Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study

This was a Phase IIIa, multicenter, randomized, double-blind, placebo-controlled, parallel-group study (GSK study number DB2113359; ClinicalTrials.gov identifier NCT01316887) conducted between January 2011 and July 2012. Patients who met eligibility criteria entered a run-in period of 7–10 days, followed by a 52-week treatment period. Patients who experienced a COPD exacerbation or lower respiratory tract infection (LRTI) during the run-in period or at Visit 2 were allowed to re-screen and repeat the run-in period.

The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH) guidelines, all applicable subject privacy requirements, and the ethical principles outlined in the Declaration of Helsinki, 2008 [13, 14].

Eligible patients were current or former smokers of ≥40 years of age, with a smoking history of ≥10 pack-years and an established clinical history of COPD as defined by the American Thoracic Society/European Respiratory Society criteria [1]. Patients had a post-salbutamol forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) ratio <0.70 and a post-salbutamol FEV₁ ≥35% and ≤80% of predicted values (as determined by Nutrition Health and Examination Survey III reference equations) [15]. Female patients were eligible for participation if they were of non-childbearing potential, or agreed to practice acceptable methods of birth control, as defined by the protocol.

Patients with a current diagnosis of asthma or other respiratory disorder (including pulmonary hypertension and interstitial lung disease) were excluded, as were patients with historical/current evidence of clinically significant, uncontrolled, cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine, or hematological abnormalities that the investigator felt may have put the patient at risk or affected the safety analysis of the study. Patients were also excluded if they: had been hospitalized for COPD/pneumonia within 12 weeks prior to Visit 1 or had undergone lung resection in the 12 months prior to screening; were hypersensitive to any anticholinergic drug or β₂-agonist; were unable to withhold salbutamol and/or ipratropium bromide use for the 4-hour period prior to spirometry; had a known or suspected history of alcohol or drug abuse; were participating in the acute phase of a pulmonary rehabilitation program; or had abnormal and significant findings from electrocardiogram (ECG) monitoring, 24-hour Holter monitoring, chest X-rays, clinical chemistry, or hematology tests. Prohibited medications prior to study entry are summarized in Additional file 1: Table S1.

Patients were randomized in a 2:2:1 ratio to once-daily UMEC/VI 125/25 mcg (delivering 113/22 mcg), UMEC 125 mcg (delivering 113 mcg), and placebo (Figure 1), using a telephone-based randomization system and codes generated by RandAll version 2.5. All treatments were administered in the morning via the ELLIPTA™ dry powder inhaler. Salbutamol and/or ipratropium bromide were permitted as rescue medication throughout the run-in and treatment periods, administered via metered dose inhaler or nebules.

Safety assessments included the incidence of adverse events (AEs), vital signs and clinical chemistry, hematology, 12-lead ECG, and 24-hour Holter ECG parameters. AE groups of special interest, such as those associated with LAMA and LABA pharmacologic classes, were also assessed. These included: cardiovascular effects, effects on glucose and potassium, tremor, urinary retention, ocular effects, gallbladder disorders, intestinal obstruction, and anticholinergic effects. Pneumonia and LRTI were also assessed as AEs of special interest as these are common in the COPD patient population. Additional symptomatic endpoints included COPD exacerbations (incidence and time to first COPD exacerbation) and rescue medication use. Lung function endpoints included trough FEV₁ and trough FVC.

For patients who did not need to re-screen as a result of a COPD exacerbation or LRTI during the run-in period (as outlined in the study design), there were a total of 7 study visits at: screening (Visit 1), randomization (Visit 2) and 1, 3, 6, 9, and 12 months (Visits 3–7). A follow-up assessment via telephone was conducted approximately 1 week after Visit 7, or following withdrawal. No subsequent active follow-up was performed. Spirometry assessments were conducted at Visit 1 (pre- and post-salbutamol) and pre-dose at Visits 2–7 to obtain FEV₁ and FVC. ECGs and vital signs were assessed prior to salbutamol dosing for spirometry (Visit 1), and for Visits 2–7 immediately prior to dosing and at 10 and 45 minutes post dose. Holter ECG monitoring and the collection of clinical laboratory samples were conducted at Visit 1 and Visits 4–7.

The sample size was determined based on ICH guidelines and practical considerations. To ensure that ≥300 patients completed the study (≥120 subjects per active treatment arm and ≥60 patients in the placebo arm), assuming a maximum withdrawal rate of 40% during the 52-week treatment period [16‐20], it was planned that 500 patients would be randomized from approximately 50 study centers. The primary study population for all data presentation and analyses was the intent-to-treat (ITT) population, defined as all patients randomized to treatment who received at least one dose of study drug.

Formal statistical analyses were performed for vital signs and ECG parameters (analysis of covariance), time to first COPD exacerbation (Kaplan–Meier analysis, Cox proportional hazards model), trough FEV₁ and trough FVC (repeated measures models). No formal statistical analyses were performed for other safety parameters or for comparison of active treatments with placebo. Results are presented as differences and confidence intervals (CIs). All other data are presented as patient numbers and percentages by study treatment group.

Of the 563 patients randomized to treatment, one did not receive treatment and so 562 were included in the ITT population across 53 centers in the US (28% of patients), Romania (26%), Russian Federation (21%), South Africa (14%), Chile (7%), and Slovakia (4%). Of these, 342 patients completed the study (UMEC/VI 125/25 mcg, 63%; UMEC 125 mcg, 59%; placebo, 61%). Reasons for discontinuation included the meeting of protocol-defined stopping criteria (14%), AEs (9%), withdrawal of patient consent (7%), lack of efficacy (2%), protocol deviation (2%), study close/termination (2%), and loss to follow-up (2%). Although similar overall withdrawal rates were reported between UMEC/VI 125/25 mcg (37%), UMEC 125 mcg (41%), and placebo (39%), higher incidences of withdrawals due to protocol-defined stopping criteria were reported with UMEC/VI 125/25 mcg and UMEC 125 mcg (16% in each) compared with placebo (7%), particularly for ECG abnormalities (5–6% vs 0%) and Holter abnormalities (11–12% vs 7%). However, fewer patients were withdrawn due to a lack of efficacy on active treatments compared with placebo (≤1% vs 8%). For patients who reported ECG/protocol-defined stopping criteria as their primary reason for withdrawal, the ECG and Holter abnormalities meeting the withdrawal criteria are presented in Additional file 1: Tables S2 and S3; no single ECG or Holter abnormality was predominant.

Patient demographics, characteristics, and comorbid conditions were similar across treatment groups. Overall, patients had moderate-to-severe airflow obstruction, extensive smoking histories, and the majority were White and male (Table 1).

Most patients had concurrent medical conditions in addition to COPD; the most commonly reported conditions were cardiovascular risk factors (67%; defined as a current medical history of angina, myocardial infarction, stroke, diabetes, hypertension, or hyperlipidemia) and cardiac disorders (34%) (Table 1).

In the 12 months prior to screening, 31% of patients in both active treatment groups and 36% of patients in the placebo group reported at least one COPD exacerbation that required oral/systemic corticosteroids and/or antibiotics. The proportion of patients who reported at least two of these exacerbations during this period was 11%, 14%, and 16% for UMEC 125 mcg, UMEC/VI 125/25 mcg, and placebo groups, respectively. For exacerbations that required hospitalization, 14%, 16%, and 17% of patients in the UMEC 125 mcg, UMEC/VI 125/25 mcg, and placebo groups reported at least one exacerbation, and 3%, 3%, and 6% reported at least two exacerbations.