Efficacy and Safety of Indacaterol Plus Tiotropium Versus Tiotropium Alone in Patients With Chronic Obstructive Pulmonary Disease (INTRUST2)

A Randomized, Double-blind, Controlled, Parallel-group, 12-week Study to Compare the Efficacy and Safety of the Combination of Indacaterol 150 µg Once Daily With Open Label Tiotropium 18 µg Once Daily Versus Open Label Tiotropium 18 µg Once Daily in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease

This study assessed the efficacy and safety of indacaterol (150 µg once daily [od]) when combined with tiotropium (18 µg od) versus tiotropium (18 µg od) treatment alone in patients with chronic obstructive pulmonary disease (COPD).

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: Placebo to indacaterol; Drug: Indacaterol 150 μg; Drug: Tiotropium 18 μg

• Study Type: Interventional
• Enrollment (Actual): 1142
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Gatineau, Canada
    • Novartis Investigator Site
  • Joliette, Canada
    • Novartis Investigator Site
  • Mirabel, Canada
    • Novartis Investigator Site
  • Mississauga, Canada
    • Novartis Investigator Site
  • Montreal, Canada
    • Novartis Investigator Site
  • Quebec, Canada
    • Novartis Investigative Site
  • Sainte-Foy, Canada
    • Novartis Investigator Site
  • Sherbrooke, Canada
    • Novartis Investigator Site
  • St-Jerome, Canada
    • Novartis Investigator Site
  • Toronto, Canada
    • Novartis Investigator Site
  • Trois-Rivières, Canada
    • Novartis Investigator Site
  • Windsor, Canada
    • Novartis Investigator Site
• Colombia
  • Armenia, Colombia
    • Novartis Investigative Site
  • Barranquilla, Colombia
    • Novartis Investigator Site
  • Bogota, Colombia
    • Novartis Investigative Site
  • Cali, Colombia
    • Novartis Investigator Site
• Czech Republic
  • Karlovy Vary, Czech Republic
    • Novartis Investigative Site
  • Kladno, Czech Republic
    • Novartis Investigative Site
  • Kromeriz, Czech Republic
    • Novartis Investigative Site
  • Liberec, Czech Republic
    • Novartis Investigative Site
  • Rokycany, Czech Republic
    • Novartis Investigative Site
  • Strakonice, Czech Republic
    • Novartis Investigative Site
  • Trebic, Czech Republic
    • Novartis Investigative Site
• Hungary
  • Erd, Hungary
    • Novartis Investigative Site
  • Füzesabony, Hungary
    • Novartis Investigative Site
  • Gyor, Hungary
    • Novartis Investigator Site
  • Százhalombatta, Hungary
    • Novartis Investgative Site
• India
  • Ahmedabad, India
    • Novartis Investigator Site
  • Bangalore, India
    • Novartis Investigator Site
  • Coimbatore, India
    • Novartis Investigator Site
  • Hyderabad, India
    • Novartis Investigative Site
  • Indore, India
    • Novartis Investigative Site
  • Jaipur, India
    • Novartis Investigative Site
  • Ludhiana, India
    • Novartis Investigator Site
  • Panjim, India
    • Novartis Investigative Site
  • Trivandrum, India
    • Novartis Investigator Site
• Netherlands
  • Almelo, Netherlands
    • Novartis Investigative Site
  • Breda, Netherlands
    • Novartis Investigative Site
  • Heerlen, Netherlands
    • Novartis Investigative Site
  • Helmond, Netherlands
    • Novartis Investigative Site
  • Veldhoven, Netherlands
    • Novartis Investigative Site
  • Zutphen, Netherlands
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia
    • Novartis Investigative Site
  • Bardejov, Slovakia
    • Novartis Investigative Site
  • Bratislava, Slovakia
    • Novartis Investigator Site
  • Bratislava, Slovakia
    • Novartis Investigative Site
  • Martin, Slovakia
    • Novartis Investigative Site
  • Poprad, Slovakia
    • Novartis Investigative Site
  • Povazska Bystrica, Slovakia
    • Novartis Investigative Site
  • Štúrovo, Slovakia
    • Novartis Investigative Site
• Spain
  • Alicante, Spain
    • Novartis Investigative Site
  • Almeria, Spain
    • Novartis Investigative Site
  • Baracaldo, Spain
    • Novartis Investigative Site
  • Madrid, Spain
    • Novartis Investigator Site
  • Palma de Mallorca, Spain
    • Novartis Investigative Site
  • Pozuelo de Alarcón, Spain
    • Novartis Investigator Site
  • Riudecols, Spain
    • Novartis Investigator Site
  • San Boi De Llobregat, Spain
    • Novartis Investigative Site
  • Sevilla, Spain
    • Novartis Investigator Site
  • Vilassar de Mar, Spain
    • Novartis Investigative Site
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207-5710
      • Novartis Investigator Site
    • Birmingham, Alabama, United States, 35249-2181
      • Novartis Investigator Site
    • Jasper, Alabama, United States, 35501
      • Novartis Investigator Site
    • Mobile, Alabama, United States, 36608-1128
      • Novartis Investigator Site
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Novartis Investigator Site
    • Phoenix, Arizona, United States, 85006
      • Novartis Investigator Site
    • Phoenix, Arizona, United States, 85013
      • Novartis Investigator Site
    • Scottsdale, Arizona, United States, 85251
      • Novartis Investigator Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Novartis Investigator Site
  • California
    • Buena Park, California, United States, 90620
      • Novartis Investigator Site
    • Fullerton, California, United States, 92835
      • Novartis Investigator Site
    • Mission Viejo, California, United States, 92691
      • Novartis Investigator Site
    • San Ramon, California, United States, 94583
      • Novartis Investigator Site
    • Santa Barbara, California, United States, 93110
      • Novartis Investigator Site
    • Sepulveda, California, United States, 91343
      • Novartis Investigator Site
    • Spring Valley, California, United States, 91978
      • Novartis Investigator Site
    • Torrance, California, United States, 90505
      • Novartis Investigator Site
    • Torrance, California, United States, 90502
      • Novartis Investigator Site
    • Vista, California, United States, 92083
      • Novartis Investigator Site
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Novartis Investigator Site
    • Centennial, Colorado, United States, 80112
      • Novartis Investigator Site
    • Colorado Springs, Colorado, United States, 80907
      • Novartis Investigator Site
    • Denver, Colorado, United States, 80206
      • Novartis Investigator Site
  • Connecticut
    • Glastonbury, Connecticut, United States, 06033
      • Novartis Investigative Site
    • Waterbury, Connecticut, United States, 06708
      • Novartis Investigative Site
  • Florida
    • Clearwater, Florida, United States, 33765
      • Novartis Investigator Site
    • Destin, Florida, United States, 32541
      • Novartis Investigator Site
    • Maitland, Florida, United States, 32751
      • Novartis Investigator Site
    • Miami, Florida, United States, 33125
      • Novartis Investigator Site
    • Miami Beach, Florida, United States, 33140
      • Novartis Investigator Site
    • Ocala, Florida, United States, 34471
      • Novartis Investigator Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigator Site
    • Pensacola, Florida, United States, 32504
      • Novartis Investigator Site
    • Pensacola, Florida, United States, 32514
      • Novartis Investigator Site
    • Port Orange, Florida, United States, 32127
      • Novartis Investigator Site
    • South Miami, Florida, United States, 33143
      • Novartis Investigator Site
    • Tamarac, Florida, United States, 33321
      • Novartis Investigator Site
    • Tampa, Florida, United States, 33603
      • Novartis Investigator Site
    • Tampa, Florida, United States, 33613
      • Novartis Investigator Site
  • Idaho
    • Couer D'Alene, Idaho, United States, 98314
      • Novartis Investigator Site
  • Illinois
    • Downers Grove, Illinois, United States, 60515
      • Novartis Investigator Site
    • Elk Grove Village, Illinois, United States, 60007
      • Novartis Investigator Site
    • River Forest, Illinois, United States, 60305
      • Novartis Investigator Site
    • Springfield, Illinois, United States, 62781
      • Novartis Investigator Site
  • Kansas
    • Shawnee, Kansas, United States, 66217
      • Novartis Investigator Site
  • Kentucky
    • Crescent Springs, Kentucky, United States, 41017
      • Novartis Investigator Site
    • Lexington, Kentucky, United States, 40504
      • Novartis Investigator Site
    • Louisville, Kentucky, United States, 40202
      • Novartis Investigator Site
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Novartis Investigator Site
  • Maryland
    • Waldorf, Maryland, United States, 20602
      • Novartis Investigative Site
  • Massachusetts
    • Burlington, Massachusetts, United States, 01803
      • Novartis Investigative Site
  • Michigan
    • Troy, Michigan, United States, 48085
      • Novartis Investigator Site
  • Minnesota
    • Chaska, Minnesota, United States, 55318
      • Novartis Investigator Site
    • Edina, Minnesota, United States, 55435
      • Novartis Investigator Site
    • Minneapolis, Minnesota, United States, 55402
      • Novartis Investigative Site
    • Rochester, Minnesota, United States, 55905
      • Novartis Investigator Site
    • St Paul, Minnesota, United States, 55130
      • Novartis Investigator Site
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Novartis Investigator Site
    • Kansas City, Missouri, United States, 64128
      • Novartis Investigator Site
    • Ozark, Missouri, United States, 65721
      • Novartis Investigator Site
    • St. Louis, Missouri, United States, 63141
      • Novartis Investigator Site
    • St. Louis, Missouri, United States, 63110
      • Novartis Investigator Site
    • St. Louis, Missouri, United States, 63317
      • Novartis Investigator Site
  • Montana
    • Billings, Montana, United States, 59102
      • Novartis Investigator Site
    • Kalispell, Montana, United States, 59901
      • Novartis Investigator Site
  • Nebraska
    • Bellevue, Nebraska, United States, 68005
      • Novartis Investigator Site
    • Lincoln, Nebraska, United States, 68516
      • Novartis Investigator Site
    • Papillion, Nebraska, United States, 68046
      • Novartis Investigator Site
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Novartis Investigator Site
  • New Jersey
    • Brick, New Jersey, United States, 08723
      • Novartis Investigative Site
    • New Brunswick, New Jersey, United States, 08902
      • Novartis Investigative Site
    • Ocean, New Jersey, United States, 07712
      • Novartis Investigative Site
  • New York
    • Bayside, New York, United States, 11361
      • Novartis Investigative Site
    • Great Neck, New York, United States, 11023
      • Novartis Investigative Site
    • Larchmont, New York, United States, 10538
      • Novartis Investigative Site
  • North Carolina
    • Burlington, North Carolina, United States, 27215
      • Novartis Investigative Site
    • Charlotte, North Carolina, United States, 28207
      • Novartis Investigator Site
    • Charlotte, North Carolina, United States, 28277
      • Novartis Investigator Site
    • Raleigh, North Carolina, United States, 27607
      • Novartis Investigative Center
    • Shelby, North Carolina, United States, 28150
      • Novartis Investigative Site
    • Statesville, North Carolina, United States, 28625
      • Novartis Investigator Site
    • Winston Salem, North Carolina, United States, 27103
      • Novartis Investigative Site
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Novartis Investigator Site
    • Grand Forks, North Dakota, United States, 58201
      • Novartis Investigator Site
  • Ohio
    • Akron, Ohio, United States, 44313
      • Novartis Investigative Site
    • Cincinnati, Ohio, United States, 45231
      • Novartis Investigator Site
    • Cincinnati, Ohio, United States, 45242
      • Novartis Investigator Site
    • Cleveland, Ohio, United States, 44109
      • Novartis Investigator Site
    • Toledo, Ohio, United States, 43608
      • Novartis Investigator Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Novartis Investigator Site
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Novartis Investigator Site
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Novartis Investigative Site
    • Beaver, Pennsylvania, United States, 15009
      • Novartis Investigative Site
    • Erie, Pennsylvania, United States, 16506
      • Novartis Investigative Site
    • Philadelphia, Pennsylvania, United States, 19104
      • Novartis Investigative Site
    • Philadelphia, Pennsylvania, United States, 19140
      • Novartis Investigative Site
    • Phoenixville, Pennsylvania, United States, 19460
      • Novartis Investigative Site
  • Rhode Island
    • Pawtucket, Rhode Island, United States, 02860
      • Novartis Investigative Site
    • Providence, Rhode Island, United States, 02903
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • Novartis Investigator Site
    • Easley, South Carolina, United States, 26940
      • Novartis Investigator Site
    • Greenville, South Carolina, United States, 29615
      • Novartis Investigator Site
    • North Charleston, South Carolina, United States, 29406-7108
      • Novartis Investigator Site
    • Spartanburg, South Carolina, United States, 29303
      • Novartis Investigator Site
    • Union, South Carolina, United States, 29379
      • Novartis Investigator Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Novartis Investigator Site
    • Dallas, Texas, United States, 75216
      • Novartis Investigator Site
    • Fort Worth, Texas, United States, 76109
      • Novartis Investigator Site
    • Houston, Texas, United States, 77030
      • Novartis Investigator Site
    • Tyler, Texas, United States, 75708
      • Novartis Investigator Site
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Novartis Investigator Site
  • Virginia
    • Abingdon, Virginia, United States, 24210
      • Novartis Investigative Site
    • Fredericks, Virginia, United States, 22401
      • Novartis Investigative Site
  • Washington
    • Renton, Washington, United States, 98055
      • Novartis Investigator Site
    • Spokane, Washington, United States, 99204
      • Novartis Investigator Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26505
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of chronic obstructive pulmonary disease (COPD) (moderate-to-severe as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2007) and:

  • Smoking history of at least 10 pack-years
  • Post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤ 65% and ≥ 30% of the predicted normal value
  • Post-bronchodilator FEV1/FVC (forced vital capacity) < 70%

Exclusion Criteria:

• Patients who have received systemic corticosteroids and/or antibiotics and/or was hospitalized for a COPD exacerbation in the 6 weeks prior to screening or during the run-in period
• Patients who have had a respiratory tract infection within 6 weeks prior to screening
• Patients with concomitant pulmonary disease
• Patients with a history of asthma
• Patients with diabetes Type I or uncontrolled diabetes Type II
• Any patient with lung cancer or a history of lung cancer
• Patients with a history of certain cardiovascular comorbid conditions

Other protocol-defined inclusion/exclusion criteria applied to the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Indacaterol 150 μg and tiotropium 18 μg; Patients inhaled indacaterol 150 μg and tiotropium 18 μg once daily in the morning between 8:00 AM and 11:00 AM for 12 weeks. Indacaterol was delivered blinded via a single-dose dry-powder inhaler (SDDPI). Tiotropium was delivered open-label via the manufacturer's proprietary inhalation device (HandiHaler®). 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.	Drug: Indacaterol 150 μg; Indacaterol was supplied in powder filled capsules together with a single-dose dry-powder inhaler (SDDPI) device.; Drug: Tiotropium 18 μg; Tiotropium was supplied in powder filled capsules together with the manufacturer's proprietary inhalation device (HandiHaler®).
Active Comparator: Tiotropium 18 μg; Patients inhaled placebo to indacaterol 150 μg and tiotropium 18 μg once daily in the morning between 8:00 AM and 11:00 AM for 12 weeks. Placebo to indacaterol was delivered blinded via a single-dose dry-powder inhaler (SDDPI). Tiotropium was delivered open-label via the manufacturer's proprietary inhalation device (HandiHaler®). 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.	Drug: Placebo to indacaterol; Placebo to indacaterol was supplied in powder filled capsules together with a single-dose dry-powder inhaler (SDDPI) device.; Drug: Tiotropium 18 μg; Tiotropium was supplied in powder filled capsules together with the manufacturer's proprietary inhalation device (HandiHaler®).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 8 Hours Post-dose at the End of the Study (Week 12, Day 84)	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose at the end of the study (Week 12, Day 84). The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	From 5 minutes to 8 hours post-dose at the end of the study (Week 12, Day 84)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose on Day 2	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 on Day 2. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	24 hours post-dose on Day 2
Trough Forced Expiratory Volume in 1 Second (FEV1) 24 Hours Post-dose at the End of the Study (Week 12 + 1 Day, Day 85)	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 the end of the study. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	End of the study (Week 12 + 1 day, Day 85)
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 8 Hours Post-dose on Day 1	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, 4, 6, and 8 hours post-dose on Day 1. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	From 5 minutes to 8 hours post-dose on Day 1
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose on Day 1	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose on Day 1. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	From 5 minutes to 4 hours post-dose on Day 1
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Length of Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of the Study (Week 12, Day 84)	FEV1 was measured with spirometry conducted according to internationally accepted standards. Measurements were made at 5 and 30 minutes; and 1, 2, 3, and 4 hours post-dose at the end of the study (Week 12, Day 84). The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time. The analysis included baseline FEV1, FEV1 pre-dose and 10-15 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.	From 5 minutes to 4 hours post-dose at the end of the study (Week 12, Day 84)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, Lassen C, Kramer B; INTRUST-1 and INTRUST-2 study investigators. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax. 2012 Sep;67(9):781-8. doi: 10.1136/thoraxjnl-2011-201140. Epub 2012 Apr 27.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: April 6, 2009
• First Submitted That Met QC Criteria: April 6, 2009
• First Posted (Estimate): April 7, 2009

Study Record Updates

• Last Update Posted (Estimate): August 25, 2011
• Last Update Submitted That Met QC Criteria: August 23, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: COPD; indacaterol; chronic obstructive pulmonary disease; tiotropium; bronchodilation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide
• Other Study ID Numbers: CQAB149B2351