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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01610037
First received: May 30, 2012
Last updated: May 9, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Chronic Obstructive Pulmonary Disease (COPD)
Drug: QVA149
Drug: Tiotropium
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Patients With Serious Adverse Events [ Time Frame: Week 52 ] [ Designated as safety issue: Yes ]
    The overall rate of serious adverse events reported from initiation through 30 days post last dose.


Secondary Outcome Measures:
  • Percentage of Patients With Composite Endpoint of All-cause Mortality, and Serious Cardio- and Cerebrovascular (CCV) Events. [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    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.

  • Post-hoc Analysis: Percentage of Patients With Composite Endpoint of Cardiovascular Death and MACE [ Time Frame: 52 weeks ] [ Designated as safety issue: Yes ]
    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.

  • Change From Baseline in Pre-Dose Forced Expiratory Volume Over in Second (FEV1) [ Time Frame: Day 22, 43, 85, 183, 274 and 364 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Health Status as Measured by St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) [ Time Frame: Measurment at day 364 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Daily, Morning and Evening Symptom Scores [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Percentage of Nights With 'no Nighttime Awakenings [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    A night with 'no nighttime awakenings' is defined from diary data as any night where the patient did not wake up due to symptoms.

  • Change From Baseline in Percentage of no Daytime Symptoms [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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).

  • Change From Baseline in Percentage of Days Able to Perform Usual Daily Activities. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in 1 Hour Post-dose Forced Vital Capacity (FVC) Measurements [ Time Frame: Day 1, 22, 43, 85, 183, 274 and 364 ] [ Designated as safety issue: No ]
    Pulmonary function assessments were performed using centralized spirometry according to international standards

  • Time to Premature Discontinuation [ Time Frame: Time varied from 5 - 407 days ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in 1 Hour Post-dose FEV1 Measurements [ Time Frame: Day 1, 22, 43, 85, 183, 274 and 364 ] [ Designated as safety issue: No ]
    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.


Enrollment: 1215
Study Start Date: October 2012
Study Completion Date: February 2015
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Active Comparator: Tiotropium Drug: Tiotropium
Tiotropium 18 µg will be supplied as capsules in blister packs for once daily inhalation using the HandiHaler SDDPI
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

  Eligibility

Ages Eligible for Study:   40 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01610037

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Locations
Argentina
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Caba, Buenos Aires, Argentina, 1028
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Caba, Buenos Aires, Argentina, C1113AAC
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Caba, Buenos Aires, Argentina, C1122AAK
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Caba, Buenos Aires, Argentina, C1180AAX
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Caba, Buenos Aires, Argentina, C1425AUA
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Florencio Varela, Buenos Aires, Argentina, B2705XAE
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Florida, Buenos Aires, Argentina, B1602DQD
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Lanus, Buenos Aires, Argentina, B8000XAV
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Mar del Plata, Buenos Aires, Argentina, B7600FZN
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Quilmes, Buenos Aires, Argentina, B1878FNR
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San Isidro, Buenos Aires, Argentina, B1642DCD
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Vicente Lopez, Buenos Aires, Argentina, B1638AAI
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Concepcion del Uruguay, Entre Rios, Argentina, E3260EPD
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Santa Fe, Rosario, Argentina, S2000DBS
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Rosario, Santa Fe, Argentina, S2000AII
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Rosario, Santa Fe, Argentina, S2000CXH
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San Miguel de Tucuman, Tucuman, Argentina, 4000
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Buenos Aires, Argentina, 1425
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Corrientes, Argentina, W3400
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Mendoza, Argentina, 5500
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Mendoza, Argentina, M5500CBA
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Salta, Argentina, 4000
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Bogota, Cundinamarca, Colombia
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Armenia, Colombia
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Barranquilla, Colombia
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Bogota, Colombia
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Osijek, Croatia, 31000
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Sisak, Croatia, 44000
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Zagreb, Croatia, 10 000
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Zagreb, Croatia, 10000
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Tallinn, Estonia, 13419
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Tartu, Estonia, 51014
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Budapest, HUN, Hungary, 1204
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Debrecen, Hungary, 4032
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Erd, Hungary, H-2030
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Godollo, Hungary, 2100
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Monor, Hungary, 2200
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Mosonmagyarovar, Hungary, 9200
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Siofok, Hungary, 8600
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Szarvas, Hungary, 5540
India
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Hyderabad, A.p., India, 500 001
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Hyderabad, Andhra Pradesh, India, 500004
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Panjim, Goa, India, 403 002
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Bangalore, Karnataka, India, 560002
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Mysore, Karnataka, India, 570004
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Trivandrum, Kerala, India, 695 011
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Bikaner, Rajasthan, India, 334 001
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Bucheon-Si, Gyeonggi-Do, Korea, Republic of, 14584
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Seoul, Korea, Korea, Republic of, 130-709
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Daegu, Korea, Republic of, 705-703
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Incheon, Korea, Republic of, 403-720
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Seoul, Korea, Republic of, 156-755
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Daugavpils, Latvia, LV-5401
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Riga, Latvia, 1002
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Riga, Latvia, LV-1038
Mexico
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Mexico, Distrito Federal, Mexico, 06726
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Mexico, Distrito Federal, Mexico, 14050
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León, Guanajuato, Mexico, 37000
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Panama City, Panamá, Panama, 0834-00363
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Bialystok, Poland, 15-044
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Katowice, Poland, 40-752
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Lodz, Poland, 90-153
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Russian Federation
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Moscow, Russian Federation, 115280
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Moscow, Russian Federation, 125315
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N.Novgorod, Russian Federation, 603126
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Nizhny Novgorod, Russian Federation, 603018
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Ryazan, Russian Federation, 390026
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Saratov, Russian Federation, 410012
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St-Petersburg, Russian Federation, 193312
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St. Petersburg, Russian Federation, 194354
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St.-Petersburg, Russian Federation, 193231
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Yaroslavl, Russian Federation, 150003
Serbia
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Knez Selo, Serbia, 18204
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Kragujevac, Serbia, 34000
Slovenia
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Golnik, Slovenia, 4204
Turkey
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Kartal, Turkey, 34890
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Kocaeli, Turkey, 41380
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Mersin, Turkey, 33079
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Pendik / Istanbul, Turkey, 1330
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Yenisehir/Izmir, Turkey, 35110
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Leamington Spa, Warwickshire, United Kingdom, CV32 4RA
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Birmingham, United Kingdom, B15 2WB
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Portsmouth, United Kingdom, PO6 3AD
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Wolverhampton, United Kingdom, WV10 0QP
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01610037     History of Changes
Other Study ID Numbers: CQVA149A2339  2012-002057-38 
Study First Received: May 30, 2012
Results First Received: February 1, 2016
Last Updated: May 9, 2016
Health Authority: Argentina: Administracion Nacional de Alimentos, Medicamentos y Tecnologia Medica (ANMAT)
Croatia: Ministry of Health
Dominican Republic: Consejo Nacional de Bioetica en Salud (CONABIOS)
Estonia: State Agency of Medicine
Hungary: Directorate General of National Institute of Pharmacy/ National Institute for Quality and Organisational Development in Healthcare and Medicines
India: Drugs Controller General of India
Ireland: Irish Medicines Board (IMB)
Israel: Israeli Ministry of Health
South Korea: Korea Food and Drug Administration (KFDA)
Latvia: State Agency of Medicines of Latvia
Mexico: Ministry of Health
Panama: Comite Nacional de Bioetica de la Investigacion con sede en Instituto Conmemorativo Gorgas de Estudios de la Salud (Ministry of Health)
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Serbia: Medicines and Medical Devices Agency of Serbia
Slovenia: Public Agency of the Republic of Slovenia for Medicinal Products and Medical Devices
Turkey: Ministry of Health - Turkish Medicines and Medical Devices Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Venezuela: Instituto Nacional de Higiene Rafael Rangel

Keywords provided by Novartis:
chronic obstructive pulmonary disease
COPD
QVA149
QAB149
NVA237
Indacaterol maleate
Glycopyronnium bromide

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Tiotropium Bromide
Glycopyrrolate
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Muscarinic Antagonists

ClinicalTrials.gov processed this record on August 23, 2016