Skip to main content
SpringerLink
Log in

Evaluation of New Drugs for Asthma and COPD: Endpoints, Biomarkers and Clinical Trial Design

  • Chapter
  • First Online:
Pharmacology and Therapeutics of Asthma and COPD

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 237))

Abstract

There remains a considerable need to develop novel therapies for patients with asthma and chronic obstructive pulmonary disease (COPD). The greatest challenge at the moment is measuring the effects of novel anti-inflammatory drugs, as these drugs often cause only small effects on lung function. Measurements that demonstrate the pharmacological and clinical effects of these drugs are needed. Furthermore, we now recognise that only subgroups of patients are likely to respond to these novel drugs, so using biomarkers to determine the clinical phenotype most suitable for such therapies is important. An endotype is a subtype of a (clinical) condition defined by a distinct pathophysiological mechanism. An endotype-driven approach may be more helpful in drug development, enabling drugs to be targeted specifically towards specific biological mechanisms rather than clinical characteristics. This requires the development of biomarkers to define endotypes and/or to measure drug effects. This newer approach should continue alongside efforts to optimise the measurement of clinical endpoints, including patient-reported outcome measurements, required by drug regulatory authorities.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agusti A (2014) The path to personalised medicine in COPD. Thorax 69:857–864

    Article  PubMed  Google Scholar 

  • Anderson WJ, Short PM, Williamson PA, Lipworth BJ (2012) Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENO type trial. Chest 142:1553–1561

    Article  CAS  PubMed  Google Scholar 

  • Arron JR, Choy DF, Scheerens H, Matthews JG (2013) Non-invasive biomarkers that predict treatment benefit from biologic therapies in asthma. Ann Am Thorac Soc 10(Suppl):S206–S213

    Article  PubMed  Google Scholar 

  • Aul R, Armstrong J, Duvoix A, Lomas D, Hayes B, Miller BE, Jagger C, Singh D (2012) Inhaled LPS challenges in smokers: a study of pulmonary and systemic effects. Br J Clin Pharmacol 74:1023–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aul R, King H, Kolsum U, Singh D (2013) The reproducibility of bolus allergen challenges; power calculations for clinical trials. Eur J Clin Pharmacol 69:1187–1188

    Article  PubMed  Google Scholar 

  • Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE (2012a) Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 186:48–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bafadhel M, McCormick M, Saha S, McKenna S, Shelley M, Hargadon B, Mistry V, Reid C, Parker D, Dodson P, Jenkins M, Lloyd A, Rugman P, Newbold P, Brightling CE (2012b) Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration 83:36–44

    Article  CAS  PubMed  Google Scholar 

  • Barnes NC, Qiu YS, Pavord ID, Parker D, Davis PA, Zhu J, Johnson M, Thomson NC, Jeffery PK, SCO30005 Study Group (2006) Anti-inflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med 173:736–743

    Article  CAS  PubMed  Google Scholar 

  • Barnes NC, Saetta M, Rabe KF (2014a) Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulm Med 14:9. doi:10.1186/1471-2466-14-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Barnes PJ, Casale TB, Dahl R, Pavord ID, Wechsler ME (2014b) The Asthma Control Questionnaire as a clinical trial endpoint: past experience and recommendations for future use. Allergy 69:1119–1140

    Article  CAS  PubMed  Google Scholar 

  • Betts JC, Mayer RJ, Tal-Singer R, Warnock L, Clayton C, Bates S, Hoffman BE, Larminie C, Singh D (2015) Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trial. Pharmacol Res Perspect 3

    Google Scholar 

  • Bonini M, Di Maria G, Paggiaro P, Rossi A, Senna G, Triggiani M, Canonica GW (2014) Potential benefit of omalizumab in respiratory diseases. Ann Allergy Asthma Immunol 113:513–519

    Article  CAS  PubMed  Google Scholar 

  • Boorsma M, Lutter R, van de Pol MA, Out TA, Jansen HM, Jonkers RE (2007) Repeatability of inflammatory parameters in induced sputum of COPD patients. COPD 4:321–329

    Article  PubMed  Google Scholar 

  • Borrill ZL, Clough D, Truman N, Morris J, Langley SJ, Singh SD (2006) A comparison of exhaled nitric oxide measurements performed using 3 different analysers. Respir Med 100:1392–1396

    Article  PubMed  Google Scholar 

  • Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, Pavord ID (2000) Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 356:1480–1485

    Article  CAS  PubMed  Google Scholar 

  • Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, Berry M, Parker D, Monteiro W, Pavord ID, Bradding P (2005) Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 60:193–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, Jones PW, Mahler DA, Make B, Miravitlles M, Page CP, Palange P, Parr D, Pistolesi M, Rennard SI, Rutten-van Mölken MP, Stockley R, Sullivan SD, Wedzicha JA, Wouters EF, American Thoracic Society, European Respiratory Society Task Force on outcomes of COPD (2008) Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 31:416–469

    Article  CAS  PubMed  Google Scholar 

  • Celli BR, Barnes PJ (2007) Exacerbations of chronic obstructive pulmonary disease. Eur Respir J 29:1224–1238

    Article  CAS  PubMed  Google Scholar 

  • Cockcroft D, Davis B (2009) Direct and indirect challenges in the clinical assessment of asthma. Ann Allergy Asthma Immunol 103:363–369

    Article  CAS  PubMed  Google Scholar 

  • Corren J (2012) Inhibition of interleukin-5 for the treatment of eosinophilic diseases. Discov Med 13:305–312

    PubMed  Google Scholar 

  • Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365:1088–1098

    Article  CAS  PubMed  Google Scholar 

  • Diamant Z, Sidharta PN, Singh D, O’Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J (2014) Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy 44:1044–1052

    Article  CAS  PubMed  Google Scholar 

  • Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, Lettis S, Crim C, Calverley PM (2013) Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 1:210–223

    Article  CAS  PubMed  Google Scholar 

  • Duong M, Gauvreau G, Watson R, Obminski G, Strinich T, Evans M et al (2007) The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge. J Allergy Clin Immunol 119:322–327

    Article  CAS  PubMed  Google Scholar 

  • Fahy JV (2015) Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol 15:57–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faner R, Tal-Singer R, Riley JH, Celli B, Vestbo J, MacNee W, Bakke P, Calverley PM, Coxson H, Crim C, Edwards LD, Locantore N, Lomas DA, Miller BE, Rennard SI, Wouters EF, Yates JC, Silverman EK, Agusti A, ECLIPSE Study Investigators (2014) Lessons from ECLIPSE: a review of COPD biomarkers. Thorax 69:666–672

    Article  PubMed  Google Scholar 

  • Franciosi LG, Diamant Z, Banner KH, Zuiker R, Morelli N, Kamerling IM, de Kam ML, Burggraaf J, Cohen AF, Cazzola M, Calzetta L, Singh D, Spina D, Walker MJ, Page CP (2013) Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med 1:714–727

    Article  CAS  PubMed  Google Scholar 

  • Gietema HA, Muller NL, Fauerbach PV, Sharma S, Edwards LD, Camp PG, Coxson HO (2011) Quantifying the extent of emphysema: factors associated with radiologists’ estimations and quantitative indices of emphysema severity using the ECLIPSE cohort. Acad Radiol 18:661–671

    Article  PubMed  Google Scholar 

  • Gizycki MJ, Hattotuwa KL, Barnes N, Jeffery PK (2002) Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue. Thorax 57:799–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbröker D, Bethke TD, Hiemstra PS, Rabe KF (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62:1081–1087

    Article  PubMed  PubMed Central  Google Scholar 

  • Gupta V, Banyard A, Mullan A, Sriskantharajah S, Southworth T, Singh D (2014) Characterisation of the inflammatory response to inhaled LPS in mild to moderate COPD. Br J Clin Pharmacol 79(5):767–776. doi:10.1111/bcp.12546

    Article  Google Scholar 

  • Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID (2009) Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 360:973–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodsman P, Ashman C, Cahn A, De Boever E, Locantore N, Serone A, Pouliquen I (2013) A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics. Br J Clin Pharmacol 75:118–128

    Article  CAS  PubMed  Google Scholar 

  • Hohlfeld JM, Schoenfeld K, Lavae-Mokhtari M, Schaumann F, Mueller M, Bredenbroeker D, Krug N, Hermann R (2008) Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial. Pulm Pharmacol Ther 21:616–623

    Article  CAS  PubMed  Google Scholar 

  • Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P et al (2010) SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J 35:564–570

    Article  CAS  PubMed  Google Scholar 

  • Houghton CM, Langley SJ, Singh SD, Holden J, MoniciPreti AP, Acerbi D, Poli G, Woodcock AA (2004) Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study. Br J Clin Pharmacol 58:359–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators, (2010) Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 363(12):1128–1138

    Article  CAS  PubMed  Google Scholar 

  • Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, Carter R, Audusseau S, Hamid Q, Bradding P, Fahy JV, Woodruff PG, Harris JM, Arron JR, Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group (2012) Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 130:647–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones PW, Donohue JF, Nedelman J, Pascoe S, Pinault G, Lassen C (2011) Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respir Res 12:161

    Article  PubMed  PubMed Central  Google Scholar 

  • Jones P, Miravitlles M, van der Molen T, Kulich K (2012) Beyond FEV1 in COPD: a review of patient-reported outcomes and their measurement. Int J Chron Obstruct Pulmon Dis 7:697–709

    Article  PubMed  PubMed Central  Google Scholar 

  • Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA (2014a) Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med 189:250–255

    Article  PubMed  Google Scholar 

  • Jones PW, Lamarca R, Chuecos F, Singh D, Agustí A, Bateman ED, de Miquel G, Caracta C, Garcia GE (2014b) Characterisation and impact of reported and unreported exacerbations: results from ATTAIN. Eur Respir J 44:1156–1165

    Article  PubMed  Google Scholar 

  • Kent SE, Boyce M, Diamant Z, Singh D, O’Connor BJ, Saggu PS, Norris V (2013) The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma. Clin Exp Allergy 43:177–186

    Article  CAS  PubMed  Google Scholar 

  • Ketchell RI, Jensen MW, Lumley P, Wright AM, Allenby MI, O’Connor BJ (2002) Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5′-monophosphate in mild asthma. J Allergy Clin Immunol 110:603–606

    Article  CAS  PubMed  Google Scholar 

  • Khurana S, Ravi A, Sutula J, Milone R, Williamson R, Plumb J, Vestbo J, Singh D (2014) Clinical characteristics and airway inflammation profile of COPD persistent sputum producers. Respir Med 108:1761–1770

    Article  CAS  PubMed  Google Scholar 

  • Kim V, Davey A, Comellas AP, Han MK, Washko G, Martinez CH, Lynch D, Lee JH, Silverman EK, Crapo JD, Make BJ, Criner GJ, OPDGene® Investigators (2014) Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPD Gene study. Respir Res 15:52

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirsten A, Watz H, Kretschmar G, Pedersen F, Bock D, Meyer-Sabellek W et al (2011) Efficacy of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects--a double blind, randomized, placebo-controlled, cross-over clinical trial. Pulm Pharmacol Ther 24:555–558

    Article  CAS  PubMed  Google Scholar 

  • Korevaar DA, Westerhof GA, Wang J, Cohen JF, Spijker R, Sterk PJ, Bel EH, Bossuyt PM (2015) Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med. pii: S2213–2600(15)00050-8

    Google Scholar 

  • Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C, Tal-Singer R (2011) SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br J Clin Pharmacol 72:282–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356:2144–2148

    Article  CAS  PubMed  Google Scholar 

  • Lee DK, Haggart K, Currie GP, Bates CE, Lipworth BJ (2004) Effects of hydrofluoroalkane formulations of ciclesonide 400 microg once daily vs fluticasone 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Br J Clin Pharmacol 58:26–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee WY, Southworth T, Booth S, Singh D (2014) High and low dose allergen challenges in asthma patients using inhaled corticosteriods. Br J Clin Pharmacol. doi:10.1111/bcp.12508 [Epub ahead of print]

    Google Scholar 

  • Leidy NK, Murray LT, Monz BU, Nelsen L, Goldman M, Jones PW, Dansie EJ, Sethi S (2014) Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials. Respir Res 15:124

    Article  PubMed  PubMed Central  Google Scholar 

  • Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H, Barnes NC, Tal-Singer R, Losmapimod Study Investigators (2012) An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol 52:416–424

    Article  CAS  PubMed  Google Scholar 

  • Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA (2011) Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 127:355–360

    Article  PubMed  Google Scholar 

  • MacNee W, Allan RJ, Jones I, De Salvo MC, Tan LF (2013) Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 68:738–745

    Article  PubMed  Google Scholar 

  • Maris NA, de Vos AF, Dessing MC, Spek CA, Lutter R, Jansen HM, van der Zee JS, Bresser P, van der Poll T (2005) Anti-inflammatory effects of salmeterol after inhalation of lipopolysaccharide by healthy volunteers. Am J Respir Crit Care Med 172:878–884

    Article  PubMed  Google Scholar 

  • Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF (2015) Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 385:857–866

    Article  CAS  PubMed  Google Scholar 

  • Michel O, Nagy AM, Schroeven M, Duchateau J, Neve J, Fondu P et al (1997) Dose–response relationship to inhaled endotoxin in normal subjects. Am J Respir Crit Care Med 156:1157–1164

    Article  CAS  PubMed  Google Scholar 

  • Michel O, Dentener M, Cataldo D, Cantinieaux B, Vertongen F, Delvaux C et al (2007) Evaluation of oral corticosteroids and phosphodiesterase-4 inhibitor on the acute inflammation induced by inhaled lipopolysaccharide in human. Pulm Pharmacol Ther 20:676–683

    Article  CAS  PubMed  Google Scholar 

  • Moretti M (1999) Spontaneous and induced sputum to measure indices of airway inflammation in COPD. Eur J Respir Dis Suppl 14(supp 30):24s

    Google Scholar 

  • Morgan AR, Parker GJ, Roberts C, Buonaccorsi GA, Maguire NC, Hubbard Cristinacce PL, Singh D, Vestbo J, Bjermer L, Jögi J, Taib Z, Sarv J, Bruijnzeel PL, Olsson LE, Bondesson E, Nihlén U, McGrath DM, Young SS, Waterton JC, Nordenmark LH (2014) Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD. Eur J Radiol 83:2093–2101

    Article  PubMed  Google Scholar 

  • Nolte H, Pavord I, Backer V, Spector S, Shekar T, Gates D, Nair P, Hargreave F (2013) Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma. Respir Med 107:656–664

    Article  PubMed  Google Scholar 

  • Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P, MENSA Investigators (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 371:1198–1207

    Article  PubMed  Google Scholar 

  • Palmqvist M, Bruce C, Sjöstrand M, Arvidsson P, Lötvall J (2005) Differential effects of fluticasone and montelukast on allergen-induced asthma. Allergy 60:65–70

    Article  CAS  PubMed  Google Scholar 

  • Pizzichini E, Pizzichini MM, Efthimiadis A, Evans S, Morris MM, Squillace D et al (1996) Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med 154:308–317

    Article  CAS  PubMed  Google Scholar 

  • Pizzichini E, Pizzichini MM, Leigh R et al (2002) Safety of sputum induction. Eur Respir J Suppl 37:9s–18s

    CAS  PubMed  Google Scholar 

  • Porsbjerg C, Sverrild A, Backer V (2013) The usefulness of the mannitol challenge test for asthma. Expert Rev Respir Med 7:655–663

    Article  CAS  PubMed  Google Scholar 

  • Purokivi M, Randell J, Hirvonen MR, Tukiainen H (2000) Reproducibility of measurements of exhaled NO, and cell count and cytokine concentrations in induced sputum. Eur Respir J 16:242–246

    Article  CAS  PubMed  Google Scholar 

  • Rossall MR, Cadden PA, Molphy SD, Plumb J, Singh D (2014) Repeatability of induced sputum measurements in moderate to severe asthma. Respir Med 108:1566–1568

    Article  PubMed  Google Scholar 

  • Sapey E, Bayley D, Ahmad A et al (2008) Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability. Thorax 63493–499

    Google Scholar 

  • Simpson JL, Scott R, Boyle MJ, Gibson PG (2006) Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 11:54–61

    Article  PubMed  Google Scholar 

  • Singh D (2015) New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future perspectives. Br J Clin Pharmacol 79:695–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh SD, Richards D, Knowles RG, Schwartz S, Woodcock AA, Langley SJ, O’Connor BJ (2007) Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma. Am J Respir Crit Care Med 176:988–993

    Article  CAS  PubMed  Google Scholar 

  • Singh D, Petavy F, Macdonald AJ, Lazaar AL, O’Connor BJ (2010) The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 11:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Singh D, Cadden P, Hunter M, Collins LP, Perkins M, Pettipher R, Townsend E, Vinall S, O’Connor B (2013) Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J 41:46–52

    Article  CAS  PubMed  Google Scholar 

  • Stockley RA (2014) Biomarkers in chronic obstructive pulmonary disease: confusing or useful? Int J Chron Obstruct Pulmon Dis 9:163–177

    Article  PubMed  PubMed Central  Google Scholar 

  • Taylor DA, Jensen MW, Kanabar V, Engelstätter R, Steinijans VW, Barnes PJ, O’Connor BJ (1999) A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5′-monophosphate in asthmatic patients. Am J Respir Crit Care Med 160:237–243

    Article  CAS  PubMed  Google Scholar 

  • van Beek EJ, Dahmen AM, Stavngaard T, Gast KK, Heussel CP, Krummenauer F, Schmiedeskamp J, Wild JM, Søgaard LV, Morbach AE, Schreiber LM, Kauczor HU (2009) Hyperpolarised 3He MRI versus HRCT in COPD and normal volunteers: PHIL trial. Eur Respir J 34:1311–1321

    Article  PubMed  Google Scholar 

  • Virchow JC, Backer V, de Blay F, Kuna P, Ljørring C, Prieto JL, Villesen HH (2015) Defining moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement. Respir Med 109(5):547–556

    Article  PubMed  Google Scholar 

  • Wedzicha JA, Rabe KF, Martinez FJ, Bredenbröker D, Brose M, Goehring UM, Calverley PM (2013) Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest 143:1302–1311

    Article  CAS  PubMed  Google Scholar 

  • Wedzicha JA, Singh D, Vestbo J, Paggiaro PL, Jones PW, Bonnet-Gonod F, Cohuet G, Corradi M, Vezzoli S, Petruzzelli S, Agusti A, FORWARD Investigators (2014) Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med 108:1153–1162

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M (2007) Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370:1422–1431

    Article  CAS  PubMed  Google Scholar 

  • Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G (2013) Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 368:2455–2466

    Article  CAS  PubMed  Google Scholar 

  • Witt CA, Sheshadri A, Carlstrom L, Tarsi J, Kozlowski J, Wilson B, Gierada DS, Hoffman E, Fain SB, Cook-Granroth J, Sajol G, Sierra O, Giri T, O’Neill M, Zheng J, Schechtman KB, Bacharier LB, Jarjour N, Busse W, Castro M, NHLBI Severe Asthma Research Program (SARP) (2014) Longitudinal changes in airway remodeling and air trapping in severe asthma. Acad Radiol 21:986–993

    Article  PubMed  PubMed Central  Google Scholar 

  • Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A 104:15858–15863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolhouse IS, Bayley DL, Stockley RA (2002) Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax 57:667–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Worth A, Hammersley V, Knibb R, Flokstra-de-Blok B, Dunn Galvin A, Walker S, Dubois AE, Sheikh A (2014) Patient-reported outcome measures for asthma: a systematic review. NPJ Prim Care Respir Med 24:14020

    PubMed  PubMed Central  Google Scholar 

  • Zhang WJ, Hubbard Cristinacce PL, Bondesson E, Nordenmark LH, Young SS, Liu YZ, Singh D, Naish JH, Parker GJ (2015) MR Quantitative Equilibrium Signal Mapping: a reliable alternative to CT in the assessment of emphysema in patients with chronic obstructive pulmonary disease. Radiology 132953 [Epub ahead of print]

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medicines Evaluation Unit, University of Manchester, University Hospital of South Manchester Foundations Trust, Langley Building, Southmoor Road, Wythenshawe, Manchester, M23 9Q2, UK

    Dave Singh

Authors
  1. Dave Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dave Singh .

Editor information

Editors and Affiliations

  1. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, United Kingdom

    Clive P. Page

  2. Airway Disease Section, Imperial College, National Heart and Lung Institute, London, United Kingdom

    Peter J. Barnes

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Singh, D. (2016). Evaluation of New Drugs for Asthma and COPD: Endpoints, Biomarkers and Clinical Trial Design. In: Page, C., Barnes, P. (eds) Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, vol 237. Springer, Cham. https://doi.org/10.1007/164_2016_70

Download citation

Publish with us

Policies and ethics

Search

Navigation