A Dose Ranging Study With CHF 1531 in Subjects With Asthma (FLASH)

Summary

To evaluate the dose-response of different doses of CHF 1531 pressurized metered dose inhaler (pMDI) containing formoterol fumarate, on lung function and other clinical outcomes and to identify the optimal dose(s) with regard to benefit/ risk ratio for further development in the target subject population.

Timeline

Start

2017-09-08

Primary completion

2018-07-23

Completion

2018-07-28

Publications

• Background Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O'Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De Leon FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2095-128. doi: 10.1016/S0140-6736(12)61728-0.
• Background Tilert T, Dillon C, Paulose-Ram R, Hnizdo E, Doney B. Estimating the U.S. prevalence of chronic obstructive pulmonary disease using pre- and post-bronchodilator spirometry: the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Respir Res. 2013 Oct 9;14(1):103. doi: 10.1186/1465-9921-14-103.
• Background Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest. 2002 May;121(5 Suppl):121S-126S. doi: 10.1378/chest.121.5_suppl.121s.
• Background Tonnesen P. Smoking cessation and COPD. Eur Respir Rev. 2013 Mar 1;22(127):37-43. doi: 10.1183/09059180.00007212.
• Background van Eerd EA, van der Meer RM, van Schayck OC, Kotz D. Smoking cessation for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016 Aug 20;2016(8):CD010744. doi: 10.1002/14651858.CD010744.pub2.
• Background Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013 Oct 15;2013(10):CD010177. doi: 10.1002/14651858.CD010177.pub2.
• Background McGarvey L, Niewoehner D, Magder S, Sachs P, Tetzlaff K, Hamilton A, Korducki L, Bothner U, Vogelmeier C, Koch A, Ferguson GT. One-Year Safety of Olodaterol Once Daily via Respimat(R) in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis. COPD. 2015;12(5):484-93. doi: 10.3109/15412555.2014.991864. Epub 2015 Feb 18.
• Background Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, Bleasdale P, Owen R, Higgins M, Kramer B; INVOLVE (INdacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety) Study Investigators. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010 Jun;65(6):473-9. doi: 10.1136/thx.2009.125435.
• Background Keating GM. Tiotropium bromide inhalation powder: a review of its use in the management of chronic obstructive pulmonary disease. Drugs. 2012 Jan 22;72(2):273-300. doi: 10.2165/11208620-000000000-00000.
• Background Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005 Mar;127(3):809-17. doi: 10.1378/chest.127.3.809.
• Background Kesten S, Casaburi R, Kukafka D, Cooper CB. Improvement in self-reported exercise participation with the combination of tiotropium and rehabilitative exercise training in COPD patients. Int J Chron Obstruct Pulmon Dis. 2008;3(1):127-36. doi: 10.2147/copd.s2389.
• Background Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;(7):CD009285. doi: 10.1002/14651858.CD009285.pub2.
• Background Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222-34. doi: 10.1056/NEJMoa1516385. Epub 2016 May 15.
• Background Yang IA, Clarke MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012 Jul 11;2012(7):CD002991. doi: 10.1002/14651858.CD002991.pub3.
• Background Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014 Mar 10;2014(3):CD010115. doi: 10.1002/14651858.CD010115.pub2.
• Background Yawn BP, Li Y, Tian H, Zhang J, Arcona S, Kahler KH. Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis. Int J Chron Obstruct Pulmon Dis. 2013;8:295-304. doi: 10.2147/COPD.S42366. Epub 2013 Jun 27.
• Background Rachelefsky GS, Liao Y, Faruqi R. Impact of inhaled corticosteroid-induced oropharyngeal adverse events: results from a meta-analysis. Ann Allergy Asthma Immunol. 2007 Mar;98(3):225-38. doi: 10.1016/S1081-1206(10)60711-9.
• Background Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004 Jul;126(1):213-9. doi: 10.1378/chest.126.1.213.
• Background Tashkin DP, Murray HE, Skeans M, Murray RP. Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II. Chest. 2004 Oct;126(4):1123-33. doi: 10.1016/S0012-3692(15)31287-3.
• Background Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009 Sep;34(3):641-7. doi: 10.1183/09031936.00193908. Epub 2009 May 14.
• Background Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Lettis S, Calverley PM. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015 Jan;12(1):27-34. doi: 10.1513/AnnalsATS.201409-413OC.
• Background Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016 Sep;4(9):731-741. doi: 10.1016/S2213-2600(16)30148-5. Epub 2016 Jul 23.
• Background Johnell O, Pauwels R, Lofdahl CG, Laitinen LA, Postma DS, Pride NB, Ohlsson SV. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler. Eur Respir J. 2002 Jun;19(6):1058-63. doi: 10.1183/09031936.02.00276602.
• Background Ferguson GT, Calverley PMA, Anderson JA, Jenkins CR, Jones PW, Willits LR, Yates JC, Vestbo J, Celli B. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Chest. 2009 Dec;136(6):1456-1465. doi: 10.1378/chest.08-3016. Epub 2009 Jul 6.
• Background Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011 Aug;66(8):699-708. doi: 10.1136/thx.2011.160028. Epub 2011 May 20.
• Background Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med. 2010 Nov;123(11):1001-6. doi: 10.1016/j.amjmed.2010.06.019. Epub 2010 Oct 1.
• Background Wang JJ, Rochtchina E, Tan AG, Cumming RG, Leeder SR, Mitchell P. Use of inhaled and oral corticosteroids and the long-term risk of cataract. Ophthalmology. 2009 Apr;116(4):652-7. doi: 10.1016/j.ophtha.2008.12.001. Epub 2009 Feb 25.
• Background Miller DP, Watkins SE, Sampson T, Davis KJ. Long-term use of fluticasone propionate/salmeterol fixed-dose combination and incidence of cataracts and glaucoma among chronic obstructive pulmonary disease patients in the UK General Practice Research Database. Int J Chron Obstruct Pulmon Dis. 2011;6:467-76. doi: 10.2147/COPD.S14247. Epub 2011 Sep 16.
• Background Andrejak C, Nielsen R, Thomsen VO, Duhaut P, Sorensen HT, Thomsen RW. Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis. Thorax. 2013 Mar;68(3):256-62. doi: 10.1136/thoraxjnl-2012-201772. Epub 2012 Jul 10.
• Background Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel N, FitzGerald M; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007 Apr 17;146(8):545-55. doi: 10.7326/0003-4819-146-8-200704170-00152. Epub 2007 Feb 19.
• Background Singh D, Brooks J, Hagan G, Cahn A, O'Connor BJ. Superiority of "triple" therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax. 2008 Jul;63(7):592-8. doi: 10.1136/thx.2007.087213. Epub 2008 Feb 1.
• Background Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med. 2012 Jan;106(1):91-101. doi: 10.1016/j.rmed.2011.09.002. Epub 2011 Oct 29.
• Background Frith PA, Thompson PJ, Ratnavadivel R, Chang CL, Bremner P, Day P, Frenzel C, Kurstjens N; Glisten Study Group. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax. 2015 Jun;70(6):519-27. doi: 10.1136/thoraxjnl-2014-206670. Epub 2015 Apr 3.
• Background Siler TM, Kerwin E, Singletary K, Brooks J, Church A. Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies. COPD. 2016;13(1):1-10. doi: 10.3109/15412555.2015.1034256. Epub 2015 Oct 9.
• Background Singh D, Papi A, Corradi M, Pavlisova I, Montagna I, Francisco C, Cohuet G, Vezzoli S, Scuri M, Vestbo J. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016 Sep 3;388(10048):963-73. doi: 10.1016/S0140-6736(16)31354-X. Epub 2016 Sep 1.
• Background Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006 Jan;129(1):15-26. doi: 10.1378/chest.129.1.15.
• Background Wijesinghe M, Weatherall M, Perrin K, Harwood M, Beasley R. Risk of mortality associated with formoterol: a systematic review and meta-analysis. Eur Respir J. 2009 Oct;34(4):803-11. doi: 10.1183/09031936.00159708.
• Background Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med. 2010 Apr 1;362(13):1169-71. doi: 10.1056/NEJMp1002074. Epub 2010 Feb 24. No abstract available.
• Background Drazen JM, O'Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med. 2009 Apr 16;360(16):1671-2. doi: 10.1056/NEJMe0902057. No abstract available.
• Background Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med. 2011 Jun 30;364(26):2473-5. doi: 10.1056/NEJMp1104375. No abstract available.
• Background Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, Buaron KS, Pascoe SJ; AUSTRI Investigators. Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone. N Engl J Med. 2016 May 12;374(19):1822-30. doi: 10.1056/NEJMoa1511049. Epub 2016 Mar 6.
• Background Stempel DA, Szefler SJ, Pedersen S, Zeiger RS, Yeakey AM, Lee LA, Liu AH, Mitchell H, Kral KM, Raphiou IH, Prillaman BA, Buaron KS, Yun Kirby S, Pascoe SJ; VESTRI Investigators. Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma. N Engl J Med. 2016 Sep 1;375(9):840-9. doi: 10.1056/NEJMoa1606356.
• Background Novartis Pharma. FORADIL®AEROLIZER® US Prescribing Information. Whitehouse Station, New Jersey; 2012 Sep.
• Background Chiesi Farmaceutici S.p.A. A randomized, double blind, double dummy, cumulative dose, safety cross-over trial comparing 4 increasing doses of Formoterol-HFA (pMDI) versus 4 increasing doses of formoterol-DPI (Aerolizer®) and placebo (pMDI or Aerolizer ®) in asthmatic patients. RA/PR/3301/002/01.
• Background Chiesi Farmaceutici S.p.A. A randomized, double blind, double dummy, single dose, crossover trial comparing the efficacy and safety of a single dose administered via 1 puff of 6 μg or 2 puffs of 6 μg of formoterol-HFA (pMDI) versus a single dose of 12 μg of formoterol- DPI (Foradil®Aerolizer®) and of placebo (pMDI or Aerolizer®) in moderate to severe asthmatic patients. RA/PR/3301/009/03.
• Background Bensch G, Lapidus RJ, Levine BE, Lumry W, Yegen U, Kiselev P, Della Cioppa G. A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler. Ann Allergy Asthma Immunol. 2001 Jan;86(1):19-27. doi: 10.1016/s1081-1206(10)62351-4.
• Background Pleskow W, LaForce CF, Yegen U, Matos D, Della Cioppa G. Formoterol delivered via the dry powder Aerolizer inhaler versus albuterol MDI and placebo in mild-to-moderate asthma: a randomized, double-blind, double-dummy trial. J Asthma. 2003;40(5):505-14. doi: 10.1081/jas-120018780.
• Background Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, Till D, Della Cioppa G; Formoterol in Chronic Obstructive Pulmonary Disease I Study Group. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Sep 1;164(5):778-84. doi: 10.1164/ajrccm.164.5.2007006.
• Background Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, Della Cioppa G; Formoterol in Chronic Obstructive Pulmonary Disease (FICOPD) II Study Group. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest. 2002 Apr;121(4):1058-69. doi: 10.1378/chest.121.4.1058.
• Background Mylan Specialty L.P. PERFOROMIST® US Prescribing Information. Morgantown, West Virginia; 2013 Mar.
• Background Gross NJ, Nelson HS, Lapidus RJ, Dunn L, Lynn L, Rinehart M, Denis-Mize K; Formoterol Study Group. Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. Respir Med. 2008 Feb;102(2):189-97. doi: 10.1016/j.rmed.2007.10.007.
• Background Chiesi Farmaceutici S.p.A. CHF 1535 HFA : BDP + formoterol 100/6 μg pressurized inhalation solution : Common Technical Document. Module 2.5: 8.
• Background Bousquet J, Guenole E, Duvauchelle T, Vicaut E, Lefrancois G. A randomized, double-blind, double-dummy, single-dose, crossover trial evaluating the efficacy and safety profiles of two dose levels (12 and 24 microg) of formoterol-HFA (pMDI) vs. those of a dose level (24 microg) of formoterol-DPI (Foradil/Aerolizer) and of placebo (pMDI or Aerolizer) in moderate to severe asthmatic patients. Respiration. 2005;72 Suppl 1:13-9. doi: 10.1159/000083688.
• Background Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5-40. No abstract available.
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• Background Arievich H, Overend T, Renard D, Gibbs M, Alagappan V, Looby M, Banerji D. A novel model-based approach for dose determination of glycopyrronium bromide in COPD. BMC Pulm Med. 2012 Dec 8;12:74. doi: 10.1186/1471-2466-12-74.
• Background Center for Drug Evaluation and Research Medical Review. Clinical Team Leader Memorandum: Formoterol fumarate inhalation solution 20mcg/2mL; NDA # 22-007: 2007 Mar 15.
• Background Gross NJ, Kerwin E, Levine B, Kim KT, Denis-Mize K, Hamzavi M, Carpenter M, Rinehart M. Nebulized formoterol fumarate: Dose selection and pharmacokinetics. Pulm Pharmacol Ther. 2008 Oct;21(5):818-23. doi: 10.1016/j.pupt.2008.07.002. Epub 2008 Jul 8.
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• Background Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of American Thoracic Society-recommended spirometry reference values in a multiethnic sample of adults: the multi-ethnic study of atherosclerosis (MESA) lung study. Chest. 2010 Jan;137(1):138-45. doi: 10.1378/chest.09-0919. Epub 2009 Sep 9.
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Indications