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

Asthma Clinical Trial

Official title:

A 26-week Treatment, Randomized, Multicenter, Double-blind, Double-dummy, Parallel-group Study to Assess the Safety of Indacaterol (300 and 600 µg o.d.) in Patients With Moderate to Severe Persistent Asthma, Using Salmeterol (50 µg b.i.d.) as an Active Control

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00529529
• Other study ID #: CQAB149B2338
• Status: Completed
• Phase: Phase 3
• First received: September 12, 2007
• Last updated: August 25, 2011
• Start date: September 2007
• Est. completion date: August 2008

Study information

• Verified date: August 2011
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationGermany: Federal Institute for Drugs and Medical DevicesArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaCanada: Health CanadaCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Hungary: Ministry of Health, Social and Family AffairsItaly: Ministry of HealthPeru: Ministry of HealthSlovakia: State Institute for Drug ControlSpain: Spanish Agency of MedicinesTurkey: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 805
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Indacaterol 300 µg
Indacaterol was supplied as powder filled capsules together with a single dose dry powder inhaler (SDDPI).
• Salmeterol 50 µg
Salmeterol was supplied as powder filled capsules together with the manufacturer's proprietary dry powder inhalation device.
• Placebo to indacaterol
Placebo to indacaterol was supplied as powder filled capsules together with a single dose dry powder inhaler (SDDPI).
• Placebo to salmeterol
Placebo to salmeterol was supplied as powder filled capsules together with the manufacturer's proprietary dry powder inhalation device.

Locations

Country	Name	City	State
Argentina	Novartis Investigator Site	Buenos Aires
Argentina	Novartis Investigator Site	Cordoba
Argentina	Novartis Investigator Site	Rosario
Argentina	Novartis Investigator Site	San Miguel de Tucuman
Canada	Novartis Investigator Site	Halifax
Canada	Novartis Investigator Site	London
Canada	Novartis Investigator Site	Mississauga
Canada	Novartis Investigator Site	Montreal
Canada	Novartis Investigator Site	Ste-Foy
Czech Republic	Novartis Investigator Site	Brno
Czech Republic	Novartis Investigative Site	Praha
Czech Republic	Novartis Investigator Site	Praha
France	Novartis Investigator Site	Brest cedex
France	Novartis Investigator Site	Castelnau-le-Lez
France	Novartis Investigator Site	Chauny
France	Novartis Investigator Site	Paris Cedex 14
France	Novartis Investigator Site	Tarbes Cedex
France	Novartis Investigator Site	Vandoeuvre Les Nancy
Germany	Novartis Investigator Site	Berlin
Germany	Novartis Investigator Site	Bochum
Germany	Novartis Investigator Site	Borstel
Germany	Novartis Investigator Site	Geesthacht
Germany	Novartis Investigator Site	Hamburg
Germany	Novartis Investigator Site	Kiel
Germany	Novartis Investigator Site	Leipzig
Germany	Novartis Investigator Site	Luebeck
Germany	Novartis Investigator Site	Mainz
Germany	Novartis Investigator Site	Marburg
Germany	Novartis Investigator Site	Neumunster
Germany	Novartis Investigator Site	Neuss
Germany	Novartis Investigator Site	Schwetzingen
Germany	Novartis Investigator Site	Wiesloch
Germany	Novartis Investigator Site	Wittem
Hungary	Novartis Investigator Site	Debrecen
Hungary	Novartis Investigator Site	Nyiregyhaza
Hungary	Novartis Investigator Site	Sopron
Hungary	Novartis Investigator Site	Szombathely
Hungary	Novartis Investigator Site	Tatabanya
Italy	Novartis Investigator Site	Brescia
Italy	Novartis Investigator Site	Catania
Italy	Novartis Investigator Site	Modena
Italy	Novartis Investigator Site	Parma
Italy	Novartis Investigator Site	Pietra Ligure
Italy	Novartis Investigator Site	Pisa
Italy	Novartis Investigator Site	Terni
Italy	Novartis Investigator Site	Torino
Italy	Novartis Investigator Site	Trieste
Peru	Novartis Investigator Site	Lima
Slovakia	Novartis Investigator Site	Bardejov
Slovakia	Novartis Investigator Site	Bratislava
Slovakia	Novartis Investigator Site	Kosice
Slovakia	Novartis Investigator Site	Nitra
Slovakia	Novartis Investigator Site	Trencin
Spain	Novartis Investigator Site	Alicante
Spain	Novartis Investigator Site	Barcelona
Spain	Novartis Investigator Site	Begonte
Spain	Novartis Investigator Site	Caceres
Spain	Novartis Investigator Site	Cádiz
Spain	Novartis Investigator Site	Granollers
Spain	Novartis Investigative Site	Hospitalet de Llobregat
Spain	Novartis Investigator Site	Hostalets de Balenyà
Spain	Novartis Investigator Site	Illescas
Spain	Novartis Investigator Site	Mataró
Spain	Novartis Investigator Site	Oviedo
Spain	Novartis Investigator Site	Sevilla
Spain	Novartis Investigator Site	Valencia
Turkey	Novartis Investigator Site	Ankara
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigator Site	Istanbul
Turkey	Novartis Investigator Site	Izmir
United States	Novartis Investigator Site	Albany	Georgia
United States	Novartis Investigator Site	Ann Arbor	Michigan
United States	Novartis Investigator Site	Baltimore	Maryland
United States	Novartis Investigator Site	Brandon	Florida
United States	Novartis Investigator Site	Charlotte	North Carolina
United States	Novartis Investigator Site	Cincinnati	Ohio
United States	Novartis Investigator Site	Dallas	Texas
United States	Novartis Investigator Site	Denver	Colorado
United States	Novartis Investigator Site	Denver	Colorado
United States	Novartis Investigator Site	Edmond	Oklahoma
United States	Novartis Investigator Site	Encinitas	California
United States	Novartis Investigator Site	Englewood	Colorado
United States	Novartis Investigator Site	Florence	Kentucky
United States	Novartis Investigator Site	Glendale	Arizona
United States	Novartis Investigator Site	Greenville	South Carolina
United States	Novartis Investigator Site	High Point	North Carolina
United States	Novartis Investigator site	Houston	Texas
United States	Novartis Investigator Site	Houston	Texas
United States	Novartis Investigator Site	Houston	Texas
United States	Novartis Investigator Site	Houston	Texas
United States	Novartis Investigator Site	Huntington Beach	California
United States	Novartis Investigator Site	Kirkland	Washington
United States	Novartis Investigator Site	Lakewood	Colorado
United States	Novartis Investigator Site	Largo	Florida
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	Miami	Florida
United States	Novartis Investigator Site	North Dartmouth	Massachusetts
United States	Novartis Investigator Site	Northfield	New Jersey
United States	Novartis Investigator Site x 2 sites	Oakland	California
United States	Novartis Investigator Site	Oklahoma City	Oklahoma
United States	Novartis Investigator Site	Omaha	Nebraska
United States	Novartis Investigator Site	Omaha	Nebraska
United States	Novartis Investigator Site	Orange	California
United States	Novartis Investigator Site	overland Park	Kansas
United States	Novartis Investigator Site	Overland Park	Kansas
United States	Novartis Investigator Site	Palmdale	California
United States	Novartis Investigator Site	Panama City	Florida
United States	Novartis Investigator Site	Pensacola	Florida
United States	Novartis Investigator Site x 2 sites	Pensacola	Florida
United States	Novartis Investigator Site	Phoenix	Arizona
United States	Novartis Investigator Site	Rockville Centre	New York
United States	Novartis Investigator Site	San diego	California
United States	Novartis Investigator Site	San Diego	California
United States	Novartis Investigator Site	Seattle	Washington
United States	Novartis Investigator Site	Springfield	Missouri
United States	Novartis Investigator Site	St louis	Missouri
United States	Novartis Investigator Site	Stockbridge	Georgia
United States	Novartis Investigator Site	Tamarac	Florida
United States	Novartis Investigator Site	Toledo	Ohio
United States	Novartis Investigator Site	Topeka	Kansas
United States	Novartis Investigator Site	Walnut Creek	California
United States	Novartis Investigator Site	Wheaton	Maryland
United States	Novartis Investigator Site	Winston-Salem	North Carolina
United States	Novartis Investigator Site	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Czech Republic,  France,  Germany,  Hungary,  Italy,  Peru,  Slovakia,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 ß2-agonists or an increase in inhaled corticosteroids only was not considered an asthma exacerbation.	Baseline (Day 1) to end of study (Week 26)	Yes
Primary	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.	Day 1	Yes
Primary	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.	Week 12	Yes
Primary	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.	Day 1	Yes
Primary	Diastolic Blood Pressure 1 Hour Post-dose at Week 12	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.	Week 12	Yes
Primary	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.	Day 1	Yes
Primary	Corrected QT (QTc) Interval Using Fridericia's Formula Measured 1 Hour Post-dose at Week 12	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.	Week 12	Yes
Primary	Corrected QT (QTc) Interval Using Fridericia's Formula Measured 1 Hour Post-dose at Week 21	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.	Week 21	Yes
Primary	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.	Week 12	Yes
Primary	24 Hour Mean Heart Rate Determined From ECG Holter Monitoring at Week 26	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.	Week 26	Yes
Primary	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.	Day 1	Yes
Primary	Serum Potassium 1 Hour Post-dose at Week 12	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.	Week 12	Yes
Primary	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.	Day 1	Yes
Primary	Blood Glucose 1 Hour Post-dose at Week 12	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.	Week 12	Yes
Primary	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.	Baseline (Day 1) to end of study (Week 26)	Yes
Secondary	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.	24 hours post-dose at Week 12 + 1 day, Day 85	No
Secondary	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.	Baseline (Day 1) to end of study (Week 26)	No