Using Fridericia's Formula Measured 1 Hour Post-dose at Day 1

The QTc interval (in milliseconds, ms) is calculated from electrocardiogram (ECG) data collected 1 hour post-dose using Fridericia's formula: QTc = QT/RR\^0.33. QTc is the interval between the Q and T waves corrected for heart rate and RR is the interval between two R waves. ECGs included all 12 standard leads and a Lead II rhythm strip of at least 10-second duration. All results were sent to a central laboratory for review by a cardiologist. The analysis included baseline QTc interval and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Day 1

Corrected QT (QTc) Interval Using Fridericia's Formula Measured 1 Hour Post-dose at Week 12

Time frame: Week 12

Corrected QT (QTc) Interval Using Fridericia's Formula Measured 1 Hour Post-dose at Week 21

Time frame: Week 21

24 Hour Mean Heart Rate Determined From ECG Holter Monitoring at Week 12

Continuous 24 hour electrocardiography (Holter monitoring) was conducted in a subset of patients at designated study centers, and was used to calculate the mean heart rate (in beats per minute, bpm). Patients returned the Holter monitor recorder to the clinic the morning after the 24 hour recording was complete. The results of Holter monitoring were processed centrally. The analysis included baseline 24 hour mean heart rate and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Week 12

24 Hour Mean Heart Rate Determined From ECG Holter Monitoring at Week 26

Time frame: Week 26

Serum Potassium 1 Hour Post-dose at Day 1

Serum potassium (in millimoles per liter, mmol/L) was measured from venous blood samples. Samples were sent to a central laboratory for analysis. The analysis included baseline serum potassium and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Day 1

Serum Potassium 1 Hour Post-dose at Week 12

Time frame: Week 12

Blood Glucose 1 Hour Post-dose at Day 1

Blood glucose (in millimoles per liter, mmol/L) was measured from venous blood samples. Samples were sent to a central laboratory for analysis. The analysis included baseline blood glucose and FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening as covariates.

Time frame: Day 1

Blood Glucose 1 Hour Post-dose at Week 12

Time frame: Week 12

Percentage of Patients With Clinically Significant Asthma Exacerbations During the 26 Weeks of the Study

A clinically significant asthma exacerbation was defined as a worsening of asthma as judged clinically significant by the physician, requiring treatment with systemic corticosteroids. This includes events recorded on the asthma exacerbation clinical report form (CRF) page and events recorded on the adverse events CRF page with "asthma" as a key word in the preferred term.

Time frame: Baseline (Day 1) to end of study (Week 26)

Secondary Outcomes

Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at Week 12 + 1 Day, Day 85

FEV1 (in liters, L) 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 Week 12, Day 85. The analysis included baseline FEV1 and FEV1 pre-dose and 30 minutes post-dose of salbutamol during screening as covariates.

Time frame: 24 hours post-dose at Week 12 + 1 day, Day 85

Number of Asthma Exacerbations Per Patient (Without Imputation) During the 26 Weeks of the Study

An asthma exacerbation was defined as a worsening of asthma as judged clinically significant by the physician, requiring treatment with rescue oral or intravenous (IV) corticosteroids. The number of asthma exacerbations includes events recorded on the asthma exacerbation clinical report form (CRF) page and events recorded on the adverse events CRF page with "asthma" as a key word in the preferred term.

Time frame: Baseline (Day 1) to end of study (Week 26)