Comparative Study on the effectiveness of Glycopyrrolate/Formoterol versus Tiotropium/Formoterol in patients with Chronic Obstructive Pulmonary Disease

Background Chronic Obstructive Pulmonary Disease (COPD) has several implications on health, lifestyle, and economic burden. Combinational therapy using muscarinic antagonists and beta-2 agonists has long been warranted for use as maintenance therapy. A lack of studies directly comparing Glycopyrrolate/Formoterol (GFF) versus Tiotropium/Formoterol (TFF) was observed which led us to analyze the effectiveness of these combinations. Methods In this pilot, prospective, randomized, open-label, parallel-arm, 12-week period study, 60 patients with COPD (moderate-severe) were randomized in a 1:1 ratio to receive either GFF or TFF (n = 30 each). The primary outcome was to demonstrate non-inferiority between the two groups concerning FEV1 for 12 weeks. The secondary outcome was the assessment of the ratio of FEV1/FVC and state of health evaluation by St. George's Respiratory Questionnaire (SGRQ). Results Out of 60 participants, 58 subjects completed the study. At week 12, the mean and standard deviation value of FEV1 between groups were 1.49 ± 0.38 and 1.38 ± 0.30 (p > 0.05) and FEV1/FVC ratio were 0.67 ± 0.09 and 0.74 ± 0.08 (p < 0.01) respectively. A significant difference was observed in the FEV1 and FEV1/FVC values in comparison with baseline versus last follow up in both the groups (p < 0.01). However, no remarkable variation was identified in the FEV1 values over the two groups. The health status assessment by SGRQ showed significant improvement in both groups after the treatment. Conclusion Non-inferiority of GFF when compared to TFF was established along with good tolerability and comparable adverse effect profile.


Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a preventable, common, and treatable disease, symbolized by incessant airflow limitation which is generally progressive and is precipitated by an increased inflammatory response in the lungs and airways due to toxic gases or particles. Symptoms such as dyspnea, sputum production, and cough have been largely reported by patients. Furthermore, the presence of underlying chronic co-morbidities contributes to its morbidity and mortality [1]. Majority of the hospital admissions related to COPD have been attributed to exacerbations (a sudden worsening of symptoms) which have enforced a compelling economic burden globally. Repeated exacerbations also lead to an overall decline in lung function, poor quality of life, and elevated risk of death [2]. According to WHO, low and middle-income countries account for 90% of COPD-related deaths. Although the primary etiological factors are considered to be cigarette smoking and air pollution, there are additional factors that increase the risk of COPD in low and middle-income countries. These include smoke from biomass fuels, other indigenous methods of smoking, previous history of tuberculosis and low socioeconomic status are the important risk factor for the development of COPD. In India, indigenous tobacco smoking methods such as hookah, chillum, bidis are more common when compared to cigarette smoking which is associated with an even greater risk [3][4][5].
Inhalational bronchodilators namely, Long Acting β-Agonists (LABAs) and Long-Acting Muscarinic Antagonists (LAMAs) prescribed either alone or as a combination with inhaled corticosteroids are the backbone for stable moderate-severe COPD management [6,7]. The rationale behind combining LABA and LAMA co-administration is an optimization of pharmacological therapy via greater bronchodilation, lesser side effects, and boost medication adherence, as only a single inhaler device is used [8].
Glycopyrronium (50 μg), a once-daily LAMA that acts on muscarinic M 1, M 2 , M 3 receptors, has a high affinity for M 3 receptors over M 2 receptors when compared to Tiotropium. Therefore, it is hypothesized to possess lesser cardiovascular side effects than Tiotropium [9]. Glycopyrrolate/Formoterol Fumarate (GFF) is a LAMA/LABA combination drug, approved for patients with moderate-severe COPD in India in the year 2016. Tiotropium often called the gold standard of long-term COPD management, is one of the first LAMAs approved for use in COPD patients and has also shown to improve patient symptoms and health status [10]. Previous studies comparing Glycopyrrolate and Tiotropium have reported comparable efficacy and safety with Glycopyrrolate having a faster onset of action [11][12][13][14][15].
The current pilot study aimed to compare GFF with Tiotropium/ Formoterol (TFF) combination as no direct head to head trials comparing these two combinations have been carried out and to establish the equivalence of GFF relative to TFF combination therapy.

Selection of study subjects
Male and female participants of age ≥40 years with prior history of smoking (calculated according to pack-years) assessed with moderatesevere COPD (Stage 2 or 3 according to GOLD 2019 guidelines) were included in the study. Participants were also enrolled if they had a postbronchodilator Forced Expiratory Volume in 1 s (FEV 1 ) ≥ 30% and <80% of predicted as well as post-bronchodilator FEV 1 /Forced Vital Capacity (FVC) < 0.70 at the screening (post bronchodilator volume was assessed 1 h after inhalation of 400 μg Salbutamol and 84 μg of Ipratropium bromide). Patients who had COPD history and were already receiving treatment underwent a washout period for seven days and thereafter received their respective trial drugs according to the randomization. The condition that requires hospitalizations due to sudden worsening of symptoms defined as exacerbations were treated with antibiotics, oral corticosteroids, and bronchodilators. Rescue medication use was also recorded. The trial drugs were then continued when an improvement in the symptoms after the management of exacerbation was observed.
Participants with the following conditions were excluded from the study: i) Pregnant and/or nursing mothers (ii) Women of childbearing potential-unless adequate contraceptive measures were being taken (iii) Known underlying cardiovascular abnormalities (arrhythmias, congestive heart failure, coronary artery disease) (iv) Renal impairment (v) Patients with urinary retention (vi) Narrow-angle glaucoma (vii) familiar history of psychiatric illness (viii) Undergone surgeries including lobectomy or bronchoscopic lung volume reduction (ix) Inability to produce acceptable spirometry results (x) Contraindications/hypersensitivity to any of the study drugs (xi) History of adverse reactions to inhaled anticholinergics (xii) Known malignancies.

Ethical approval
This study has approval from Institutional Ethics Committee (1785/ IEC/2019) of SRM Medical College Hospital and Research Centre and the research was performed in abidance to Declaration of Helsinki. The patients were subjected to treatment allocation only after obtaining the written informed consent for participation in the study. This research has also been registered under the Clinical Trial Registry of India (Registration number CTRI/2020/01/022780).

Study design
A randomized, prospective, pilot, open-label, parallel-arm study was undertaken in a tertiary care hospital in Chengalpattu district, Tamil Nadu for 12 weeks. A sample size of approximately 30 in each group was determined at 80% power of the study and an alpha value of 0.05 for a two-arm parallel study. The maximum clinically significant allowable difference of FEV 1 between two groups used 50 mL (0.05L) and pooled standard deviation 200 mL (0.2L) were extracted from the study by Chapman et al. (GLOW-5) [11]. Block randomization method was followed using a block size of 4 and randomization sequencing was created using Random Allocation Software (version 2.0). Allocation concealment was done using Sequentially Numbered, Opaque Sealed Envelopes (SNOSE). One investigator who did not participate in patient recruitment prepared the sealed envelopes. Spirometry was performed in order to assess the study outcomes.

Intervention
A total of 60 subjects were assigned randomly in a ratio of 1:1 to either one of the two groups (Group A or Group B). Subjects in Group A received GFF Dry Powder Inhaler (DPI) (25 μg/6 μg) twice daily whereas participants in Group B received TFF DPI (18μg/12 μg) once daily.

Study outcomes and assessment
The primary outcome of the study was to demonstrate noninferiority between the two groups in terms of improvement in the FEV 1 values by the end of week 12. The secondary outcome was an improvement in FEV 1 /FVC ratio and health status. FEV 1 /FVC ratio and FEV 1 values were assessed using spirometry at baseline, weeks 4, 8, and 12 (EasyOne spirometer, NDD Medical Technologies). Health status was evaluated using St. George's Respiratory Questionnaire (SGRQ) [16]. Eligibility was assessed by checking for post-bronchodilator reversibility upon inhalation of Salbutamol (2.5 mg). Side effects reported by the patients at every follow-up were recorded and assessed using the Naranjo scale.

Statistical analysis
The demographic and baseline characteristics were represented by descriptive statistics. The normality distribution of the data was analyzed using the Kolmogorov Smirnov test. The primary and secondary outcomes were analyzed using repeated measures Analysis of Variance (ANOVA) and post hoc Bonferroni tests for pairwise comparisons using Statistical Product and Service Solutions (SPSS) Version 27.

Demographic and baseline characteristics
A total number of 79 patients were selected and screened for eligibility, of which 60 patients were randomized into two groups. 30 subjects were allocated in the GFF group and 30 subjects were in the TFF group. Completion of the study was achieved by 58 patients. The dropout rate was similar in both groups with the prime reasons being non-adherence to the medication and withdrawal due to adverse drug reaction (Fig. 1).
The disposition of the baseline characteristics was tabulated ( Table 1). The mean age distribution between the groups was 52.5 and 69.5 years respectively. The majority of the patients over the groups had moderate to severe COPD. The mean duration of COPD was found to be 4.6 years. In both the groups, over half of the patients had a positive smoking history. The mean post-bronchodilator FEV 1 predicted percentage was 61% and the post-bronchodilator FEV 1 /FVC ratio was 64%. The percentage of diabetic patients was highest in each of the two groups followed by hypertensive patients.

Spirometry observations
The primary outcome was an improvement in FEV 1 values (in liters). We performed two way repeated measures ANOVA to check if there was any significant difference in the average FEV 1 at different time points as well as between groups. It was observed that there was a significant difference in the average FEV 1 from baseline up to the 12th week of study (p < 0.01). Post-hoc Bonferroni pairwise comparison of the means revealed that there was significant progress in the average FEV 1 values among all the pairs of time points (p < 0.01) ( Table 2). Furthermore, the results of FEV 1 between both the treatment groups shows no remarkable variation (p = 0.14).
The secondary outcome was to apprehend important difference in the average FEV 1 /FVC at various time points, between treatment groups. A statistically significant difference was found in the pattern of average FEV 1 /FVC over the time between groups GFF and TFF (p = 0.02). The post-hoc comparison have shown a significant difference in the average FEV 1 /FVC (p < 0.01) values between all pairs of time points (Table 3). 5 patients in the GFF group and 4 patients in the TFF group reported using rescue medication during the study period for exacerbations.
The health status, quality of life assessment were analyzed using SGRQ which consists of three domains-symptom, activity, and impact scores which are added to give a total score. There was a considerable difference in the average total score including symptom, impact, and activity before and after the intervention (p < 0.01). The results from the post-hoc analysis show no significant difference in the score between group A and group B (p = 0.61) ( Table 4).

Adverse drug reactions
The incidence of adverse drug reactions was more in number in the TFF group (Group B) in comparison to GFF (Group A). The most commonly reported adverse effects in Group B were dry mouth, constipation, and frequent urination/urinary retention. Increased secretions and dyspnea were periodically encountered in the GFF group. One patient withdrew from the study due to severe dry mouth in the TFF group (Table 5).

Discussion
Our pilot study showed a significant improvement in our set primary and secondary spirometry endpoints. We found that GFF was noninferior to TFF in improving COPD patient outcomes. A post-hoc analysis was done to better comprehend differences or improvements from baseline to the last time point (12th week). Two landmark studies, namely the GLOW2 and GLOW5 [11,14] clinical trials directly compared the safety and efficacy of Glycopyrronium and Tiotropium in head-to-head trials, and their results were found similar to the current study. A significant improvement in FEV 1 /FVC ratio at baseline to 12th week was found in both these studies and was comparable to the prevailing study [11,12]. Patients with COPD are known to have severe morning symptoms which have repercussions on their daily tasks. The utilization of LAMAs is postulated to play a vital role in the improvement of these symptoms. Our results were also analogous to the SPRING [17] study wherein glycopyrrolate was compared to blinded tiotropium to improve these morning symptoms and non-inferiority of the former drug was established.
Our study also showed a similar progression from initiation of treatment when the status of health of patients was assessed from the SGRQ. Larger clinical trials have also reported similar results [11,17]. Studies have also reported glycopyrrolate to have a faster onset of action when compared to tiotropium but this was not evident on repeated administration of dose [18,19].
Currently, it is not precisely acquainted if there had been any differences in safety and efficacies amongst other LAMA/LABAs. More clinical trials are imperative to confirm this as the COPD burden is on a rising trend and more patients would potentially require more than one LABA or LAMA for better management of their symptoms.
The safety of these drugs was also comparable as the frequency of adverse drug reactions was similar. The Glycopyrrolate/Formoterol combination shows a persistent safety profile in comparison with its components, placebo and open-label tiotropium in its phase 3 clinical development studies (PINNACLE-1, 2; PT003011and PT003012) [20][21][22].
We were unable to find relevant studies comparing the same combination as our study drugs. Limitations of this study were chiefly the small sample size due to it being a pilot study and the short time duration of the study was also a factor. Thirdly, the trial was an open-label study which could have led to selection bias.

Conclusion
The results of the present study indicated that the Glycopyrrolate/ Formoterol combination was non-inferior to TFF with a similar safety profile and good tolerability. On comparing the safety profiles, GFF had better tolerability to TFF and can be used in those patients who cannot tolerate the adverse effects posed by TFF. Therefore, GFF can be considered for use instead of TFF in the long-term maintenance of COPD.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments
We would like to thank the treating physicians in the Respiratory Medicine department of SRM Medical College Hospital and Research Centre. The authors would also like to thank Dr. K.S Lakshmi, Dean of SRM College of Pharmacy, SRMIST, and Dr. T.M. Vijayakumar, Head of department of Pharmacy Practice, SRM College of Pharmacy, SRMIST.