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A POST-APPROVAL, OBSERVATIONAL STUDY TO ASSESS CLINICAL IMPACT OF GLYCOPYRRONIUM IN HIGH RISK COPD WITH FREQUENT EXACERBATIONS: POST HOC ANALYSES

Agrawal G1, Mahashur A.A.2 and Korukonda K3 1. Sr. Consultant Pulmonologist, Jaypee Hospitals, Sector 128, Noida, India 201304. 2. Sr. Consultant Chest Physician, Saifee Hospital, Department of Respiratory and Chest Medicine, Maharshi Karve Marg, Mumbai, India 400004. 3. General Manager, Medical Services, Glenmark Pharmaceuticals Ltd, Mumbai, India 400099. . Manuscript Info Abstract . . Manuscript History Received: 15 January 2020 Final Accepted: 17 February 2020 Published: March 2020

The updated GOLD (2019) guidelines recommend the role of LAMA in High risk GOLD C category cases. In the randomized, controlled clinical trial of POET-COPD (Vogelmeier, 2011), Tiotropium monotherapy has shown clinically superior risk reduction when compared with Salmeterol in High risk cases of Severe COPD with prior history of exacerbations. The UPLIFT (Tashkin, 2008) study on other hand outlined the long-term impact on mortality and disease course with LAMA for Stable Severe cases of COPD while ∼60% of the patients continued with background ICS+/-LABA In real-world settings, most of the patients are symptomatic with history of at least one exacerbation in the last year. The complimentary anti-inflammatory action against neutrophils or macrophages with selective muscarinic antagonists or Glycopyrronium offers translational action in Severe or Highrisk COPD cases (Shen, 2014). The results of the Tiotropium monotherapy randomized trials (Vogelmeier, 2011;Tashkin, 2008) conducted in Severe COPD cases can be confounded by the lack of clear outcomes for patients with Frequent exacerbations and/or bronchodilator reversibility observed especially in UPLIFT (Tashkin, 2008) trial International guidelines (GOLD, 2019) have suggested the triple drug combination of ICS/LABA/LAMA as therapeutic strategy in these cases to offer comprehensive reduction in symptoms while preventing further exacerbations especially in patients with Frequent exacerbators and Sr. eosinophils >300 c/mm. In this line the triple drug combination studies of IMPACT (Lipson, 2018) and TRIBUTE (Papi, 2018) studies have successively shown significantly greater reduction in symptoms and exacerbation rate when utilized as initial-line or as sequential therapy for obstructive airway disease patients with COPD or Asthma. However ACO remains a distinct clinical entity with overlapping symptoms and characteristics of either Br. asthma or COPD (GINA 2018). The prevalence of ACO in the general population ranges between 1.6% and 4.5%, in COPD patients (Barrecheguren, 2015) between 12.1% and 55.2%, and in patients with asthma, between13.3% and 61% (Kauppi, 2011). GesEPOC-GEMA consensus document defines ACO as the presence of persistent airflow limitation in a smoker or former smoker who presents characteristics of asthma. This definition requires the concomitant presence of 3 basic elements ie. persistent airflow limitation over time, essential to confirm the presence of permanent obstruction that does not change spontaneously or after treatment; accumulated history of smoking (current or past) as a principal risk factor; typical characteristics of asthma, including clinical, biological and functional manifestations (Plaza, 2017).
There is however little evidence to highlight the omnipresence of ACO in India with relevant therapeutic strategy of utilizing LAMA in combination with ICS/LABA. To further explore the clinical outcome of LAMA in High risk COPD with prior exacerbations, a case cohort analyses as Glycopyrronium in cOpd phenotypes, A drug utilization surveilLance (GOAAL) study in outpatient settings of India was planned 669

Methods:-
This post-approval, observational, drug utilization, concurrent analysis-GOAAL study (Clinical Trial Registry of India CTRI/2018/04/012944)-of Glycopyrronium 'add on' therapy were performed in patients with High risk COPD after obtaining approval from the local ethics committee, with registration in the Clinical Trial Registry of India. Consecutive patient records from the last three weeks receiving Glycopyrronium 'add-on' therapy were collated from 128 outpatient centers that utilized the CAT score for assessing symptom control in spirometrically assessed COPD cases across India were accessed in September 2017. The concurrent analyses involved follow up of these cases for for 12 weeks with the study conducted as per the principles of International Conference of Harmonization for Good clinical practice and Declaration of Helsinki while ensuring confidentiality of patient identifiers during transcription of records before analyses The inclusion criteria included COPD pts with GOLD B/C status who were Symptomatic with ≥1 moderate-to severe exacerbation in last six months that required antibiotics or short course oral corticosteroids, COPD diagnoses with FEV1/FVC<0.7 with FVC<80%. The consecutive records were assessed for follow-up visits at 4 and 12 weeks. Per protocol analyses was conducted for patient records with at least one follow up visit for analyses of primary endpoints involving pre-bronchodilator FEV1 and CAT score improvement at 12 th wk. Safety variables were assessed as treatment emergent adverse event rate at 12 weeks with Karch and Lasagna scale used to risk assess the intensity of adverse events as Mild, moderate or severe. Cases were identified as pure COPD or asthma copd overlap (ACO) on the basis of bronchodilator reversibility of ≤10 % and ≥12% FEV1 improvement following short-acting bronchodilator or Salbutamol inhalation of 400 mcg respectively Any AE that is associated with death, inpatient hospitalization (in case the study was being conducted on outpatients), prolongation of hospitalization (in case the study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening was classified as SAEs. In case of any of these Serious Adverse Events, appropriate notification records on notification to National Coordination Centre, PvPI (CDSCO) utilizing Suspected Adverse Drug Reaction Reporting form on pvpi.ipcindia@gmail.com were also assessed for analyses Descriptive statistical analyses was planned for the epidemiological variables with the primary endpoints on prebronchodilator FEV1 and CAT score improvement were conducted by Student's T test. Statistical analyses was carried out by Quick Calcs Graphpad Prism ver. 7 software with p<0.05 considered as statistically significant The clinical study was registered on Clinical Trial Registry of India as CTRI/2018/04/012944

Discussion:-
This real-world, observational, cross-sectional, concurrent study highlights the clinical impact and utilization of Glycopyrronium in High risk COPD cases. LAMA add on therapy to ICS/LABA is usually recommended for GOLD D cases or as sequential therapy for uncontrolled, progressive cases on LAMA/LABA combination. In this line, this is the first Indian study to demonstrate the clinical benefit of Glycopyrronium 'add on' therapy in High risk COPD cases predominantly with frequent exacerbations, similar to the trials of TRILOGY (Singh, 2016) and TRIBUTE (Papi, 2018) that involved patients with severe exacerbation or as sequential therapy following progression due to dual drug or LAMA/LABA combination use.
The mean prebronchodilator FEV1 improvement of 315, 210.9 and 523 ml in these High risk COPD cases (≥1 exacerbation/yr), COPD with frequent exacerbation (≥2 exacerbation/yr)& ACO with frequent exacerbations at the 671 end of twelve weeks therapy demonstrates the clinical impact of the add-on therapy in providing bronchodilation or Trough FEV1 that is meaningfully clinically important difference of >100 ml thereby further substantiating the role of Glycopyrronium as a Ultra LAMA that is useful for Severe or very severe COPD cases. Real world evidence on the role and delivery of Tiotropium as add-on or fixed dose combination with ICS/LABA through a single dry powder inhaler device or as add-on therapy is limited. In a real world study to assess the effectiveness of a triple drug combination in Severe COPD, the results with Tiotropium/Formoterol/Ciclesonide dry powder inhaler resulted in prebronchodilator FEV1 improvement of 200 ml (p<0.0001) for Smoker COPD patients with infrequent exacerbations (Deb, 2016) The study reported the results for twelve weeks Glycopyrronium add on therapy to ICS/LABA before rationalizing the review of ICS use in frequent exacerbators or Asthma COPD overlap cases. Asthma COPD overlap or COPD cases with BDR (>15%,400ml) and related exacerbations have often remained a clinical challenge with GesEPOC-GEMA (Plaza, 2017) recommendations on a likely diagnosis of overlap syndrome. The complexity of the diagnoses was further commented by GINA for likely BDR (>12%, 200 ml) along with other risk factors to be considered as Asthma-COPDoverlap. Post-hoc analyses for this ACO subgroup with or without frequent exacerbations was further evaluated in this study. The mean prebronchodilator FEV1 and CAT score improvement in ACO subgroups were clinically significant including the test of interaction for clinical impact assessment as compared to the High risk COPD or overall group results. The exposure including Smoking or Nonsmoking risk factors or Biomass and occupational hazards were documented in these cases for atleast five years as recommended by GINA for a diagnosis of ACO. The results of the study for this subgroup are till date the first of its kind for Glycopyrronium when used as mono-or combination therapy The study results are limited by the cross-sectional, concurrent design that evaluated Glycopyrronium 'addon' therapy clinical records for Highrisk COPD. The lack of homogeneity in the ICS/LABA background or current co-therapy with Salmeterol/Fluticasone or Formoterol/Budesonide may have also confounded the overall results in terms of bronchodilation or Trough FEV1 improvement. Nevertheless the results of this post-hoc analyses are significant and first in its kind in demonstrating the effects of LAMA or Glycopyrronium 'add on' therapy in Frequent exacerbator and ACO ie. COPD with Reversibility that can be further validated through randomized or case control clinical studies

Conclusion:-
LAMA remains the backbone of COPD management with their antisecretory and complimentary bronchodilatory actions. The current post-approval, observational, drug utilization, case cohort concurrent analyses highlights the clinical impact of Glycopyrronium 50 mcg dry powder inhaler as 'add on' therapy in High risk severe, symptomatic COPD cases with prior exacerbation. The post-hoc analyses in addition highlights the flexibility of Glycopyrronium 50 mcg dry powder inhaler as 'add on' strategy to ICS/LABA especially for COPD cases due to smoking or nonsmoking risk factors demonstrating reversibility in addition to frequent exacerbators 673 Fig 3:-Treatment emergent adverse events observed for the overall group (n=1117) at 12 wks.