Comparison of Long-term Safety of the Combination Product QVA149A Against Placebo and Standard of Care Treatment in Chronic Obstructive Pulmonary Disease Patients With Moderate to Severe Airflow Limitation

A Placebo and Active Controlled Study to Assess the Long-term Safety of Once Daily QVA149 for 52 Weeks in Chronic Obstructive Pulmonary Disease (COPD) Patients With Moderate to Severe Airflow Limitation

The study will assess the long-term safety of the fixed combination product QVA149 versus placebo and a standard of care treatment (tiotropium) in Chronic Obstructive Pulmonary Disease (COPD) patients with moderate to severe airflow limitation.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease (COPD)
• Intervention / Treatment: Drug: QVA149; Drug: Tiotropium; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 1215
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1842DID
    • Novartis Investigative Site
  • Buenos Aires, Argentina, 1425
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400
    • Novartis Investigative Site
  • Mendoza, Argentina, 5500
    • Novartis Investigative Site
  • Mendoza, Argentina, M5500CBA
    • Novartis Investigative Site
  • Salta, Argentina, 4000
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FIL
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FWO
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1180AAX
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1122AAK
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, 1028
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1113AAC
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1425AUA
      • Novartis Investigative Site
    • Florencio Varela, Buenos Aires, Argentina, B2705XAE
      • Novartis Investigative Site
    • Florida, Buenos Aires, Argentina, B1602DQD
      • Novartis Investigative Site
    • Lanus, Buenos Aires, Argentina, B8000XAV
      • Novartis Investigative Site
    • Mar del Plata, Buenos Aires, Argentina, B7600FZN
      • Novartis Investigative Site
    • Quilmes, Buenos Aires, Argentina, B1878FNR
      • Novartis Investigative Site
    • San Isidro, Buenos Aires, Argentina, B1642DCD
      • Novartis Investigative Site
    • Vicente Lopez, Buenos Aires, Argentina, B1638AAI
      • Novartis Investigative Site
  • Entre Rios
    • Concepcion del Uruguay, Entre Rios, Argentina, E3260EPD
      • Novartis Investigative Site
  • Rosario
    • Santa Fe, Rosario, Argentina, S2000DBS
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000CXH
      • Novartis Investigative Site
    • Rosario, Santa Fe, Argentina, S2000AII
      • Novartis Investigative Site
  • Tucuman
    • San Miguel de Tucuman, Tucuman, Argentina, 4000
      • Novartis Investigative Site
• Colombia
  • Armenia, Colombia
    • Novartis Investigative Site
  • Barranquilla, Colombia
    • Novartis Investigative Site
  • Bogota, Colombia
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia
      • Novartis Investigative Site
• Croatia
  • Osijek, Croatia, 31000
    • Novartis Investigative Site
  • Sisak, Croatia, 44000
    • Novartis Investigative Site
  • Zagreb, Croatia, 10000
    • Novartis Investigative Site
  • Zagreb, Croatia, 10 000
    • Novartis Investigative Site
• Estonia
  • Tallinn, Estonia, 13419
    • Novartis Investigative Site
  • Tallinn, Estonia, 13619
    • Novartis Investigative Site
  • Tartu, Estonia, 51014
    • Novartis Investigative Site
• Hungary
  • Cegled, Hungary, 2700
    • Novartis Investigative Site
  • Csorna, Hungary, H-9300
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Eger, Hungary, 3300
    • Novartis Investigative Site
  • Erd, Hungary, H-2030
    • Novartis Investigative Site
  • Godollo, Hungary, 2100
    • Novartis Investigative Site
  • Monor, Hungary, 2200
    • Novartis Investigative Site
  • Mosonmagyarovar, Hungary, 9200
    • Novartis Investigative Site
  • Siofok, Hungary, 8600
    • Novartis Investigative Site
  • Szarvas, Hungary, 5540
    • Novartis Investigative Site
  • HUN
    • Budapest, HUN, Hungary, 1204
      • Novartis Investigative Site
• India
  • Ahmedabad, India, 380009
    • Novartis Investigative Site
  • Nagpur - Maharashtra, India, 440012
    • Novartis Investigative Site
  • A.p.
    • Hyderabad, A.p., India, 500 001
      • Novartis Investigative Site
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500004
      • Novartis Investigative Site
  • Goa
    • Panjim, Goa, India, 403 002
      • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560002
      • Novartis Investigative Site
    • Mysore, Karnataka, India, 570004
      • Novartis Investigative Site
  • Kerala
    • Trivandrum, Kerala, India, 695 011
      • Novartis Investigative Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 440033
      • Novartis Investigative Site
  • Rajasthan
    • Bikaner, Rajasthan, India, 334 001
      • Novartis Investigative Site
    • Jaipur, Rajasthan, India, 302023
      • Novartis Investigative Site
    • Jaipur, Rajasthan, India, 302 039
      • Novartis Investigative Site
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India, 641 045.
      • Novartis Investigative Site
    • Vellore, Tamil Nadu, India, 632004
      • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 91031
    • Novartis Investigative Site
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Petach Tikva, Israel, 49100
    • Novartis Investigative Site
  • Rehovot, Israel, 76100
    • Novartis Investigative Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 705-703
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 403-720
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 405-760
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 156-755
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 130-872
    • Novartis Investigative Site
  • Gyeonggi-Do
    • Bucheon-Si, Gyeonggi-Do, Korea, Republic of, 14584
      • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 03080
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 130-709
      • Novartis Investigative Site
• Latvia
  • Daugavpils, Latvia, LV-5401
    • Novartis Investigative Site
  • Riga, Latvia, LV-1038
    • Novartis Investigative Site
  • Riga, Latvia, 1002
    • Novartis Investigative Site
• Mexico
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 06726
      • Novartis Investigative Site
    • Mexico, Distrito Federal, Mexico, 14050
      • Novartis Investigative Site
  • Guanajuato
    • León, Guanajuato, Mexico, 37000
      • Novartis Investigative Site
  • Hidalgo
    • Pachuca, Hidalgo, Mexico, 42090
      • Novartis Investigative Site
• Panama
  • Panamá
    • Panama City, Panamá, Panama
      • Novartis Investigative Site
    • Panama City, Panamá, Panama, 0834-00363
      • Novartis Investigative Site
• Poland
  • Bialystok, Poland, 15-044
    • Novartis Investigative Site
  • Katowice, Poland, 40-752
    • Novartis Investigative Site
  • Krakow, Poland, 31-159
    • Novartis Investigative Site
  • Lodz, Poland, 90-153
    • Novartis Investigative Site
  • Lodz, Poland, 90-302
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 125315
    • Novartis Investigative Site
  • Moscow, Russian Federation, 115280
    • Novartis Investigative Site
  • N.Novgorod, Russian Federation, 603126
    • Novartis Investigative Site
  • Nizhny Novgorod, Russian Federation, 603018
    • Novartis Investigative Site
  • Ryazan, Russian Federation, 390026
    • Novartis Investigative Site
  • Saratov, Russian Federation, 410012
    • Novartis Investigative Site
  • St-Petersburg, Russian Federation, 193312
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation, 194354
    • Novartis Investigative Site
  • St.-Petersburg, Russian Federation, 193231
    • Novartis Investigative Site
  • Yaroslavl, Russian Federation, 150003
    • Novartis Investigative Site
• Serbia
  • Knez Selo, Serbia, 18204
    • Novartis Investigative Site
  • Kragujevac, Serbia, 34000
    • Novartis Investigative Site
• Slovenia
  • Golnik, Slovenia, 4204
    • Novartis Investigative Site
• Turkey
  • Kartal, Turkey, 34890
    • Novartis Investigative Site
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site
  • Mersin, Turkey, 33079
    • Novartis Investigative Site
  • Pendik / Istanbul, Turkey, 1330
    • Novartis Investigative Site
  • Yenisehir/Izmir, Turkey, 35110
    • Novartis Investigative Site
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Birmingham, United Kingdom, B15 2WB
    • Novartis Investigative Site
  • Cheshire, United Kingdom, CW1 4QJ
    • Novartis Investigative Site
  • Doncaster, United Kingdom, DN2 5LT
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Merseyside, United Kingdom, CH49 5PE
    • Novartis Investigative Site
  • Newport, United Kingdom, P030 5TG
    • Novartis Investigative Site
  • Portsmouth, United Kingdom, PO6 3AD
    • Novartis Investigative Site
  • Wolverhampton, United Kingdom, WV10 0QP
    • Novartis Investigative Site
  • Warwickshire
    • Leamington Spa, Warwickshire, United Kingdom, CV32 4RA
      • Novartis Investigative Site
  • West Yorkshire
    • Bradford, West Yorkshire, United Kingdom, BD9 6RJ
      • 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:

• Male and female adults aged ≥40 years.
• Patients with stable COPD according to GOLD strategy (GOLD 2011).
• Patients with airflow limitation indicated by a post-bronchodilator FEV1 ≥ 30% and <80% of the predicted normal, and a post-bronchodilator.
• FEV1/FVC < 0.70.
• Current or ex-smokers who have a smoking history of at least 10 pack years.
• Patients with an mMRC ≥ grade 2

Exclusion criteria:

• History of long QT syndrome or prolonged QTc.
• Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to Visit 1.
• Patients with Type I or uncontrolled Type II diabetes.
• Patients with a history of asthma or have concomitant pulmonary disease.
• Patients with paroxysmal (e.g. intermittent) atrial fibrillation. Only patients with persistent atrial fibrillation and controlled with a rate control strategy for at least six months could be eligible.
• Patients who have clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities which could interfere with the assessment of safety.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo	Drug: placebo; placebo to QVA149A and Tiotropium will be supplied in the appropriate capsule in blister packs for use in either the Novartis Concept1 SDDPI or the HandiHaler SDDPI
Active Comparator: Tiotropium	Drug: Tiotropium; Tiotropium 18 µg will be supplied as capsules in blister packs for once daily inhalation using the HandiHaler SDDPI
Experimental: QVA149	Drug: QVA149; QVA149 110/50 µg will be supplied as capsules in blister packs for once daily inhalation using the Novartis Concept1 SDDPI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Serious Adverse Events	The overall rate of serious adverse events reported from initiation through 30 days post last dose.	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events.	The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug.	52 weeks
Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE	The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug.	52 weeks
Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1)	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1.	Day 22, 43, 85, 183, 274 and 364
Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C)	The SGRQ-C contains 40 items divided into two parts covering three aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts" which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score will be calculated for each of these three subscales and a "Total" score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.	Measurment at day 364
Change From Baseline in Daily, Morning and Evening Symptom Scores	Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline.	52 weeks
Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings	A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms.	52 weeks
Change From Baseline in Percentage of no Daytime Symptoms	A day with 'no daytime symptoms' is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm).	52 weeks
Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities.	A day able to perform usual daily activities' is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms.	52 weeks
Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements	Pulmonary function assessments were performed using centralized spirometry according to international standards	Day 1, 22, 43, 85, 183, 274 and 364
Time to Premature Discontinuation	Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the 'time to treatment discontinuation' varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks.	Time varied from 5 - 407 days
Change From Baseline in 1 Hour Post-dose FEV1 Measurements	The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed.	Day 1, 22, 43, 85, 183, 274 and 364

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: May 30, 2012
• First Submitted That Met QC Criteria: May 30, 2012
• First Posted (Estimate): June 1, 2012

Study Record Updates

• Last Update Posted (Estimate): June 15, 2016
• Last Update Submitted That Met QC Criteria: May 9, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: COPD; QAB149; QVA149; NVA237; chronic obstructive pulmonary disease; Indacaterol maleate; Glycopyronnium bromide
• 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: CQVA149A2339; 2012-002057-38 (EudraCT Number)