Das perfekte Paar bei COPD langwirksame Betaagonisten und langwirksame Muskarinrezeptorantagonisten als Standard?

Transkript

1 Das perfekte Paar bei COPD langwirksame Betaagonisten und langwirksame Muskarinrezeptorantagonisten als Standard?

2 Das perfekte Paar bei COPD langwirksame Betaagonisten und langwirksame Muskarinrezeptorantagonisten als Standard? Claus F. Vogelmeier

3 COPD Behandlungsalgorithmen Möglichkeiten Behandlungsalgorithmus 1 Behandlungsalgorithmus 2 Symptompersistenz Einzelner Bronchodilatator Häufige Exazerbationen Einzelner Bronchodilatator 2 Bronchodilatatoren Weiterhin fehlende Kontrolle 1 Bronchodilatator + 1 Entzündungshemmer Symptompersistenz 2 Bronchodilatatoren und häufige Exazerbationen dreifach (2 Bronchodilatatoren + Entzündungshemmer) Weiterhin fehlende Kontrolle + Andere dreifach (2 Bronchodilatatoren + Entzündungshemmer) + Andere Weiterhin fehlende Kontrolle

4 COPD Behandlungsalgorithmen Möglichkeiten Behandlungsalgorithmus 1 Behandlungsalgorithmus 2 Symptompersistenz Einzelner Bronchodilatator Häufige Exazerbationen Einzelner Bronchodilatator 2 Bronchodilatatoren 1 Bronchodilatator + 1 Entzündungshemmer Symptompersistenz 2 Bronchodilatatoren und häufige Exazerbationen

5 COPD-Patienten: Prototypen für Therapie(n) mit Bronchodilatatoren Einzelsubstanz Neu diagnostiziert Keine Vortherapie Moderate Symptomatik Exazerbationshistorie /+ Duale Bronchodilatation Noch symptomatisch trotz LAMA oder LABA Hoch symptomtisch Exazerbationshistorie +

6 UPLIFT - Study Design Run in 2 weeks Treatment period 4 years (48 month) 30 days follow-up Tiotropium qd All previously prescribed respiratory medications permitted (except inhaled anticholinergics) Stop: Tiotropium qd Start: Ipratropium qid Placebo qd Screening Day 1 Randomization Day 30 Every 6 months 4 years End of trial End of follow up Spirometry Spirometry + SGRQ Spirometry Spirometry + SGRQ Spirometry + SGRQ Spirometry Vital status Tashkin, et al. NEJM 2008

7 UPLIFT: Therapienaive Patienten Tiotropium Plazebo Patienten (n) Alter (Jahre) FEV1 (% Soll) 53 ± ± 12 Troosters et al., AJRCCM 179:A2467, 2009

8 FEV 1 - Verlust (ml/jahr) UPLIFT: Therapienaive Patienten FEV 1 - Verlust Tiotropium Plazebo p = Troosters et al., AJRCCM 179:A2467, 2009

9 GOLD 2015 Effekte von langwirksamen Bronchodilatatoren LAMAs Lungenfunktion Symptome Lebensqualität Exazerbationen/Hospi talisierungen Kein Effekt auf Verlust an Lungenfunktion LABAs Lungenfunktion Symptome Lebensqualität Exazerbationen Kein Effekt auf Verlust an Lungenfunktion Kein Effekt auf Mortalität Modifiziert nach GOLD Summary 2015

10 Indacaterol vs tiotropium in severe COPD: INVIGORATE study design Severe COPD + 1 exacerbation last year (n=3,444, FEV 1 = 40.5%) ICS use (72%) Indacaterol 150 µg Tiotropium 18 µg 1 yr Trough FEV 1 at Week 12 Exacerbation rate at Week 52 FEV 1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid Decramer ML et al. Lancet Respir Med 2013;1:

11 Patients with exacerbations (%) Indacaterol vs tiotropium in severe COPD: INVIGORATE Time to first moderate/severe exacerbation Indacaterol (150 μg) Tiotropium (18 μg) Number at risk Indacaterol Tiotropium Time to first exacerbation (months) Decramer ML et al. Lancet Respir Med 2013;1:

12 Aclidinium in COPD: ATTAIN study design Double-blind, multicentre trial Patients (n=819 a ) with moderate-to-severe COPD Run-in Aclidinium bromide 200 µg BID Aclidinium bromide 400 µg BID Follow-up Placebo BID -2 wks Screening Wk 0 Randomization / baseline Wk 1 Wk 4 Wk 8 Wk 12 Wk 18 Wk 24 Primary endpoint Wk 26 Primary variable: Change from baseline in morning pre-dose (trough) FEV 1 Aclidinium 200 g is not licensed for use in patients with COPD a Intent-to-treat and safety populations BID, twice-daily; FEV 1, forced expiratory volume in 1 second Jones P et al. Eur Respir J 2012;40:

13 Rate of COPD exacerbations per patient per year Aclidinium in COPD - ATTAIN Exacerbations Placebo BID Aclidinium 200 µg BID Aclidinium 400 µg BID * * * * HCRU 0.0 EXACT Aclidinium 200 g is not licensed for use in patients with COPD *p<0.05 vs placebo BID, twice-daily; EXACT, Exacerbations of Chronic Pulmonary Disease Tool; HCRU, Healthcare resource utilisation Jones P et al. Eur Respir J 2014;44:

14 COPD-Patienten: Prototypen für Therapie(n) mit Bronchodilatatoren Einzelsubstanz Neu diagnostiziert Keine Vortherapie Moderate Symptomatik Exazerbationshistorie /+ Duale Bronchodilatation Noch symptomatisch trotz LAMA oder LABA Hoch symptomtisch Exazerbationshistorie +

15 LABA/LAMA - Kombinationen Einmal täglich Zweimal täglich Glycopyrronium/Indacaterol Umeclidinium/Vilanterol Tiotropium/Olodaterol Aclidinium/Formoterol Glycopyrronium/Formoterol Glycopyrronium/Indacaterol

16 AECOPDs bei Glycopyrronium+Indacaterol vs Glycopyrronium vs. Tiotropium SPARK Studiendesign (N=2224) Pre-Randomization Period Double-blind Treatment Period* Variable Double-blind Treatment Period* Prescreening Screening/ Run-in period QVA /50μg qd via Breezhaler (SDDPI) Glycopyrronium 50μg qd via Breezhaler (SDDPI) Open-label tiotropium 18μg qd via Handihaler Day -21 to Day -15 Day -14 to Day -1 Day 1 to Day 448 Day 448 to Day 532 Randomization JA Wedzicha et al., Lancet Respir Med 2013;1:

17 AECOPDs bei Glycopyrronium+Indacaterol vs Glycopyrronium vs. Tiotropium SPARK Einschlusskriterien Inclusion criteria Male or female, 40 years, severe to very severe COPD (Stage III or IV) Current or ex-smokers with smoking history 10 pack years Post-bronchodilator FEV 1 <50% of the predicted normal value, and post-bronchodilator FEV 1 /FVC <0.7 at Visit 2 (Day 14) Documented history of at least one COPD exacerbation in previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics JA Wedzicha et al., Lancet Respir Med 2013;1:

18 AECOPDs bei Glycopyrronium+Indacaterol vs Glycopyrronium vs. Tiotropium SPARK Rate an AECOPDs JA Wedzicha et al., Lancet Respir Med 2013;1:

19 Aclidinium/Formoterol: Studiendesign der Zulassungsstudien (ACLIFORM 1 und AUGMENT 2 ) Doppelblinde, 24-wöchige Studien mit mittelgradiger bis schwerer COPD Primäre Endpunkte: FEV1 (1-h post dose & Trough) Sekundäre Endpunkte: Transitional Dyspnoe Index (TDI), SGRQ 2 3 Wochen Run-in Phase ACLI/FORM 400/12 μg b.i.d. ACLI/FORM 400/6 μg b.i.d. ACLI 400 μg b.i.d. FORM 12 μg b.i.d. Placebo 2 Wochen Follow-up Woche 1 Screening Woche 4 Woche 12 Woche 18 Woche 24 1 Singh D et al. BMC Pulm Med 2014; 2 D Urzo et al. Respir Res 2014 ACLI Aclidiniumbromid, FORM Formoterolfumarat-Dihydrat

20 Δ TDI Focal Score von Ausgangswert Aclidinium/Formoterol Dyspnoe (TDI) ACLIFORM 1 AUGMENT 2 1.3**** 1.4**** MCID MCID Placebo FORM 12 µg ACLI 400 µg ACLI/FORM 400/12 µg Placebo FORM 12 µg ACLI 400 µg ACLI/FORM 400/12 µg 1 Singh et al. BMC Pulm Med 2014;14:178; 2 D Urzo et al. Respir Res 2014;12:123 ****p ACLI aclidinium bromide, FORM formoterol fumarat dihydrate MCID, minimum clinically important difference ( 1 unit increase in TDI focal score)

21 Exazerbationsrate Aclidinium/Formoterol Moderate/schwere Exazerbationen (HCRU) 0,6 0,5 0,4-29 %* 0,3 0,2 0,1 0 0,41 0,36 0,35 0,29 Placebo FORM 12 µg ACLI 400 µg ACLI/FORM 400/12 µg *p < 0,05 vs. Placebo, HCRU (Health Care Resource Utilization) = Patientenangaben über Inanspruchnahmen von Gesundheitsdiensten ACLI/FORM 400/12µg signifikant vs. Placebo (gepoolte Analyse) Bateman et al. Eur Respir J 2014;44:Suppl. 58:Abstract 285 ACLI Aclidiniumbromid, FORM Formoterolfumarat-Dihydrat

22 Studies of LABA/LAMA vs ICS/LABA: COPD patients without frequent exacerbations ILLUMINATE 1 LANTERN 2 AFFIRM 3 LABA/LAMA vs ICS/LABA non-inferior or superior (for some endpoints) ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist 1. Vogelmeier C et al. Lancet Respir Med 2013;1: Zhong N et al. Eur Respir J 2014;44(Suppl 58):P Vogelmeier C et al. Presented at American Thoracic Society 2015, A3974.

23 AFFIRM: Aclidinium/formoterol vs salmeterol/fluticasone in COPD Study design 24-week treatment period 1-week Run-in Aclidinium bromide 400 µg / Formoterol fumarate 12 µg BID Salmeterol 50 µg / Fluticasone propionate 500 µg BID N=933 randomized (1:1) Serial spirometry sub-study in 29% (n=271) 2-week Follow-up Primary endpoint: Peak FEV 1 at Week 24 Secondary endpoint: Improvement in TDI focal score at Week 24 BID, twice-daily; FEV 1, forced expiratory volume in 1 second; TDI, transition dyspnoea index Vogelmeier C et al. Presented at American Thoracic Society 2015, A3974.

24 Peak FEV 1 (L) Least square means Aclidinium/formoterol vs salmeterol/fluticasone in COPD: Primary endpoint Peak FEV 1 at Week ml p<0.001 Aclidinium/formoterol Salmeterol/fluticasone FEV 1, forced expiratory volume in 1 second Vogelmeier C et al. Presented at American Thoracic Society 2015, A3974.

25 TDI Focal score (improvement from baseline) Aclidinium/formoterol vs salmeterol/fluticasone in COPD: TDI (dyspnoea) 2,5 Aclidinium/formoterol Salmeterol/fluticasone 2,0 1,5 1,0 MCID 0,5 0,0 Week 4 Week 12 Week 24 MCID, minimal clinically important difference; TDI, transition dyspnoea index Vogelmeier C et al. Presented at American Thoracic Society 2015, A3974.

26 LAC-39 AFFIRM: safety profile n (%) Aclidinium bromide / formoterol fumarate 400/12 µg BID (n=467) Salmeterol/ fluticasone 500/50 µg BID (n=466) AEs 235 (50.3) 265 (56.9) AEs leading to discontinuation 25 (5.4) 34 (7.3) SAEs 35 (7.5) 33 (7.1) ICS-related AEs of interest Any event 20 (4.3) 50 (10.7) Pneumonia 2 (0.4) 9 (1.9) Osteoporosis / osteopenia 0 3 (0.6) Vogelmeier C et al. Am J Respir Crit Care Med 2015;191:A3974

27 Dieter Chmelar