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Kirill Zhudenkov,1 Robert Palmér,2 Alexandra Jauhiainen,3 Gabriel Helmlinger,4,5 Oleg Stepanov,1 Kirill Peskov,1,6 Ulf G Eriksson,2 Ulrika Wählby Hamrén2 1M&S Decisions LLC, Moscow, Russia; 2Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 3BioPharma Early Biometrics and Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Boston, MA, USA; 5Clinical Pharmacology, Toxicology, Quantitative Sciences, Obsidian Therapeutics, Cambridge, MA, USA; 6I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Moscow, RussiaCorrespondence: Ulrika Wählby HamrénR&D, AstraZeneca, Pepparedsleden 1, Mölndal SE-431 83, SwedenTel +46 31 776 2295Email Ulrika.wahlby-hamren@astrazeneca.comBackground: Lung function, measured as forced expiratory volume in one second (FEV1), and exacerbations are two endpoints evaluated in chronic obstructive pulmonary disease (COPD) clinical trials. Joint analysis of these endpoints could potentially increase statistical power and enable assessment of efficacy in shorter and smaller clinical trials.Objective: To evaluate joint modelling as a tool for analyzing treatment effects in COPD clinical trials by quantifying the association between longitudinal improvements in FEV1 and exacerbation risk reduction.Methods: A joint model of longitudinal FEV1 and exacerbation risk was developed based on patient-level data from a Phase III clinical study in moderate-to-severe COPD (1740 patients), evaluating efficacy of fixed-dose combinations of a long-acting bronchodilator, formoterol, and an inhaled corticosteroid, budesonide. Two additional studies (1604 and 1042 patients) were used for external model validation and parameter re-estimation.Results: A significant (p< 0.0001) association between FEV1 and exacerbation risk was estimated, with an approximate 10% reduction in exacerbation risk per 100 mL improvement in FEV1, consistent across trials and treatment arms. The risk reduction associated with improvements in FEV1 was relatively small compared to the overall exacerbation risk reduction for treatment arms including budesonide (10– 15% per 160 μg budesonide). High baseline breathlessness score and previous history of exacerbations also influenced the risk of exacerbation.Conclusion: Joint modelling can be used to co-analyze longitudinal FEV1 and exacerbation data in COPD clinical trials. The association between the endpoints was consistent and appeared unrelated to treatment mechanism, suggesting that improved lung function is indicative of an exacerbation risk reduction. The risk reduction associated with improved FEV1 was, however, generally small and no major impact on exacerbation trial design can be expected based on FEV1 alone. Further exploration with other longitudinal endpoints should be considered to further evaluate the use of joint modelling in analyzing COPD clinical trials.Keywords: lung function, bronchodilator, anti-inflammatory |
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