Supplementary appendix

Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic
obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149
compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind,
parallel-group study. Lancet Respir Med 2013; published online April 23. http://dx.doi.
org/10.1016/S2213-2600(13)70052-3.
1
Supplementary Appendix
Supplement to: Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of
COPD Exacerbations with the Dual Bronchodilator QVA149 Compared
with Glycopyrronium and Tiotropium (SPARK): a Randomized, Doubleblind, Parallel-group Study.
Contents
Section 1.
Study investigators
Section 2.
Exacerbation adjudication procedure
Section 3.
Patient exclusion criteria
Section 4.
Exacerbation efficacy outcomes
Section 5.
Adjudication of serious CCV adverse events
Section 6.
Statistical methods
Section 7.
Sample size calculations
Section 8.
Countries involved in the studies and numbers of patients enrolled
Section 9.
History of cardiovascular disease and presence of cardiovascular risk factors at
baseline
Section 10.
Baseline characteristics of the patients who opted in and out of continuing in
the study extension period
Section 11.
Analysis of the number of moderate or severe COPD exacerbations per patient
during the study treatment period
Section 12.
Analysis of moderate to severe COPD exacerbations by ICS use
Section 13.
Sensitivity analyses of primary variable
Section 14.
Cox regression analysis of time to first severe COPD exacerbation
Section 15.
(a) Annualized exacerbation rates by severity of exacerbation, and (b)
annualized rates of moderate/severe exacerbations by treatment requirements
Section 16.
Post-hoc sensitivity analysis of the primary efficacy variable
Section 17.
Analysis of odds ratios associated with percentages of patients achieving the
MCID in SGRQ total score
Section 18.
SGRQ component scores
Section 19.
Overall and individual adverse events
Section 20.
Incidences of overall mortality and individual causes of death
Section 21.
Incidence of adjudicated CCV adverse events
2
Section 1
Study investigators
Argentina: Dr. Alberto Tolcachier, Dr. Alicia Rodriguez, Dr. Alvaro Alonso, Dr. Ana Lopez, Dr.
Anahi Yanez, Dr. Andrea Medina, Dr. Angel Piacenza, Dr. Carlos Luna, Dr. Cristian Carminio,
Dr. Eduardo Giugno, Dr. Enrrique Casal, Dr. Fernando Scherbovsky, Dr. Fernando Verra, Dr.
Gabriel Garcia, Dr. Gisela Delgado Vizcarra, Dr. Guillermo Montiel, Dr. Horacio Budani, Dr.
Jorge Rosso, Dr. Juan Belloni, Dr. Juan Carlos Figueroa Casas, Dr. Lucia Marzoratti, Dr. Luis
Nannini, Dr. Luis Larrateguy, Dr. Luis Wehbe, Dr. Luisa Beatriz Rey, Dr. Marcelo Fernandez,
Dr. Maria De Salvo, Dr. Martin Maillo, Dr. Miguel Bergna, Dr. Ramon Alchapar, Dr. Ramon
Rojas, Dr. Ricardo del Olmo, Dr. Ricardo Gene, Dr. Walter Mattarucco, Dr. Xavier Bocca.
Austria: Dr. Josef Wuertz, Dr. Joze Messner, Dr. Othmar Ablinger, Dr. Peter Wuertz, Dr.
Robert Voves.
Canada: Dr. Bonavuth Pek, Dr. Bruno Paradis, Dr. Claude Poirier, Dr. François Blouin, Dr.
Guy Chouinard, Dr. Jean Roy, Dr. Mohit Bhutani, Dr. Ronald Grossman.
Colombia: Dr. Alejandro Echavarria, Dr. Alvaro Urbina, Dr. Carlos Matiz, Dr. Fernando
Londoño, Dr. Guido Cardona, Dr. Jaime Sanchez Vallejo, Dr. Ruben Contreras.
Czech Republic: Dr. Ales Tauchman, Dr. Ivana Bouckova, Dr. Jana Psikalova, Dr. Jaroslav
Mares, Dr. Jiri Zimmer, Dr. Jolana Presperinova, Dr. Josef Fratrik, Dr. Josef Veverka, Dr.
Luba Strouhova, Dr. Marie Buresova, Dr. Martin Hadrava, Dr. Martina Cmakalova, Dr.
Masroor Ali, Dr. Milos Havlik, Dr. Miluse Zitkova, Dr. Petr Kolman, Dr. Stanislav Holub, Dr.
Viktor Kasak.
Denmark: Dr. Carl Nielsen, Dr. Charlotte Suppli Ulrik , Dr. Claus Johnsen, Dr. Niels
Seersholm, Dr. Povl Revsbech, Dr. Vibeke Backer, Dr. Zofia Grzywacz.
Estonia: Dr. Eve Kuulpak, Dr. Mari Meren, Dr. Rain Jogi.
Finland: Dr. Juhani Elo, Dr. Kari Venho, Dr. Pekka Saarelainen.
France: Dr. Bertrand Herer, Dr. Cecil Chenivesse, Dr. Christophe Verkindre, Dr. Houari
Meziane.
Germany: Dr. Anatoli Kaiser, Dr. Andreas Benedix, Dr. Anneliese Linnhoff, Dr. Axel Kroker,
Dr. Christian Gessner, Dr. Claudia Büttner, Dr. Dagmar Eberhard-Forschner, Dr. Frank
Eberhardt, Dr. Frank Feldmeyer, Dr. Franz-Josef Berger, Dr. Grit Lammert-Huenger, Dr.
Harald Mueller-Pawlowski, Dr. Helen Arievich, Dr. Helmuth Leiner, Dr. Hilger Mueller, Dr.
Joachim Kirschner, Dr. Joachim Weimer, Dr. Joerg Reinhardt, Dr. Karin Foerster, Dr. Ludger
Lindemann, Dr. Lutz Volgmann, Dr. Lutz von Versen, Dr. Margit Korduan, Dr. Margret Jandl,
Dr. Markus Hoefer, Dr. Martin Hoster, Dr. Matthias Rolke, Dr. Oliver Kornmann, Dr. Peter
Ring, Dr. Peter van Bodegom, Dr. Peter-Uwe Haase, Dr. Rainer Gebhardt, Dr. Regina
Deckelmann, Dr. Reiner Laumen, Dr. Roland Balzer, Dr. Rudolf Henning, Dr. Sebastian
Sohrab, Dr. Stefan Kehm, Dr. Sven Birkholz, Dr. Thomas Ginko, Dr. Tibor Schmoller, Dr.
Ulrich Botzen, Dr. Ulrike Westerhausen, Dr. Umberto Gehling, Dr. Wassilis Tzimas, Dr.
Wolfgang Schurmann, Dr. Wolfram Zingler, Prof. Dr. Joachim Ficker.
Greece: Assist. Prof. Georgios Tatsis, Dr. Angeliki Rapti, Dr. Asimina Gaga, Dr. Despoina
Papakosta, Dr. Epaminondas Kosmas, Dr. Marianna Kakoura, Dr. Michalis Toumbis, Dr. Niki
Georgatou-Papageorgiou, Dr. Paraskevi Katsaounou, Prof. Konstantinos Gourgoulianis, Prof.
Spyridon Papiris.
Hungary: Dr. Aranka Bánvolgyi, Dr. Beatrix Balint, Dr. Csaba Salamon, Dr. Ildiko Szarka, Dr.
Istvan Varkonyi, Dr. Karoly Fonay, Dr. Katalin Csicsari, Dr. Katalin Rajkai, Dr. Maria
Jedlinszki, Dr. Zsuzsanna Szalai, Prof. Dr. György Losonczy.
India: Dr. Anthony Mesquita, Dr. Jagdish Suri, Dr. Padukudru Mahesh, Dr. Pradyut Waghray,
Dr. Rajendran Nair, Dr. Rajesh Swarnakar, Dr. Sameer Chandratre, Dr. Sandeep Saboo, Dr.
Srikanth Krishnamurthy, Dr. Srinivasan Nagarajan, Dr. Sundeep Salvi, Dr. Vallandramam
PattabhiRaman, Dr. Vijai Ratnavelu, Dr. Virendra Singh.
Ireland: Dr. Liam Cormican, Prof. Stephen Lane.
3
Israel: Dr. David Lieberman, Dr. David Shitrit, Dr. Gershon Fink, Dr. Yehuda Schwarz, Dr.
Zeev Vilayi-Weiler, Prof. Issahar Ben-Dov, Prof. Mordechai Kramer, Prof. Raphael Breuer.
Italy: Dr. Antonio Miadonna, Dr. Marco Bonavia, Dr. Maria Pia Foschino Barbaro, Dr.
Maurizio Dottorini, Dr. Maurizio Feliciani, Dr. Simonetta Monti, Prof. Carlo Mereu, Prof. Isa
Cerveri, Prof. Nunzio Crimi, Prof. Paola Rottoli, Prof. Pierluigi Paggiaro, Prof. Roberto
Duranti.
Mexico: Dr. Alejandro Quesada Sanchez, Dr. Ernestina Ramírez, Dr. Jesus Diaz, Dr. Raúl
Sansores, Dr. Sergio Lopez, Dr. Uriel Chavarria.
Netherlands: Dr. Christian F. Melissant, Dr. David Cheung, Dr. Dirk De Munck, Dr. Henk E.
J. Sinninghe-Damste, Dr. Henk Los, Dr. Henk R. Pasma, Dr. Paul van der Valk, Dr. Peter
M.J.M. de Vries, Dr. Ragmar Lunde, Dr. Stephanus J. Gans, Dr. Theo Bantje, Dr. Willem
Pieters.
Peru: Dr. Alberto Matsuno, Dr. Alfredo Guerreros, Dr. Cesar Villaran, Dr. Danilo Salazar Ono,
Dr. Jose Torres, Dr. Marco Camere, Dr. Socorro Castro.
Philippines: Dr. Aileen S. David-Wang, Dr. Araceli Maliwat, Dr. Dina Diaz, Dr. Edzel
Tamayo, Dr. Joel Santiaguel, Dr. Tito C. Atienza.
Poland: Dr. Grazyna Jasieniak-Pinis, Dr. Izabella Krupa-Borek, Dr. Krystyna Folcik, Dr. Piotr
Nalepa, Dr. Zenon Siergiejko, Prof. Pawel Sliwinski, Prof. Wladyslaw Pierzchala.
Russia: Dr. Elena Gaydar, Dr. Evgenii Shmelev, Prof. Alexander Emelyanov, Prof. Alexander
Komlev, Prof. Alexander Sinopalnikov, Prof. Alexander Zhestkov, Prof. Galina Ignatova, Prof.
Igor Leshchenko, Prof. Irina Ruzhova, Prof. Mikhail Kharitonov, Prof. Mikhail M. Ilkovich, Prof.
Nataliya Shaporova, Prof. Rustem Fassakhov, Prof. Shamil Palutin, Prof. Tatiana
Martynenko, Prof. Vasiliy Trofimov, Prof. Vladimir Abrosimov, Prof. Vladimir Simanenkov.
Slovakia: Dr. Alexander Golubov, Dr. Erika Pribulova, Dr. Helena Horvathova, Dr. Juraj
Mazal, Dr. Luboslava Frajtova, Dr. Maria Pobehova, Dr. Pavol Karako, Dr. Vladimir Kretik, Dr.
Yveta Kubikova, Prof. Dr. Eva Rozborilova.
South Africa: Dr. Boitomelo Sebopa, Dr. Ismail Abdullah, Dr. Tasneem Vally, Prof. Susanna
Visser.
Spain: Dr. Hector Verea, Dr. Jose Luis Velasco, Dr. Luis De Teresa.
UK: Dr. Alaisdair Stewart, Dr. Anoop Chauhan, Dr. Bhavesh Bodalia, Dr. Christine Bucknall,
Dr. David Singh, Dr. Dinesh Saralaya, Dr. Justin Pepperell, Dr. Lee Dowson, Dr. Monica
Nordstrom, Dr. Nicky Simler, Dr. Nicola Stevenson, Dr. Richard Harrison, Dr. Ross Martin ,
Dr. Terek Saba, Prof. Jadwiga Wedzicha.
USA: Dr. Allan Seibert, Dr. Amit Patel, Dr. Anjuli Nayak, Dr. Benjamin Laracuente, Dr. Brian
Kim, Dr. Charles Fogarty, Dr. Charles M. Arena, Dr. David Ostransky, Dr. David Phillips, Dr.
Edward Kerwin, Dr. Edward Lisberg, Dr. Felix Morris, Dr. George Bensch, Dr. Gustavo
Dubois, Dr. Henry Covelli, Dr. James Taylor, Dr. James L. Pearle, Dr. James Meli, Jr., Dr. Jan
Westerman, Dr. Jerome Mirkil, Dr. Joe Ramsdell, Dr. John Burk, Dr. Jose A. Santiago, Jr., Dr.
Joseph Austin, Jr., Dr. Joseph Graif, Dr. Kenneth Chinsky, Dr. Linda Ford, Dr. Manuel
Villareal, Dr. Mark Millard, Dr. Michael Noonan, Dr. Mitchell Lee, Dr. Navdeep Rai, Dr.
Padmashri Rastogi, Dr. Paul Shapero, Dr. Peter Krumpe, Dr. Phillip Korenblat, Dr. Robert
Sussman, Dr. Samir Arora, Dr. Selwyn Spangenthal, Dr. Shari Anne Brazinsky, Dr. Stephen
Basheda, Dr. Stephen Lee, Dr. Thomas Kaelin, Dr. Thomas Lemire, Dr. Thomas Siler, Dr.
William Goetter.
4
Section 2. Exacerbation adjudication procedure
Treatment of a COPD exacerbation was at the discretion of the treating physician, although a
2-week oral course of prednisone (or equivalent), and/or an oral 7-day course of amoxicillin
was recommended.
The start date for a COPD exacerbation was the first day of symptom worsening recorded in
the e-diary. The end of a COPD exacerbation was marked by the return to pre-exacerbation
symptom status. If the start date was less than 7 days after the end of a previous
exacerbation, this was assumed to be one continuous exacerbation.
COPD exacerbations were not recorded as adverse events. Any reported adverse events of
pneumonia that may have occurred with the exacerbation were confirmed by chest X-ray and
the pneumonia recorded as an adverse event.
An independent expert adjudication committee (see below) was established to assess COPD
exacerbations. The committee was not directly involved in the study conduct. The panel of
pulmonologists prospectively reviewed all moderate and severe COPD exacerbations in a
blinded fashion. The panel determined if the exacerbation met the protocol-defined criteria
and was not a case of pneumonia or other unrelated adverse event. The committee
adjudicated on whether the exacerbations were relapses/continuation of previous events. Mild
exacerbations were not adjudicated.
Exacerbation Adjudication Committee (adjudication of moderate and severe exacerbation
events)
Dr Dennis E. Niewoehner
VA Medical Center
Pulmonary Section 111N
Minneapolis, MN 55417, USA
Professor Marc Decramer, MD
Head of Department Pneumology
University Hospital Leuven
Campus Gasthuisberg
Herestraat 49, B-3000 Leuven, Belgium
Thomas Sandström, M.D. PhD
Umeå University
Departmentt of Public Health and Clinical Medicine
SE-901 85 Umeå, Sweden
5
Section 3. Patient exclusion criteria
1. Pregnant women or nursing mothers.
2. Women of child-bearing potential.
3. Patients requiring daily long-term oxygen therapy for chronic hypoxemia.
4. Patients who had a COPD exacerbation that required treatment with antibiotics, systemic
corticosteroids (oral or intravenous) or hospitalization in the 6 weeks prior to Visit 1 (Day −21)
or between Visit 1 (Day −21) and Visit 3 (Day 1).
5. Patients who developed a COPD exacerbation during a period between Visit 1 (Day −21)
and 3 (Day 1) were ineligible but were permitted to be re-screened after a minimum of 6
weeks after the resolution of the COPD exacerbation.
6. Patients who had a respiratory tract infection within 4 weeks prior to Visit 1 (Day −21).
Patients who developed an upper or lower respiratory tract infection during the screening
period (up to Visit 3 [Day 1]) were not eligible, but were permitted to be re-screened 4 weeks
after the resolution of the respiratory tract infection.
7. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless
confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis,
sarcoidosis, interstitial lung disorder or pulmonary hypertension.
8. Patients with lung lobectomy, or lung volume reduction or lung transplantation.
9. Patients who, in the judgment of the investigator, have a clinically relevant laboratory
abnormality or a clinically significant condition such as (but not limited to):






unstable ischemic heart disease, left ventricular failure, history of myocardial infarction,
arrhythmia (excluding chronic stable atrial fibrillation). Patients with such events not
considered clinically significant by the investigator may be considered for inclusion in the
study
history of malignancy of any organ system (including lung cancer), treated or untreated,
within the past 5 years whether or not there is evidence of local recurrence or
metastases, with the exception of localized basal cell carcinoma of the skin
uncontrolled hypo- or hyperthyroidism, hypokalemia or hyperadrenergic state
narrow-angle glaucoma
symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe
renal impairment or urinary retention
any condition which might have compromised patient safety or compliance, interfered
with evaluation, or precluded completion of the study.
10. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil
3
count > 600/mm (at Visit 2 [Day −14]), or onset of symptoms prior to 40 years. Patients
without asthma were excluded if their eosinophil count was >600/mm1 at Visit 2 (Day −14).
11. Patients with allergic rhinitis who used H1-antagonists or intranasal corticosteroids
intermittently (treatment with a constant dose was permitted).
12. Patients with eczema (atopic), known high IgE levels or a known positive skin prick test in
the last 5 years.
13. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.
14. Patients who were participating in the active phase of a supervised pulmonary
rehabilitation program.
15. Patients with Type I or uncontrolled Type II diabetes.
16. Patients contraindicated for treatment with, or having a history of
reactions/hypersensitivity to any of the following inhaled drugs or drugs of a similar class or
any component thereof: anticholinergic agents; long and short acting β2-agonists; or
sympathomimetic amines.
6
17. Patients with a history of long QT syndrome or whose QTc interval measured at Visit 2
(Day −14) (Fridericia’s method) was prolonged (>450 ms for males and females), as
confirmed by the central ECG assessor.
18. Patients with a clinically significant abnormality on the screening or baseline ECG who in
the judgment of the investigator would be at potential risk if enrolled into the study. (These
patients could not be re-screened.)
19. Patients who needed treatments for COPD and allied conditions after the start of the
study.
20. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis)
unless they had been stabilized.
21. Patients taking other prohibited medications.
22. Patients unable to use a dry powder inhaler (e.g. single-dose dry powder inhaler (SDDPI),
HandiHaler® device, or pressurized MDI (rescue medication).
23. Patients unable to use an electronic patient diary.
24. Patients who were, in the opinion of the investigator, known to be unreliable or
noncompliant.
25. Patients who used other investigational drugs at the time of enrollment, or within 30 days
or five half-lives of Visit 1 (Day −21), whichever was longer.
26. Patients who had live attenuated vaccination within 30 days prior to the screening visit or
during the run-in period. Inactivated influenza vaccination, pneumococcal vaccination or any
other inactivated vaccine was acceptable provided it was not administered within 48 h prior to
screening and randomization visits.
7
Section 4. Exacerbation efficacy outcomes













Rate of moderate or severe COPD exacerbations during the treatment period.
Time to first moderate or severe COPD exacerbation.
Rate of COPD exacerbations requiring systemic corticosteroids only, antibiotics only, or
both systemic glucocorticoids and antibiotics.
Proportion of patients with at least one severe COPD exacerbation that required
hospitalizations.
Time to first severe COPD exacerbation that required hospitalization.
Rate of moderate COPD exacerbations.
Rate of all COPD exacerbations (mild, moderate or severe).
Proportion of patients with at least one moderate or severe COPD exacerbation.
Proportion of the number of days with moderate or severe COPD exacerbations.
Proportion of the number of days on systemic corticosteroids for COPD exacerbation, the
proportion of the number of days on antibiotics treatment for COPD exacerbation and the
proportion of the number of days on both systemic corticosteroids and antibiotics
treatment COPD exacerbation.
Subgroup analyses for the rate of moderate or severe COPD exacerbation and the time
to first moderate or severe COPD exacerbation:
− with and without ICS use
− smoking status at baseline (current/ex-smoker)
− gender
− age category (<65, 65 to <75 and ≥75 years)
− race (Caucasian, Asian, and others)
− severity of airflow limitation (severe or very severe)
− body mass index (>30 and ≤30).
Subgroup analyses for the rate of moderate or severe COPD exacerbation only:
− region (North America, South America, Western Europe, Eastern Europe and Asia)
− reversibility at screening (≤5%, >5% and ≤12%, >12%)
− history of exacerbation (<2 , ≥2 in the previous year)
− completers and non-completers
− North and South Hemisphere (Austria, Canada, Czech Republic, Germany, Denmark,
Spain, Estonia, Finland, France, Great Britain, Greece, Hungary, India, Ireland, Israel,
Italy, Mexico, Netherlands, Philippines, Poland, Russia, Slovakia and the USA were
considered to be Northern hemisphere, and Argentina, Columbia, Peru and South
Africa to be Southern hemisphere)
− winter season and summer season.
Subgroup analyses for rates of moderate or severe COPD exacerbations that required
treatment with systemic corticosteroids only, with antibiotic only, and with both systemic
corticosteroids and antibiotics:
− with and without ICS use
− COPD severity (severe or very severe).
8
Section 5. Adjudication of serious CCV adverse events
An independent expert adjudication committee (see below) was established to assess
mortality and cardio- and cerebrovascular (CCV) safety. The committee was not directly
involved in the study conduct. The mortality and CCV safety committee reviewed the cause of
every death and the major adverse cardiovascular event (MACE) classification of reported
serious CCV adverse events. Serious CCV events were identified by Medical Dictionary for
Regulatory Activities (MedDRA) search terms and each event was assessed against the
MACE criteria: non-fatal myocardial infarction; hospitalization for unstable angina; non-fatal
stroke; heart failure requiring hospitalization; or coronary revascularization. All reported cases
of atrial fibrillation or flutter (including adverse event reporting and ECG reports) were also
adjudicated.
Clinical Endpoint Center (adjudication of cerebral, cardiovascular, atrial fibrillation and
mortality endpoints)
Scott Solomon, MD (Chair)
Eldrin Foster Lewis, MD (Co-Chair)
Peter V. Finn, MD (Physician Reviewer)
Ebrahim Barkoudah, MD (Physician Reviewer)
Chau M Duong, BS MT (Operational Director)
Brigham and Women’s Hospital
Clinical Endpoints Center
75 Francis Street
Boston, MA 02115, USA.
9
Section 6. Statistical methods
The data were analyzed by Novartis Integrated Information Sciences (IIS) associates. This
negative binomial model used for analysis of exacerbation rates accounts for most
overdispersion that may result from assuming a Poisson distribution.3 For subgroup analyses,
treatment by subgroup interaction terms were added to the model.
The estimated ratios of exacerbation rates in the treatment groups are presented with twosided 95% confidence intervals (CI). For superiority, the CI should not include 1.0 and the
ratio estimate should be less than 1.0.
The negative binomial model includes the length of time the patient was in the study as an
offset variable, which automatically accounts for patients who discontinued prematurely, the
primary analysis was done without imputation. Patients who discontinued early were followed
until the end of the 64-week study treatment period to collect adverse events, including COPD
exacerbations. For all patients, moderate or severe COPD exacerbations occurring within 14
days of the last treatment were added to the number of adjudicated COPD exacerbations.
Trough FEV1 (average of the 45 and 15 minutes pre-dose measurements) are presented as
least squares means and estimated treatment differences with associated 95% CI and pvalues for treatment differences. For FEV1 and SGRQ score, missing values were imputed by
carrying forward the last observation but not by more than 11 and 14 weeks, respectively. The
primary period for assessment of non-exacerbation-related outcomes was 64 weeks. No
adjustment for multiplicity was made beyond the primary and key secondary variables.
To maintain the overall type-I error rate at the 5% level, the primary efficacy variable was
analyzed using a two-sided superiority test at the type I error rate of 5%. If significant, the key
secondary variable was to be analyzed using a two-sided superiority test at α=0·05. Other
variables were not adjusted for multiplicity.
Section 7. Sample size calculations
In a blinded interim data review of a similar study, a rate of 0·66 exacerbations per year was
observed in the overall treatment groups and, after seasonal variability was taken into
account, a rate of 0·6 exacerbations per year was assumed in the glycopyrronium arm. Based
on clinical considerations and observations in the OPTIMAL study,2 a 20% reduction in the
rate of COPD exacerbations was assumed to be the treatment effect, and as a result a rate of
0·48 exacerbations per year was assumed for QVA149.
A dispersion parameter had to be estimated for the sample size calculations. In the TRISTAN
study4 the dispersion parameter was estimated as 0·46 with 95% confidence interval of 0·34,
0·60. An enriched subpopulation (defined as patients with at least one COPD exacerbation in
the previous year) from indacaterol studies of 52 weeks3 and 6 months4 showed a dispersion
parameter estimate of 0·329 with 95% confidence intervals of 0·098, 1·11, whereas in the
overall population of these two studies, which included moderate to severe patients, the
dispersion parameter was estimated to be 1·10 with 95% confidence intervals 0·913, 1·33.
Furthermore, enriched and severe subpopulations in these two studies showed a dispersion
parameter estimate of 0·221 with 95% confidence intervals 0·037, 1·33. The patient
population of the SPARK study was composed of enriched and severe-to-very severe
patients only. Therefore, taking into account the uncertainties surrounding the estimate from
enriched and severe subpopulations of the two indacaterol studies, a dispersion parameter
estimate of 0·625 was assumed in the sample size calculations of the present study. The
exacerbation rate for the open-label tiotropium arm was assumed to be similar with
glycopyrronium.
In two 52-week indacaterol studies3,5 the loss of information due to dropout was around 13%.
Loss of information was defined as the per cent of total of exposure treatment days reduced
from the total exposure due to dropouts relative to the planned total exposure. To account for
possible loss of information, the number of patient-years was increased by 15%. Using all the
assumptions described above and using a 5% significance level (two-sided), the total number
of patient-years was calculated in the three treatment groups as shown below.
10
Power Estimates for the Primary Variable:
Average Exposure
(months)
Number of
Patients
Total Exposure in
Patient-Years
Adjusted for 15% Loss of
Information
Power
15
2198
2748
2335
80%
16
2198
2931
2491
82%
17
2198
3112
2647
84%
18
2198
3297
2802
87%
Assuming an average exposure treatment per patient of approximately 17 months, a total of
2,198 patients randomized to the three treatment arms would give a power of 84%.
11
Section 8. Countries involved in the studies and numbers of patients enrolled
Country (number of patients screened/number of patients randomized): Argentina (447/302);
Austria (61/45); Canada (54/28); Columbia (123/55); Czech Republic (230/166); Denmark
(60/31); Estonia (47/26); Finland (33/16); France (17/8); Germany (376/243); Great Britain
(149/52); Greece (72/49); Hungary (174/131); India (258/147); Ireland (28/7); Israel (194/117);
Italy (73/30); Mexico (79/39); Netherlands (108/65); Peru (52/31); Philippines 189/106);
Poland (91/50); Puerto Rico (4/0); Russian Federation (215/145); Slovakia (103/83); South
Africa (54/22); Spain (16/7); USA (558/223).
12
Section 9. History of cardiovascular disease and presence of cardiovascular risk
factors at baseline
QVA149
N=729
Glycopyrronium
N=740
Tiotropium
N=737
Myocardial Infarction
35 (4·8)
27 (3·6)
32 (4·3)
Stroke
17 (2·3)
23 (3·1)
22 (3·0)
Peripheral arterial disease
22 (3·0)
41 (5·5)
29 (3·9)
Coronary artery bypass graft
10 (1·4)
4 (0·5)
6 (0·8)
Percutaneous coronary revascularization
15 (2·1)
12 (1·6)
11 (1·5)
History of cardiovascular disease
10 (1·4)
13 (1·8)
10 (1·4)
Hypertension
Peripheral arterial revascularization
337 (46·2)
352 (47·6)
353 (47·9)
Hyperlipidemia
187 (25·7)
184 (24·9)
193 (26·2)
68 (9·3)
76 (10·3)
68 (9·2)
Type 1
0
0
0
Type 2
68 (9·3)
76 (10·3)
68 (9·2)
Diabetes mellitus
Number of cardiovascular risk factors
0
92 (12·6)
84 (11·4)
78 (10·6)
1
232 (31·8)
225 (30·4)
222 (30·1)
2
186 (25·5)
202 (27·3)
219 (29·7)
3
136 (18·7)
138 (18·6)
114 (15·5)
≥4
83 (11·4)
91 (12·3)
104 (14·1)
Data are n (%).
Cardiovascular risk factors are: age ≥65 years, current smoker at baseline, history of cardiocerebrovascular disease (at least one of those listed under history of cardiovascular
disease), hypertension, hyperlipidemia, diabetes mellitus, and body mass index >30 kg/m2
at baseline.
13
Section 10. Baseline characteristics of the patients who opted in and out of continuing
in the study extension period
Age (years)
Male, %
Continuers
N=1030
Non-continuers
N=1176
63·1 (7·80)
63·5 (8·08)
76·1
73·7
79·4/15·6/0·7/4·3
84·5/8·4/0·8/6·3
Race, %
Caucasian/Asian/Black/other
Severity of airflow limitation, %
Severe (GOLD 3)*/very severe (GOLD 4)
Duration of COPD (years)
81·2/18·8
77·3/22·7
7·1 (5·56)
7·2 (5·48)
1·7/79·4/18·8
1·2/73·4/25·4
Number of COPD exacerbations in
previous year, %
0/1/≥2
ICS use at baseline, %
75·5
75·2
Ex-/current smoker, %
63·0/37·0
61·8/38·2
Estimated pack-years
45 (25·4)
45 (23·6)
Pre-bronchodilator FEV1 (L)
0·91 (0·299)
0·90 (0·296)
Post-bronchodilator FEV1 (L)
1·05 (0·296)
1·03 (0·298)
Post-bronchodilator FEV1 (% predicted)
37·6 (7·93)
36·9 (8·22)
Pre-/post-bronchodilator FEV1 reversibility (%)
18·9 (19·45)
17·8 (19·25)
FEV1/FVC (%) post-bronchodilator
39·5 (9·44)
39·1 (9·47)
*Includes one patient in each group with moderate (GOLD 2) airflow limitation.
14
Section 11. Analysis of the number of moderate or severe COPD exacerbations per
patient during the study treatment period
n (%)
QVA149
N=729
Glycopyrronium
N=739
Tiotropium
N=737
None
310 (42·5)
313 (42·4)
335 (45·5)
1
202 (27·7)
192 (26·0)
186 (25·2)
2
120 (16·5)
108 (14·6)
88 (11·9)
3
53 (7·3)
61 (8·3)
55 (7·5)
4
44 (6·0)
65 (8·8)
73 (9·9)
1·11 (1·345)
1.22 (1·483)
1·22 (1·659)
1 (0–8)
1 (0–9)
1 (0–11)
Mean (SD)
Median (range)
Total number of exacerbations
Total number of treatment-years
Rate of exacerbations per year
812
900
898
866·93
840·98
848·78
0·94
1·07
1·06
Model-based estimated rate (95%
CI)
0·84 (0·75, 0·94)
0·95 (0·85, 1·06)
0·93 (0·83, 1·04)
Treatment comparisons
QVA149 vs
glycopyrronium
QVA149 vs tiotropium
Glycopyrronium vs
tiotropium
Ratio of rates (95% CI)
0·88 (0·77, 0·99)*
0·90 (0·79, 1·02)
1·03 (0·91, 1·16)
0·038
0·096
0·68
p value
Ratio of rates <1 favors the treatment group in the numerator of the ratio.
15
Section 12. Analysis of moderate to severe COPD exacerbations by ICS use
No ICS use
ICS use
Treatment
Annualized Rate
(95% CI)
Comparison
Rate
Ratio 95% CI
p value
QVA149 (n=183)
0.77 (0.63, 0.95)
QVA149 vs
glycopyrronium
1.04
(0·78, 1.38)
0·81
QVA149 vs
tiotropium
0·99
(0·75, 1.30)
0·93
Glycopyrronium vs
tiotropium
0·95 (0·72,
1·27)
0·74
QVA149 vs
glycopyrronium
0·84 (0·73,
0·97)
0·015
QVA149 vs
tiotropium
0·88 (0·76,
1·01)
0·067
Glycopyrronium vs
tiotropium
1·04 (0·91,
1·20)
0·55
Glycopyrronium
(n=183)
0.75 (0.60, 0.93)
Tiotropium
(n=178)
0.78 (0.64, 0.96)
QVA149 (n=546)
0·96 (0·86, 1.08)
Glycopyrronium
(n=556)
1.14 (1.03, 1.28)
Tiotropium
(n=559)
1.10 (0·98, 1·23)
16
Section 13. Sensitivity analyses of primary variable
(a) Analysis of rate of moderate or severe COPD exacerbations over the treatment period
(adjudicated events) (full analysis set)
Treatment
QVA149 (N=736)
Annualized Rate
(95% CI)
Comparison
Rate Ratio
(95% CI)
p-value
0·83 (0·738, 0·927)
QVA149 vs
glycopyrronium
0·87 (0·769,
0·988)
0·031
QVA149 vs tiotropium
0·90 (0·791,
1·016)
0·086
Glycopyrronium vs
tiotropium
1·03 (0·909,
1·162)
0·66
Glycopyrronium
(N=739)
0·95 (0·850, 1·060)
Tiotropium (N=739)
0·92 (0·827, 1·031)
All analyses in this section used a negative binomial regression model: log (exacerbation rate)
= treatment + smoking status + baseline ICS use (yes/no) + baseline total symptom score +
history of moderate or severe COPD exacerbations + FEV1 reversibility components +
country.
(b) Analysis of rate of moderate or severe COPD exacerbations over the treatment period
(adjudicated events), with imputation (modified full analysis set)
Treatment
Annualized Rate
Comparison
(95% CI)
QVA149 (N=729)
0·86 (0·763, 0·959)
Glycopyrronium
(N=739)
0·97 (0·870, 1·085)
Tiotropium (N=737)
0·94 (0·843, 1·051)
Rate Ratio
p-value
(95% CI)
QVA149 vs
glycopyrronium
0·88 (0·777,
0·998)
0·047
QVA149 vs tiotropium
0·91 (0·802,
1·030)
0·14
Glycopyrronium vs
tiotropium
1·03 (0·913,
1·167)
0·62
For prematurely discontinued patients the number of moderate or severe COPD
exacerbations was increased by the number of events that occurred within 14 days after the
last dose.
(c) Analysis of rate of moderate or severe COPD exacerbations over the treatment period
(adjudicated events) (per-protocol set)
Treatment
QVA149 (N=666)
Annualized Rate
(95% CI)
Comparison
Rate Ratio
(95% CI)
p-value
0·88 (0·781, 0·988)
QVA149 vs
glycopyrronium
0·89 (0·785,
1·014)
0·080
QVA149 vs tiotropium
0·91 (0·798,
1·030)
0·13
Glycopyrronium vs
tiotropium
1·02 (0·896,
1·151)
0·81
Glycopyrronium
(N=687)
0·98 (0·878, 1·103)
Tiotropium (N=685)
0·97 (0·866, 1·084)
17
Section 14. Cox regression analysis of time to first severe COPD exacerbation
Treatment
QVA149 (N=729)
Glycopyrronium
(n=739)
Tiotropium (n=737)
Number of patients
with severe
exacerbation
95
108
Comparison
Hazard
Ratio (95% CI)
p-value
QVA149 vs
glycopyrronium
QVA149 vs
tiotropium
Glycopyrronium vs
tiotropium
0·79
(0·60, 1·05)
1·13
(0·83, 1·53)
1·43 (1·07, 1·92)
0·10
0·43
0·017
81
Cox regression model: log (hazard ratio) = treatment + smoking status + baseline ICS use +
baselines total symptom score + history of COPD exacerbations + FEV1 reversibility
components and country. Hazard ratio of <1 favors the treatment group in the numerator
ratio.
18
Section 15. (a) Annualized exacerbation rates by severity of exacerbation, and (b)
annualized rates of moderate/severe exacerbations by treatment requirements
19
Section 16. Post-hoc sensitivity analysis of the primary efficacy variable
(a) Annualized event rate
Treatment group
The first hypothesis generating
sensitivity analysis
QVA
NVA
Tio
1.13
1.23
1.23
The 2nd hypothesis
generating sensitivity
analysis
0.79
0.91
0.88
(b) Rate ratio, 95% C.I and p value
Treatment group
The first hypothesis generating
sensitivity analysis
The 2nd hypothesis generating
sensitivity analysis
Rate ratio
95% C.I.
p-value
Rate ratio
95% C.I.
QVA vs NVA
0.92
(0.93, 1.01)
0.082
0.87
(0.77, 0.99)
0.033
QVA vs Tio
0.92
(0.84, 1.01)
0.100
0.90
(0.79, 1.02)
0.092
NVA vs Tio
1.00
(0.91, 1.10)
0.921
1.03
(0.91, 1.17)
0.646
p-value
20
Section 17. Analysis of odds ratios associated with percentages of patients achieving
the MCID in SGRQ total score.
Analysis of the proportion of patients with clinically important improvement in the SGRQ total
score (≥4 unit change from baseline). Data are odds ratios (95% confidence intervals).
QVA149 vs glycopyrronium
QVA149 vs tiotropium
Glycopyrronium vs tiotropium
Odds ratios
(95% CIs)
p value
Odds ratios
(95% CIs)
p value
Odds ratios
(95% CIs)
p value
Week 12
1·39
(1·10, 1·74)
0·0053
1·45
(1·15, 1·82)
0·0016
1·04
(0·83, 1·31)
0·71
Week 26
1·30
(1·03, 1·64)
0·026
1·28 (1·01,
1·62)
0·040
0·98 (0·78, 1·24)
0·88
Week 38
1·45
(1·15, 1·85)
0·0022
1·39 (1·09,
1·76)
0·0074
0·95 (0·75, 1·21)
0·69
Week 52
1·62
(1·27, 2·08)
0·00013
1·48 (1·16,
1·89)
0·0017
0·91 (0·71, 1·17)
0·47
Week 64
1·28
(0·99, 1·66)
0·055
1·29 (1·00,
1·66)
0·051
1·00 (0·78, 1·30)
0·99
An odds ratio >1 favors the treatment in the numerator of the ratio (= higher chance of a
clinically important improvement).
21
Section 18. SGRQ component scores
SGRQ component scores (symptoms, activity, impacts) during study treatment. *QVA149 vs
glycopyrronium; †QVA149 vs tiotropium. Differences between QVA149 and glycopyrronium
were not statistically significant. Data are least squares means ± standard errors.
22
23
Section 19. Incidence of serious adverse events* (number per 100 patient-years)
QVA149
(N=729)
Glycopyrronium
(N=740)
Tiotropium
(N=737)
Exposure in patient years
866·9
841·6
848·8
Any serious adverse event
48·6
50·9
39·2
Cardiac disorders
3·2
4·5
3·4
Atrial fibrillation
0·8
0·4
0·5
Acute myocardial infarction
0·2
0·5
0·2
Myocardial infarction
0·2
0·4
0·5
Cardiac arrest
0·1
0·5
0·2
Cardiac failure
0·1
0·1
0·5
12·6
13·4
8·7
3·3
Infections and infestations
Pneumonia
2·9
3·1
Lower respiratory tract infection
1·8
3·2
1·5
Viral upper respiratory tract infection
0·7
0·6
0·4
Bronchitis
0·5
0·2
0·7
Lobar pneumonia
0·5
0·2
0
Lower respiratory tract infection bacterial
Neoplasms benign, malignant and unspecified
(including cysts and polyps)
Lung neoplasm malignant
0·2
0·7
0·2
2·5
2·1
2·6
0·6
0
0·5
Respiratory, thoracic and mediastinal disorders
19·8
22·2
16·6
Chronic obstructive pulmonary disease
16·3
17·8
13·4
Acute respiratory failure
0·9
0·7
0·1
Dyspnea
0·6
0·2
0·4
Respiratory failure
0·6
0·8
0·8
0
0·6
0·1
Pneumothorax
*Occurring in 0·5% or more of any treatment group. Arranged by system organ class and
preferred term.
24
Section 20. Incidences of overall mortality and individual causes of death
Adjudicated cause of deaths adjusted for exposure by category
(n per 100 patient-years)
QVA149
N=729
n (%)
Glycopyrronium
N=740
n (%)
Tiotropium
N=737
n (%)
866·9
841·6
848·8
2·7
2·6
2·9
0·9
1·3
1·9
Sudden death
0·6
0·7
1·5
Other cardiovascular
0·2
0·2
0
Fatal myocardial infarction
0·1
0·2
0·2
Pump failure
0
0
0
Congestive heart failure
0
0
0
Presumed CV death
0
0
0·1
Fatal stroke
0
0
0
Pulmonary embolism
0
0·1
0
CV procedural
0
0
0
Respiratory cause
1·0
1·0
0·5
COPD exacerbation without pneumonia
0·6
0·1
0·2
COPD exacerbation with pneumonia
0·3
0·5
0·2
Pneumonia
0·1
0·2
0
0
0·1
0
0·3
0·1
0·5
Lung
0·2
0·1
0·4
Other
0·1
0
0·1
0·3
0·1
0·1
Gastrointestinal
0·1
0·1
0
Suicide
0·1
0
0
Infection
0·1
0
0
Malignancy
0
0
0
Pulmonary
0
0
0
Hepatobiliary
0
0
0
Accidental
0
0
0
Renal
0
0
0
Procedural
0
0
0
Diabetes
0
0
0
Other
0
0
0·1
Unknown
Exposure in patient years
Death from any cause
Cardiovascular cause
Other
Cancer cause
Other non- Cardiovascular causes
0
0·1
0
Insufficient information
0
0·1
0
Unable to classify
0
0
0
Preferred terms are sorted in descending order of frequency in the QVA149 treatment group.
The classifications were determined by the independent adjudication committee.
Patients who died between the first treatment day and 30 days of the last treatment are included.
Duration of exposure = date of last dose − date of first dose + 1.
25
Section 21. Incidence of adjudicated CCV adverse events
Adjudicated CCV adverse events (MACE and atrial fibrillation/flutter events)
(% of patients)
QVA149
N=729
Glycopyrronium
N=740
Tiotropium
N=737
Patients with ≥1 serious CCV event
3·7
3·4
3·5
Major adverse cardiovascular event (MACE)
1·4
2·0
1·1
0·5
0·8
0·3
Unstable angina
0
0
0
Non-fatal stroke
0·5
0·5
0·3
Heart failure requiring hospitalization
0·3
0·4
0·4
Coronary revascularization (CABG or PCI)
0·3
0·5
0·3
Non-major serious adverse cardiovascular event (nonMACE)
2·6
1·9
2·7
New onset
1·2
0·8
1·1
Recurrent/persistent
0·8
2·0
2·2
New onset
1·1
0·7
0·9
Recurrent/persistent
0·8
1·9
2·2
New onset
0·1
0·1
0·1
Recurrent/persistent
0·0
0·3
0·0
Non-fatal myocardial infarction (MI)
Any atrial
fibrillation/flutter
Atrial fibrillation
Atrial flutter
26
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