Clinical Trial Results:
A randomized, multicenter, open-label, cross-over study to assess lung function and patient preference after a 4 week treatment each with QVA149 vs. tiotropium in patients with stable chronic obstructive pulmonary disease (COPD) and moderate to severe airflow limitation who are on a tiotropium therapy (FAVOR study). Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

Trial information Top of page
Trial identification
Sponsor protocol code	CQVA149ADE04
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02125734
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Novartis Pharma AG
Sponsor organisation address	CH-4002, Basel, Switzerland,
Public contact	Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Scientific contact	Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	12 Jan 2015
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	12 Jan 2015
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To demonstrate superiority of QVA149 (100/50 μg o.d.) as compared to tiotropium (18 μg o.d.) in terms of FEV1 1 h post-inhalation after 4 weeks of treatment in patients with stable COPD and moderate to severe airflow limitation still having symptoms (COPD Assessment Test [CAT] score of at least 10) despite treatment with tiotropium.
Protection of trial subjects	The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	24 Apr 2014
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Germany: 88
Worldwide total number of subjects	88
EEA total number of subjects	88
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	49
From 65 to 84 years	38
85 years and over	1

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	-
Pre-assignment
Screening details	119 patients were screened for study participation, 88 were randomized and all of them were exposed to treatment. 43 patients (43/88, 48.9%) were randomized into the QVA149, then tiotropium group (further referred to as QVA-Tio) and 45 patients (45/88, 51.1%) were randomized into the tiotropium, then QVA149 group (further referred to as Tio- QVA)
Period 1
Period 1 title	Overall Study (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Treatment sequence 1
Arm description	QVA149 from day 1 to day 28 and tiotropium from day 29 to day 56
Arm type	Experimental
Investigational medicinal product name	QVA149 from day 1 to day 28 and tiotropium from day 29 to day 56
Investigational medicinal product code	QVA149
Other name
Pharmaceutical forms	Capsule
Routes of administration	Inhalation use
Dosage and administration details	QVA149 capsules 110/50 µg for inhalation
Arm title	Treatment sequence 2
Arm description	Tiotropium from day 1 to day 28 and QVA149 from day 29 to day 56
Arm type	Experimental
Investigational medicinal product name	Tiotropium from day 1 to day 28 and QVA149 from day 29 to day 56
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule
Routes of administration	Inhalation use
Dosage and administration details	Tiotropium 18 µg capsules for inhalation via HandiHaler
Number of subjects in period 1 Treatment sequence 1 Treatment sequence 2 Started 40 48 Completed 40 47 Not completed 0 1      Adverse event, non-fatal - 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Treatment sequence 1
Reporting group description	QVA149 from day 1 to day 28 and tiotropium from day 29 to day 56
Reporting group title	Treatment sequence 2
Reporting group description	Tiotropium from day 1 to day 28 and QVA149 from day 29 to day 56
Reporting group values Treatment sequence 1 Treatment sequence 2 Total Number of subjects 40 48 88 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 23 26 49     From 65-84 years 16 22 38     85 years and over 1 0 1 Age Continuous | Units: Years     arithmetic mean (standard deviation) 63.9 ± 9.83 66 ± 9.31 - Gender, Male/Female Units: Participants     Female 15 16 31     Male 25 32 57

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Treatment sequence 1
Reporting group description	QVA149 from day 1 to day 28 and tiotropium from day 29 to day 56
Reporting group title	Treatment sequence 2
Reporting group description	Tiotropium from day 1 to day 28 and QVA149 from day 29 to day 56
Subject analysis set title	QVA149
Subject analysis set type	Full analysis
Subject analysis set description	All randomized patients who applied at least one dose of study medication during at least one study period
Subject analysis set title	Tiotropium
Subject analysis set type	Full analysis
Subject analysis set description	All randomized patients who applied at least one dose of study medication during at least one study period
Subject analysis set title	QVA149
Subject analysis set type	Full analysis
Subject analysis set description	All randomized patients who applied at least one dose of study medication during at least one study period
Subject analysis set title	Tiotropium
Subject analysis set type	Full analysis
Subject analysis set description	All randomized patients who applied at least one dose of study medication during at least one study period
Subject analysis set title	Tiotropium
Subject analysis set type	Full analysis
Subject analysis set description	All randomized patients who applied at least one dose of study medication during at least one study period

End points Top of page

Primary: Forced Expiratory Volume in one second (FEV1) at 1 h post-inhalation Top of page
End point title	Forced Expiratory Volume in one second (FEV1) at 1 h post-inhalation
End point description	Forced Expiratory Volume in one second (FEV1) will be calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
End point type	Primary
End point timeframe	week 4
End point values QVA149 Tiotropium Number of subjects analysed 87 88 Units: Liters     least squares mean (confidence interval 95%) 1.676 (1.635 to 1.716) 1.595 (1.555 to 1.634)
Statistical analysis title	Comparision of FEV1 between QVA149 and Tiotropium
Comparison groups	QVA149 v Tiotropium
Number of subjects included in analysis	175
Analysis specification	Pre-specified
Analysis type
P-value	= 0.0017
Method	ANCOVA
Parameter type	Mean difference (net)
Point estimate	0.081
Confidence interval
level	95%
sides	2-sided
lower limit	0.031
upper limit	0.13

Primary: Forced Expiratory Volume in one second (FEV1) at 1 h post-inhalation Top of page

Secondary: Patient preference after experiencing both treatments was assessed at the end of treatment period 2 with a Patient Preference Questionnaire. Top of page
End point title	Patient preference after experiencing both treatments was assessed at the end of treatment period 2 with a Patient Preference Questionnaire.
End point description	Patient preference after experiencing both treatments. The patient’s preference questionnaire was a two-choice question (preference for QVA149 OR Tiotropium.
End point type	Secondary
End point timeframe	8 weeks
End point values QVA149 Tiotropium Number of subjects analysed 85 85 Units: Participants 59 26
No statistical analyses for this end point

Secondary: Patient preference after experiencing both treatments was assessed at the end of treatment period 2 with a Patient Preference Questionnaire. Top of page

Secondary: Investigator preference per patient after experiencing both treatments for future suggestions. Top of page
End point title	Investigator preference per patient after experiencing both treatments for future suggestions.
End point description	The investigator preference for future treatment suggestion after experiencing both treatments was assessed at the end of treatment period 2 with the Investigator Preference Questionnaire
End point type	Secondary
End point timeframe	8 weeks
End point values QVA149 Tiotropium Number of subjects analysed 87 87 Units: Participants 71 16
No statistical analyses for this end point

Secondary: Investigator preference per patient after experiencing both treatments for future suggestions. Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Timeframe for AE
Adverse event reporting additional description	AE additional description
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	17.1
Reporting groups
Reporting group title	QVA149
Reporting group description	QVA149
Reporting group title	Tiotropium
Reporting group description	Tiotropium
Serious adverse events QVA149 Tiotropium Total subjects affected by serious adverse events      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0 Injury, poisoning and procedural complications Contusion      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Eye injury      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 1%
Non-serious adverse events QVA149 Tiotropium Total subjects affected by non serious adverse events      subjects affected / exposed 28 / 88 (31.82%) 21 / 88 (23.86%) Vascular disorders Hypertension      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 General disorders and administration site conditions Peripheral swelling      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Cough      subjects affected / exposed 12 / 88 (13.64%) 4 / 88 (4.55%)      occurrences all number 15 4 Dysphonia      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Dyspnoea      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 2 Increased viscosity of bronchial secretion      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Nasal congestion      subjects affected / exposed 0 / 88 (0.00%) 2 / 88 (2.27%)      occurrences all number 0 3 Nasal discomfort      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Oropharyngeal pain      subjects affected / exposed 3 / 88 (3.41%) 0 / 88 (0.00%)      occurrences all number 3 0 Rhinorrhoea      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Productive cough      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Throat irritation      subjects affected / exposed 2 / 88 (2.27%) 0 / 88 (0.00%)      occurrences all number 2 0 Upper-airway cough syndrome      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Investigations Alanine aminotransferase increased      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Aspartate aminotransferase increased      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Blood lactate dehydrogenase increased      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Escherichia test positive      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Gamma-glutamyltransferase increased      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Injury, poisoning and procedural complications Laceration      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Wound      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Cardiac disorders Cardiovascular disorder      subjects affected / exposed 2 / 88 (2.27%) 0 / 88 (0.00%)      occurrences all number 4 0 Arrhythmia      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Palpitations      subjects affected / exposed 1 / 88 (1.14%) 1 / 88 (1.14%)      occurrences all number 1 1 Nervous system disorders Dizziness      subjects affected / exposed 2 / 88 (2.27%) 0 / 88 (0.00%)      occurrences all number 2 0 Headache      subjects affected / exposed 4 / 88 (4.55%) 2 / 88 (2.27%)      occurrences all number 5 3 Hypotonia      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Nerve compression      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Ear and labyrinth disorders Vertigo      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Gastrointestinal disorders Diarrhoea      subjects affected / exposed 3 / 88 (3.41%) 0 / 88 (0.00%)      occurrences all number 3 0 Abdominal pain upper      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Flatulence      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Nausea      subjects affected / exposed 1 / 88 (1.14%) 1 / 88 (1.14%)      occurrences all number 1 1 Stomatitis      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Skin and subcutaneous tissue disorders Pruritus      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Renal and urinary disorders Renal pain      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Musculoskeletal and connective tissue disorders Arthralgia      subjects affected / exposed 1 / 88 (1.14%) 1 / 88 (1.14%)      occurrences all number 1 1 Pain in extremity      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Muscle spasms      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Infections and infestations Bronchitis      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Nasopharyngitis      subjects affected / exposed 3 / 88 (3.41%) 2 / 88 (2.27%)      occurrences all number 3 2 Herpes zoster      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Rhinitis      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 2 Sinusitis      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Tooth abscess      subjects affected / exposed 1 / 88 (1.14%) 0 / 88 (0.00%)      occurrences all number 1 0 Metabolism and nutrition disorders Fluid retention      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1 Hypertriglyceridaemia      subjects affected / exposed 0 / 88 (0.00%) 1 / 88 (1.14%)      occurrences all number 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
14 May 2014	The protocol was amended to correct the exact time-point when the Physician Preference Questionnaire was supposed to be filled in at Visit 6. Furthermore, minor inconsistencies and corrections were made.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

More information Top of page