Peak expiratory flow as an endpoint for clinical trials in asthma: a comparison with FEV1

David M G Halpin, Eli O Meltzer, Wendelgard Pisternick-Ruf, Petra Moroni-Zentgraf, Michael Engel, Liliana Zaremba-Pechmann, Thomas Casale, J Mark FitzGerald, David M G Halpin, Eli O Meltzer, Wendelgard Pisternick-Ruf, Petra Moroni-Zentgraf, Michael Engel, Liliana Zaremba-Pechmann, Thomas Casale, J Mark FitzGerald

Abstract

Background: The primary lung function endpoint in clinical trials in adolescent and adult patients with asthma is usually forced expiratory volume in one second (FEV1). The objective of our analysis was to assess whether peak expiratory flow (PEF) is a suitable alternative primary lung function endpoint.

Methods: For this assessment, we calculated post hoc the correlation between pre-dose FEV1 and pre-dose PEF measured under supervision in the clinic and, for both lung function parameters, the correlations between supervised clinic and unsupervised home measurements, using the results from the 8 Phase III parallel-group trials of the global clinical development programme with tiotropium Respimat® in patients with asthma aged 12 to 75 years.

Results: Across all 8 trials included in this analysis, changes in lung function from baseline correlated well between pre-dose FEV1 and pre-dose PEF when both were measured under supervision in the clinic. Correlation between supervised in-clinic and unsupervised home measurements was stronger for pre-dose PEF than for pre-dose FEV1.

Conclusions: Pre-dose PEF measured at home could be an alternative primary lung function endpoint for trials in adolescent and adult patients with asthma. Using home-measured PEF could facilitate trial conduct and improve the convenience for patients by relocating scheduled assessments from the clinic to the patient's home.

Trial registration: Adolescents aged 12 to 17 years: RubaTinA-asthma® ( NCT01257230 ), PensieTinA-asthma® ( NCT01277523 ). Adults aged 18 to 75 years: GraziaTinA-asthma® ( NCT01316380 ), MezzoTinA-asthma® ( NCT01172808 / NCT01172821 ), CadenTinA-asthma® ( NCT01340209 ), PrimoTinA-asthma® ( NCT00772538 / NCT00776984 ). All from Clinicaltrials.gov ( https://clinicaltrials.gov/ ).

Keywords: Asthma; Correlation; FEV1; Home-measurement; In-clinic measurement; PEF; Tiotropium.

Conflict of interest statement

D. M. G. H. reports personal fees from AstraZeneca, Chiesi and Pfizer, and grants and personal fees from Boehringer Ingelheim, GlaxoSmithKline and Novartis, outside the submitted work. T. C. reports grants and consultancy fees from AstraZeneca, Sanofi/Roche and Novartis, personal fees and consultancy fees from Genentech, and grants from Genentech, outside the submitted work. J. M. F. reports grants from Boehringer Ingelheim, paid directly to UBC, during the conduct of the study; and personal fees from Boehringer Ingelheim, outside the submitted work. E. O. M. reports personal fees from ALK, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Stallergenes, Meda, Merck, Mylan, Sanofi/Regeneron and Teva, outside the submitted work. W. P.-R., P. M.-Z. and M. E. are employees of Boehringer Ingelheim. L. Z.-P. was employed as a contractor by Boehringer Ingelheim during the conduct of the study and is now a contractor at Elderbrook Solutions GmbH.

Figures

Fig. 1
Fig. 1
Overview of correlation analyses. FEV1 = forced expiratory volume in one second; PEF = peak expiratory flow
Fig. 2
Fig. 2
Correlation analysis results between pre-dose FEV1 and pre-dose PEF, measured either under supervision in the clinic or unsupervised at home, at the time of primary efficacy evaluation. Phase III trials with tiotropium Respimat® in patients aged 12–75 years with persistent asthma – all patients analysed for efficacy. (a) In-clinic pre-dose FEV1 vs. in-clinic pre-dose PEF; (b) in-clinic pre-dose FEV1 vs. home-measured pre-dose FEV1a; (c) in-clinic pre-dose PEF vs. home-measured pre-dose PEFb. aHome-measured pre-dose FEV1: weekly mean morning FEV1 in the trials with morning dosing (PrimoTinA-asthma®) and weekly mean evening FEV1 in the trials with evening dosing (RubaTinA-asthma®, PensieTinA-asthma®, GraziaTinA-asthma®, MezzoTinA-asthma®, CadenTinA-asthma®), measured with AM device. bHome-measured pre-dose PEF: weekly mean morning PEF in the trials with morning dosing (PrimoTinA-asthma®) and weekly mean evening PEF in the trials with evening dosing (RubaTinA-asthma®, PensieTinA-asthma®, GraziaTinA-asthma®, MezzoTinA-asthma®, CadenTinA-asthma®), measured with AM device. PEF was not measured at clinic visits in the PrimoTinA-asthma® study. FEV1 = forced expiratory volume in one second; PEF = peak expiratory flow

References

    1. Reddel Helen K., Taylor D. Robin, Bateman Eric D., Boulet Louis-Philippe, Boushey Homer A., Busse William W., Casale Thomas B., Chanez Pascal, Enright Paul L., Gibson Peter G., de Jongste Johan C., Kerstjens Huib A. M., Lazarus Stephen C., Levy Mark L., O'Byrne Paul M., Partridge Martyn R., Pavord Ian D., Sears Malcolm R., Sterk Peter J., Stoloff Stuart W., Sullivan Sean D., Szefler Stanley J., Thomas Mike D., Wenzel Sally E. An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations. American Journal of Respiratory and Critical Care Medicine. 2009;180(1):59–99. doi: 10.1164/rccm.200801-060ST.
    1. European Medicines Agency. Guideline on the clinical investigation of medicinal products for the treatment of asthma (CHMP/EWP/2922/01 Rev. 1). 2015. . Accessed 28 June 2019.
    1. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Expert panel report 3: guidelines for the diagnosis and management of asthma. 2007. . Accessed 28 June 2019.
    1. Boehringer Ingelheim Limited. Summary of product characteristics – Spiriva Respimat 2.5 microgram, inhalation solution. October 2018. . Accessed June 28, 2019.
    1. U.S. Food and Drug Administration. Prescribing information for Spiriva® Respimat® (tiotropium bromide) inhalation spray, for oral inhalation. 2017. . Accessed 22 Oct 2018.
    1. Hamelmann Eckard, Bateman Eric D., Vogelberg Christian, Szefler Stanley J., Vandewalker Mark, Moroni-Zentgraf Petra, Avis Mandy, Unseld Anna, Engel Michael, Boner Attilio L. Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. Journal of Allergy and Clinical Immunology. 2016;138(2):441-450.e8. doi: 10.1016/j.jaci.2016.01.011.
    1. Hamelmann E, Bernstein JA, Vandewalker M, Moroni-Zentgraf P, Verri D, Unseld A, et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur Respir J. 2017;49:1601100. doi: 10.1183/13993003.01100-2016.
    1. Paggiaro Pierluigi, Halpin David M.G., Buhl Roland, Engel Michael, Zubek Valentina B., Blahova Zuzana, Moroni-Zentgraf Petra, Pizzichini Emilio. The Effect of Tiotropium in Symptomatic Asthma Despite Low- to Medium-Dose Inhaled Corticosteroids: A Randomized Controlled Trial. The Journal of Allergy and Clinical Immunology: In Practice. 2016;4(1):104-113.e2.
    1. Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015;3(5):367–376. doi: 10.1016/S2213-2600(15)00031-4.
    1. Ohta Ken, Ichinose Masakazu, Tohda Yuji, Engel Michael, Moroni-Zentgraf Petra, Kunimitsu Satoko, Sakamoto Wataru, Adachi Mitsuru. Long-Term Once-Daily Tiotropium Respimat® Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study. PLOS ONE. 2015;10(4):e0124109. doi: 10.1371/journal.pone.0124109.
    1. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–1207. doi: 10.1056/NEJMoa1208606.
    1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–338. doi: 10.1183/09031936.05.00034805.
    1. Liu J, Tang W, Chen G, Lu Y, Feng C, Tu XM. Correlation and agreement: overview and clarification of competing concepts and measures. Shanghai Arch Psychiatry. 2016;28(2):115–120.
    1. Tepper RS, Wise RS, Covar R, Irvin CG, Kercsmar CM, Kraft M, et al. Asthma outcomes: pulmonary physiology. J Allergy Clin Immunol. 2012;129(Suppl 3):S65–S87. doi: 10.1016/j.jaci.2011.12.986.
    1. Shingo S, Zhang J, Reiss TF. Correlation of airway obstruction and patient-reported endpoints in clinical studies. Eur Respir J. 2001;17(2):220–224. doi: 10.1183/09031936.01.17202200.
    1. Santanello NC, Barber BL, Reiss TF, Friedman BS, Juniper EF, Zhang J. Measurement characteristics of two asthma symptom diary scales for use in clinical trials. Eur Respir J. 1997;10(3):646–651.
    1. Meltzer EO, Pearlman DS, Eckerwall G, Uryniak T, DePietro M, Lampl K. Efficacy and safety of budesonide administered by pressurized metered-dose inhaler in children with asthma. Ann Allergy Asthma Immunol. 2015;115(6):516–522. doi: 10.1016/j.anai.2015.09.007.

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