Supplementary appendix

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1 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: Calverley P M A, Anzueto A R, Carter K, et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial. Lancet Respir Med 2018; published online March 28.

2 1 Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, activecontrolled, trial Peter M A Calverley, Antonio R Anzueto, Kerstine Carter, Lars Grönke, Christoph Hallmann, Christine Jenkins, Jadwiga Wedzicha, Klaus F Rabe Supplementary material Supplementary methods Prespecified subgroup analyses It was prespecified to examine the primary endpoint in subgroups according to baseline medications (LAMA, LABA, inhaled corticosteroid) and baseline characteristics (sex, race, smoking history, and GOLD stage). Definition of actual and planned treatment periods The primary endpoint was analyzed during the actual treatment period, defined as the time from first dose of medication until 1 day after the last dose of medication. This was also the period used for exacerbation and other endpoints. The on-treatment period is defined as the time from first dose of medication until 21 days after last dose, and was used for adverse event analysis. The planned study period is the full planned 360 days of treatment after first dose plus 21 days of follow-up (for vital status sensitivity analysis), and the planned treatment period is defined as 360 days of treatment plus 1 day for wash-out (for exacerbation sensitivity analysis). Definition of exacerbation start and end The onset of exacerbation was defined as the onset of first recorded symptom that was identified by the investigator to be due to an exacerbation; the end of the exacerbation was determined by the investigator. Rationale for the higher significance level Although the conventional scientific threshold for a significant difference between treatments is at the 5% level (p<0 05), pharmaceutical regulators require stronger proof of an effect if the results of a single treatment trial are to be included in a product label. The trial sponsors were able to support one large study and requested that we set the significance level for the primary outcome at the 1 % level (p<0 01) such that the results could be added to the product label. Supplementary results When planning the study sample size, we considered that there would be a dispersion parameter in the negative binomial model that would range between 0 8 and 0 9. This was primarily based on the assumptions used in the SPARK study, 1 where the dispersion value had been assumed to be 0 625, but we increased the value to allow for the baseline adjustments reported in that study. The observed dispersion value in our data was much larger than expected at There were significantly more patients who withdrew from the study while taking tiotropium alone than with tiotropium/olodaterol. We investigated whether there were differences in the baseline characteristics of patients withdrawing and those who continued (Supplementary Table 4), as well as running a stepwise regression analysis to determine factors predictive of discontinuation (Supplementary Table 5). The variables identified closely resemble those prospectively adjusted for in several other studies of treatment interventions on exacerbation rates in COPD patients. 1 4 Therefore, we undertook a further analysis, applying the adjustments done by others to our data as shown in Supplementary Table 6. Given the encouraging findings, we performed further analyses based on two additional models (Supplementary Table 6). In all cases, the adjusted model led to a change in the rate ratio of exacerbations, and led to a p value close to or below the 1% level we originally expected. These changes were accompanied by a reduction in the dispersion parameter to the levels we had originally expected to see.

3 2 Supplementary Tables Supplementary Table 1. Inclusion and exclusion criteria. Inclusion criteria Informed consent Exclusion criteria A significant disease other than COPD (that may put the patient at risk, influence the results of the study, or cause concern regarding patient s ability to participate) Male or female patients, aged 40 years Diagnosis of COPD and stable airway obstruction with post-bronchodilator FEV 1 <60% of predicted normal and a post-bronchodilator FEV 1/FVC <0 7 (historical spirometric data within the previous 3 months may be used) At least one moderate or severe exacerbation in the previous 12 months requiring treatment with systemic corticosteroids and/or antibiotics and/or hospitalization Clinically relevant abnormal baseline hematology, blood chemistry, or creatinine >2x upper limit of normal Current documented diagnosis of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma Symptomatically stable: no evidence of COPD exacerbation requiring use of either antibiotics and/or steroids, and no evidence of change in their usual COPD medication 4 weeks prior to screening A diagnosis of thyrotoxicosis, life-threatening cardiac arrhythmia, known active tuberculosis, any malignancy unless free of disease for at least 5 years (patients with treated basal cell carcinoma or squamous cell skin cancers are allowed), clinically relevant bronchiectasis, or severe emphysema requiring endobronchial interventions within 6 months prior to screening Current or ex-smokers with a smoking history of >10 pack-years Patients must be able to perform all trial-related procedures at the investigator discretion A history of myocardial infarction within 6 months of screening History of cystic fibrosis Patients must be able to inhale medication in a competent manner from the Respimat inhaler, and from an MDI in the opinion of the investigator A history of significant alcohol or drug abuse

4 3 Patients who have undergone thoracotomy with pulmonary resection Patients being treated with oral or patch beta-adrenergics Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than 4 weeks on a stable dose), or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day Patients being treated with antibiotics for any reason (not limited to exacerbation infection) within 4 weeks of screening Patients being treated with PDE4 inhibitors within 3 months of screening visit Patients who have taken an investigational drug within 1 month or 6 half-lives (whichever is greater) Patients with known hypersensitivity to beta-adrenergic and/or anticholinergics drugs, BAC, EDTA, or any other component of the Respimat inhalation solution Pregnant or nursing women, and women of child-bearing potential not using a highly effective method of birth control Patients who have previously been randomized in this study or are currently participating in another study Patients who are unable to comply with pulmonary medication restrictions prior to randomization BAC, benzalkonium chloride; COPD, chronic obstructive pulmonary disease; EDTA, ethylenediaminetetraacetic acid; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; MDI, metered-dose inhaler; PDE4, phosphodiesterase-4.

5 4 Supplementary Table 2. Frequency of reasons for screen failures noted in 5 patients (patients could be excluded for more than one reason). Number of Reason for screen failure screen failures, n 672 Failure to meet FEV 1 and FEV 1/FVC criteria 49 Clinically relevant abnormal baseline hematology, blood chemistry, or creatinine 42 Not symptomatically stable 27 Significant disease other than COPD 25 Lack of pulmonary function text data 25 Failure to meet exacerbation history criteria 21 Treated with oral corticosteroid at unstable doses or doses in excess of the equivalent of 10 mg prednisone per day 19 Malignancy 16 Unable to perform all trial-related procedures 15 Treated with oral or patch beta-adrenergics 15 Current diagnosis of asthma 13 Have undergone thoracotomy with pulmonary resection 13 Treated with antibiotics within 4 weeks 12 History of significant drug or alcohol abuse 12 Unable to comply with pulmonary medication restrictions prior to randomization 8 Currently treated with PDE4 inhibitors within 3 months 6 Clinically relevant bronchiectasis 5 Life-threatening cardiac arrhythmia 5 Failure to meet smoking criteria COPD, chronic obstructive pulmonary disease; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; PDE4, phosphodiesterase-4.

6 5 Supplementary Table 3. Adverse events leading to death (adjudicated) in all randomized patients during the whole trial (causes of death with frequency 0 2%). Variable Tiotropium/olodaterol (N=3,939) Tiotropium (N=3,941) Patients with adjudicated death no. (%) 110 (2 8) 123 (3 1) Cardiac disorders 7 (0 2) 6 (0 2) General disorders and administration site 33 (0 8) 32 (0 8) conditions Death 11 (0 3) 10 (0 3) Sudden cardiac death 11 (0 3) 11 (0 3) Sudden death 11 (0 3) 11 (0 3) Infections and infestations 6 (0 2) 12 (0 3) Pneumonia 3 (0 1) 8 (0 2) Neoplasms 14 (0 4) 12 (0 3) Malignant lung neoplasm 7 (0 2) 8 (0 2) Respiratory 36 (0 9) 52 (1 3) COPD 35 (0 9) 52 (1 3)

7 6 Supplementary Table 4. Differences in baseline characteristics in patients who discontinued early and those who completed the trial. Characteristic Concomitant therapy at baseline n (%) Discontinued early (N=1,138) Completed as planned (N=6,742) Total (N=7,880) LABA only 32 (2 8) 225 (3 3) 257 (3 3) LAMA only 65 (5 7) 650 (9 6) 715 (9 1) ICS only 33 (2 9) 167 (2 5) 200 (2 5) LABA/ICS 210 (18 5) 1,826 (27 1) 2,036 (25 8) LAMA/ICS 17 (1 5) 149 (2 2) 166 (2 1) LAMA/LABA 147 (12 9) 792 (11 7) 939 (11 9) LAMA/LABA/ICS 578 (50 8) 2,554 (37 9) 3,132 (39 7) None 56 (4 9) 379 (5 6) 435 (5 5) Exacerbation history in previous year n (%) 1 moderate exacerbation 541 (47 5) 3,850 (57 1) 4,391 (55 7) 2 moderate or 1 severe exacerbation FEV 1 percent predicted - mean (SD) GOLD Stage n (%) 597 (52 5) 2,890 (42 9) 3,487 (44 3) 41 1 (12 6) 45 1 (29 4) 44 5 (27 7) (26 8) 2,479 (36 8) 2,784 (35 3) (51 9) 3,448 (51 1) 4,039 (51 3) (20 7) 757 (11 2) 992 (12 6) FEV 1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; SD, standard deviation.

8 7 Supplementary Table 5. Variables identified as predictive of discontinuation using a stepwise regression. Variable Chi square Region < Screening post-bronchodilator FEV 1 % predicted < Age < Baseline CAT score < Number of exacerbations leading to hospitalization in the year prior to randomization Sex Number of exacerbations treated with steroids and antibiotics in the year prior to randomization Inhaled corticosteroid use at baseline a a Any inhaled corticosteroid use at baseline (yes/no). CAT, COPD Assessment Test; FEV 1, forced expiratory volume in 1 second.

9 8 Supplementary Table 6. Annualized rate of moderate or severe exacerbations analyzed using multiple covariates models similar to those used in previous COPD trials. Number of events Study model was based on Tiotropium Tiotropium/ olodaterol Rate ratio (Tiotropium/olodaterol vs tiotropium) 95% CI p value Dispersion parameter SPARK/FLAME a 2,960 2, HERMES b 2,968 2, TRINITY/TRILOGY c 2,968 2, a Smoking status, baseline inhaled corticosteroid, GOLD stage, region, CAT score (replacing baseline symptom score), exacerbations treated with antibiotics/steroids history in previous year (replacing 1-year history of exacerbations). Because FEV 1 reversibility was not measured, it could not be included in the model; b age, sex, smoking status, baseline LABA/inhaled corticosteroid, region, percent predicted post-bronchodilator FEV 1; c treatment, region, severity of airflow limitation, and smoking status as effects, and exacerbations treated with antibiotics/steroids in previous year. CAT, COPD Assessment Test; CI, confidence interval; FEV 1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long-acting beta-agonist.

10 9 Supplementary Figure 1. Time to treatment discontinuation. CI, confidence interval.

11 10 Supplementary Figure 2. Annualized rate of moderate or severe exacerbations by baseline therapy (A) and baseline characteristics (B). CI, confidence interval; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; T/O, tiotropium and olodaterol combination; Tio, tiotropium.

12 11 References 1 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; 1(3): Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389(10082): Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus longacting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet 2016; 388(10048): Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374(9691):