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Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients A single dose, randomised, placebo controlled crossover study lable at ScienceDirect[.]
Pulmonary Pharmacology & Therapeutics xxx (2016) 1e9 Contents lists available at ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study Dave Singh a, *, Giorgia Ciurlia b, Annalisa Piccinno b, Annamaria Muraro b, Maria Bocchi b, Mario Scuri b a University of Manchester, Medicines Evaluation Unit, The Langley Building, University Hospital of South Manchester, Southmoor Rd, Wythenshawe M23 9QZ, United Kingdom b Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy a r t i c l e i n f o a b s t r a c t Article history: Received November 2016 Received in revised form 20 December 2016 Accepted 26 December 2016 Available online xxx Introduction: An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD) A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo Methods: Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study Main inclusion criteria: aged 40e75 years; moderate to severe COPD (post-bronchodilator FEV1 40e80% predicted, FEV1/FVC 450 ms for males or >470 ms for females, diastolic blood pressure (DBP) > 90 mmHg, systolic blood pressure (SBP) > 160 mmHg, or use of cardiac anti-arrhythmic drugs; and unstable concurrent disease that, in the investigator's judgement, might interfere with the results of the study Patients who had taken the following respiratory medications within weeks of screening were excluded: systemic corticosteroids; oral or nebulised b2-agonists, antibiotics for lower respiratory tract infections and xanthine derivatives Full inclusion and exclusion criteria are presented in the supplementary material 2.2 Trial design The eligibility of patients was checked at the screening visit (Visit 1) Eligible patients entered a minimum 14-day run-in period, during which any previous long acting bronchodilator use was to be discontinued Patients on ICSs were allowed to continue the same ICS for the duration of the run-in period, and for the washout periods (with the exception of BDP, which was switched to budesonide); the last dose of ICS was to be taken approximately 48 h prior to each treatment period All patients received ipratropium puffs times per day during the run-in period until the end of the study, but not within 12 h prior to each treatment visit Salbutamol use was also allowed if symptoms were not relieved by ipratropium (but not within 24 h prior to each treatment visit) There were treatment visits (Visits 2, 3, 4, and 6), each separated by washout periods with minimum duration of days Patients fasted from 10 pm the evening prior to each study drug administration (which took place between and 10 am), and until h post-dose Between h post-dose and discharge, patients were provided standard meals at standard times In addition, from at least 60 prior to dosing and up to h post-dose, patients were asked to rest and lay in a semi-recumbent position At each treatment visit, heart rate (HR) and QTcF interval values (from a Holter monitor), and SBP and DBP (from an automated machine) were captured at 45 and 30 predose, and 5, 10, 20, 30 and 45 min, and 1, 1½, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h post-drug administration HR and QTcF interval values were also collected at 15 predose Blood was collected for serum glucose and potassium determination at predose, and 10, 20, 30 and 45 min, and 1, 1½, 2, and h post-drug administration 2.3 Interventions Two different devices were used in the study: a DPI containing 100 mg BDP and mg FF per actuation, or matching placebo; and a pMDI containing 100 mg BDP and mg FF per actuation, or matching placebo At each visit, patients received either four DPI devices (taking two inhalations per device) or two pMDI devices (taking two inhalations from one device and six from the second), to receive one of the following (all doses are BDP/FF, total dose): DPI 200/12 mg DPI 800/48 mg DPI placebo pMDI 200/12 mg pMDI 800/48 mg The 200/12 mg dose is a typical therapeutic dose (for both devices), since the dose recommendation of the approved products for COPD in adults 18 years and above is two inhalations (of 100/ mg) twice daily The 800/48 mg dose is supratherapeutic A partialblind approach was used, as it was not possible to use a doubledummy approach, given the large number of inhalations (16) that Please cite this article in press as: D Singh, et al., Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study, Pulmonary Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pupt.2016.12.004 D Singh et al / Pulmonary Pharmacology & Therapeutics xxx (2016) 1e9 this would require Patients, investigators, monitors and employees of the centre and the sponsor's clinical team were blinded to treatment assignment during the study A balanced-block randomisation scheme was prepared by the Statistics and Data Management Department of Chiesi Farmaceutici SpA (the study sponsor) using a computerised system Each patient was assigned to one of five treatment sequences arranged in a Latin Square design Serum potassium and glucose were log-transformed and analysed using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects Data are presented as adjusted means and associated 95% CIs The ratios of adjusted means between treatments were calculated, with their 95% twosided CIs; p values are presented for the comparisons with placebo For the comparisons between the formulations, if the 95% confidence intervals of the ratios included 100 this excluded with a high probability that there was a significant difference 2.4 Outcomes Results The primary variable was average 4-h heart rate (HR0e4h), the objective being to demonstrate non-inferiority between the two BDP/FF formulations at each dose level Secondary variables included: Average 0e12 HR (HR0e12h), HR peak (assessed during the first h post-dose) and individual timepoint; QTcF interval, individual timepoint and incidence of raised values and of clinically relevant changes from baseline; SBP and DBP area under the curve from to 12 h (AUC0e12h); and potassium and glucose AUC0e4h Treatment-emergent adverse events (TEAEs) were also collected 2.5 Sample size and statistical methods For the primary objective, non-inferiority between the DPI and pMDI formulations was to be demonstrated at each dose level if the upper bound of the 95% CI did not exceed bpm, using data from the pharmacodynamic (PD) population The bpm upper noninferiority margin was consistent with two previous cardiovascular safety studies of inhaled treatments in COPD [8,9] Assuming a within-patient standard deviation of 6.7 bpm, a mean difference between treatments of bpm, an upper non-inferiority margin of bpm and a one-sided significance level of 2.5%, 40 evaluable patients (8 per sequence) ensured 90% power to demonstrate the non-inferiority of BDP/FF via the DPI relative to BDP/FF via the pMDI at each dose level Sufficient patients were screened in order to randomise up to 50 patients; it was estimated that this would provide 40 evaluable patients, considering a drop-out rate of 20% The PD population comprised all patients from the safety population with available primary endpoint data and without any major protocol deviations The safety population comprised all randomised patients who received at least one dose of study medication Data were analysed using SAS® version 9.2 (SAS Institute Inc., Cary, NC, USA) The primary endpoint (HR0e4h) was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and the baseline HR value (average HR in the hour preceding study drug administration in each treatment period) as a covariate Data are presented as adjusted means and associated 2-sided 95% confidence intervals (CIs) Adjusted mean differences (and 95% CIs) between treatments are presented, along with p values for the comparisons with placebo The other HR parameters were analysed using a similar ANCOVA model to the primary endpoint, although using the safety population Change from baseline in QTcF interval was analysed using a similar ANCOVA model, but with baseline QTcF interval instead of HR For this endpoint two-sided 90% CIs were calculated for the differences between treatments The number of patients with individual raised QTcF interval values (i.e., >450 ms for men and >470 ms for women) and of clinically relevant increases from baseline (i.e., >30 ms) were calculated The SBP and DBP parameters were analysed using a similar ANCOVA model to the HR endpoints, but using baseline blood pressure as covariate For the comparisons between the formulations, if the 95% confidence intervals included this excluded with a high probability that there was a significant difference 3.1 Patients The study was conducted between December 2013 and April 2014 Of 106 COPD patients screened, 49 were randomised (and received at least one dose of study medication) with 45 (91.8%) receiving all five treatments (Fig 1) One patient had a QTcF interval value at screening of 466 ms, with a repeat value of 450 ms; this patient was randomised in error, and was excluded from the PD population The baseline demographics and disease characteristics for the 49 randomised patients are reported in Table The mean FEV1 predicted was 60% There were 16 patients with cardiovascular disease, most commonly hypercholesterolaemia and hypertension 3.2 Study outcome 3.2.1 Primary endpoint The primary endpoint results are shown in Table Noninferiority was demonstrated between the DPI and pMDI formulations for HR0e4h, both at 200/12 mg (mean difference 0.2; 95% CI e1.3 to 0.9) and 800/48 mg (mean difference 0.6; 95% CI e0.5 to 1.7) The upper limits of the 95% CIs of the differences between formulations were well below the predefined non-inferiority margin (5 bpm) There were small, although statistically significant, treatmentplacebo differences for both formulations at the 200/12 mg dose (1.5 and 1.7 bpm for DPI and pMDI, respectively) The treatmentplacebo differences for both formulations at the 800/48 mg dose were also statistically significant, and higher than the 200/12 mg doses, with the non-overlapping confidence intervals indicating that the difference between doses was statistically significant The results from the analysis in the safety population were consistent with the analysis in the PD population 3.2.2 Secondary endpoints 3.2.2.1 Heart rate For HR0e12h, both at the 200/12 mg dose and the 800/48 mg dose, the upper limits of the 95% CIs of the differences indicated that there were no significant differences between formulations, with differences being no greater than bpm (Table 2) There were no statistically significant treatment-placebo differences at the 200/12 mg dose, although there were statistically significant treatment-placebo differences for both formulations at the 800/48 mg dose (both 4.8 bpm) Similarly, for peak HR at both doses there were no significant differences between formulations (Table 2) There were no significant treatment-placebo differences between the formulations at the 200/12 mg dose; there were significant treatment-placebo differences for the two formulations at the 800/48 mg dose (5.9 and 5.6 bpm for the DPI and pMDI formulations, respectively) Individual timepoint change from baseline in HR values are shown in Fig There were minimal differences between the two formulations at any timepoint There was an immediate increase from baseline in all groups (including placebo) at post-dose, Please cite this article in press as: D Singh, et al., Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study, Pulmonary Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pupt.2016.12.004 D Singh et al / Pulmonary Pharmacology & Therapeutics xxx (2016) 1e9 Patients screened N=106 Screening failure N=57 Reasons: • inclusion/exclusion criteria not met (n=43) • consent withdrawn (n=4) • adverse event (n=3) • other (n=7) Patients randomised N=49 Patients withdrawn after randomisation N=4 Reasons: • consent withdrawn (n=1) • adverse event (n=3) Patients completed N=45 Populations analysed: • Safety population N=49 • PD population N=48 • Excluded: screening QTcF >450 ms (n=1) Fig Patient flow through the study Table Patient baseline demographics and disease characteristics (safety population) Overall (N ¼ 49) Gender, n (%) Male Female Age (years), mean (SD) Range Race, Caucasian, n (%) Smoking history, n (%) Ex-smokers Current smokers Post-bronchodilator FEV1% predicted, mean (SD) Range Post-bronchodilator FEV1/FVC, mean (SD) Heart rate at screening, bpm, mean (SD) QTcF interval at screening, ms, mean (SD) COPD medication at study entry, n (%) ICS ỵ LABA ỵ LAMA ICS ỵ LABA LAMA alone ICS ỵ LAMA ICS alone LABA alone Concomitant disease at screening, n (%)a Hypercholesterolaemia Hypertension Gastro-oesophageal reflux disease Depression Angina pectoris Myocardial ischaemia Atrial fibrillation Raynaud's phenomenon Venous insufficiency 22 (45) 27 (55) 62.8 (8.3) 48e75 49 (100) 23 (47) 26 (53) 60.0 (9.1) 41e79 0.47 (0.09) 72.3 (10.2) 420.7 (19.8) 19 (39) 12 (24) (16) (2) (2) (2) 17 (35) 14 (29) (16) (14) (4) (4) (2) (2) (2) a Reported in or more patients, and all patients in the cardiac disorders and vascular disorders system organ classes SD ¼ standard deviation; FEV1 ¼ forced expiratory volume in s; FVC ¼ forced vital capacity; bpm ¼ beats per minute; QTcF ¼ QT interval corrected with Fridericia's formula which then rapidly dropped to baseline in the two 200/12 mg dose formulations until h post-dose (the time at which patients were no longer required to rest in bed and were permitted to eat) 3.2.2.2 QTcF interval For QTcF interval, there was an immediate post-dose decrease from baseline with all treatments (including placebo), followed by an increase (Fig 3) There were no significant differences between the two formulations at all timepoints with the 200/12 mg dose, and at all timepoints except 30 post-dose with the 800/48 mg dose; the upper 90% CI of the difference between formulations was always below ms (Fig 4) Statistically significant treatment-placebo differences (p < 0.05) were observed at most of the post-dose timepoints for the two 800/48 mg formulations, but only at four (of the 16) post-dose timepoints for the 200/12 mg DPI formulation, and at six post-dose timepoints for the 200/12 mg pMDI formulation Individual raised QTcF interval values (i.e., >450 ms for men and >470 ms for women) were reported in 1, 0, 1, and patients with placebo, DPI 200/12 mg, pMDI 200/12 mg, DPI 800/48 mg and pMDI 800/48 mg respectively The only clinically relevant increase from baseline (i.e., >30 ms) was in one female patient with the 800/48 mg DPI formulation 3.2.2.3 Blood pressure For SBP and DBP AUC0e12h, there were no significant differences between the two formulations, either at 200/ 12 mg or 800/48 mg (Table 3) Statistically significant treatmentplacebo differences were observed in all SBP evaluations, and in most DBP evaluations, with maximum mean decreases of 3.5 mmHg in SBP and 3.6 mmHg in DBP There was a dose-effect (larger changes from baseline being observed with the 800/48 mg doses than the 200/12 mg doses) 3.2.2.4 Potassium and glucose Serum potassium and glucose AUC0e4h values are shown in Table There were no significant differences between the two formulations at either dose level for the potassium or glucose evaluations, with the 95% confidence intervals of the ratio between formulations including 100% The only statistically significant treatment-placebo differences were Please cite this article in press as: D Singh, et al., Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study, Pulmonary Pharmacology & Therapeutics (2016), http://dx.doi.org/10.1016/j.pupt.2016.12.004 D Singh et al / Pulmonary Pharmacology & Therapeutics xxx (2016) 1e9 Table HR0e4h, HR0e12h and peak HR Data are presented as adjusted mean (95% confidence interval); p value (for comparisons vs placebo) BDP/FF pMDI BDP/FF DPI BDP/FF pMDI Placebo BDP/FF DPI 200/12 mg (N ¼ 44, 47)a 200/12 mg (N ¼ 44, 45)a 800/48 mg (N ¼ 45, 46)a 800/48 mg (N ¼ 45, 47)a (N ¼ 45, 47)a HR0e4h, bpm (PD population) HR0e12h, bpm (safety population) Peak HR, bpm (safety population) Adjusted mean Adjusted mean difference DPI vs pMDI Adjusted mean difference vs placebo Adjusted mean Adjusted mean difference DPI vs pMDI Adjusted mean difference vs placebo Adjusted mean Adjusted mean difference DPI vs pMDI Adjusted mean difference vs placebo 69.3 (68.5, 70.1) 0.2 (e1.3, 0.9) 1.5 (0.3, 2.6); 0.0114 77.6 (76.8, 78.4) 0.2 (e1.2, 0.9) 0.6 (e0.5, 1.6); 0.2816 99.5 (97.1, 101.8) 1.2 (e4.4, 2.1) 0.7 (e2.6, 3.9); 0.6849 69.5 (68.7, 70.3) 1.7 (0.6, 2.8); 0.0038 77.8 (77.0, 78.5) 0.7 (e0.3, 1.8); 0.1749 100.7 (98.3, 103.0) 1.9 (e1.4, 5.1); 0.2663 75.5 (74.7, 76.3) 0.6 (e0.5, 1.7) 7.6 (6.5, 8.8);