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Studies

Studies. AHEAD COSMOS and COMPASS. The AHEAD Study. R. AHEAD: Study Design. Six-month, double-blind, double-dummy. 2 inh. budesonide/formoterol 160/4.5 µg b.i.d. plus as-needed (n=1154). Run-in. Regular ICS

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Studies

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  1. Studies AHEAD COSMOS and COMPASS

  2. The AHEAD Study

  3. R AHEAD: Study Design Six-month, double-blind, double-dummy 2 inh. budesonide/formoterol 160/4.5 µg b.i.d. plus as-needed (n=1154) Run-in Regular ICS ≥500 µg plus LABA* 1 inh. fluticasone/salmeterol 50/500 µg b.i.d. plus terbutaline 0.4 mg as-needed (n=1155) Enrolled: 3346 Randomized: 2309 Visit: 1 2 3 4 5 Week: –2 0 4 13 26 Randomization *Only if taken as maintenance treatment before study entry Bousquet et al. AHEAD trial. Respir Med 2008; accepted.

  4. Patient Characteristics *Pre-bronchodilator SMART = Symbicort Maintenance And Reliever Therapy Symbicort = budesonide/formoterol (bud/form) Seretide = fluticasone/salmeterol (fu/salm) Bousquet et al. AHEAD trial. Respir Med 2008; accepted.

  5. SMART Flu/salm + SABA Time to First and Second Severe Exacerbations Patients with exacerbation (%) 15 5 1st exacerbation (primary variable) 2nd exacerbation 4 10 3 2 5 1 0 0 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Days since randomization 1st exacerbation,SMART vs. flu/salm+SABA: 18% difference in exacerbation risk, P=0.12

  6. Cumulative Rate of SevereExacerbations Exacerbations/patient 0.3 SMART reduced rate by 21% vs. Flu/salm + SABA SMART Flu/salm + SABA 0.2 P<0.05 0.1 0.0 0 30 60 90 120 150 180 Days since randomization

  7. Reduction in Exacerbation Risk and Rate by Event Type Treatment group % Reduction SMART vs. flu/salm + SABA Flu/salm + SABA n=1153 SMART n=1151 All exacerbations No. (%) patients 130 (11) 108 (9) 18 Events/patient/yearª 0.31 0.25 21* Hospitalization/ ER treatment No.(%) patients 59 (5) 39 (3) 34* Events/patient/yearª 0.13 0.09 31* *P <0.05; a Extrapolated from 6-month study

  8. Flu/salm + SABA SMART Severe Exacerbations by Type No. of events Exacerbation subtypes 173 175 150 137 * 150 125 90 125 73 100 70 100 100 86 51 75 50 75 50 30 50 25 25 10 0 0 0 Oral steroid courses Hospitalizations/ ER visits Total exacerbations *P <0.05

  9. Cumulative Rate of Hospitalizations/ ER Treatments Due to Asthma Hospitalization/ER treatment/patient 0.2 SMART reduced rate by 31% vs. flu/salm + SABA SMART Flu/salm + SABA 0.1 P<0.05 0.0 0 30 60 90 120 150 180 Days since randomization

  10. As-needed Use and Symptom Score During Exacerbations Total number of as-needed inhalations * Total asthma symptom score * SMART SMART 5 5 Seretide + SABA Flu/salm + SABA 4.1 4 4 3.1 3.1 3 3 2.7 2 2 1 1 0 0 -12 -9 -6 -3 0 3 6 9 12 15 -12 -9 -6 -3 0 3 6 9 12 15 Days relative to start of exacerbation Days relative to start of exacerbation * Number of events: SMART, 137; flu/salm +SABA, 173

  11. Additional Treatments for Severe Exacerbations (descriptive statistics) % difference SMART vs. flu/salm + SABA 20 Xanthines added Beta2-agonists added Oral steroids added 0 1009-833 days 94-39 days 171-68 days -20 17% fewer days with SMART -40 -60 60% fewer days with SMART 59% fewer days with SMART -80

  12. Reduction in Exacerbation Rates in Patients Ever Using >4 Inh. As-Needed/day (mechanism of action analysis) Subgroup with high use % reduction SMART vs. flu/salm + SABA Subgroup N (%) Flu/salm + SABA 333 (29%) SMART 305 (26%) All exacerbations Events/patient/yearª 0.46 0.27 41** Hospitalization/ ER treatment Events/patient/year ª 0.21 0.10 53** **P <0.01 from post-hoc analysis of patients with at least 1 study day with high as-needed use. a Extrapolated from data in patients after the first day with greater than 4 as-needed inh. of reliever therapy

  13. Change in Awakenings Due to Asthma Awakenings (%) NS 40 20 0 Run-in Treatment Run-in Treatment Flu/salm + SABA SMART

  14. Change in As-needed Inhalation-free Days As-needed free days (%) NS 60 40 20 0 Treatment Treatment Run-in Run-in SMART Flu/salm + SABA

  15. Change in Asthma Control Days* Asthma control days (%) NS 60 40 20 0 Run-in Treatment Run-in Treatment Flu/salm + SABA SMART * Asthma control days = symptom- & rescue-free days plus awakening-free nights

  16. Day-to-Day Asthma Control Adjusted mean change SMART vs. Flu/salm + SABA P value Flu/salm + SABA n=1153 SMART n=1151 Total daily symptom score (0-6) -0.90 -0.90 P=0.92 Symptom free days, % 37 36 P=0.73 Total daily as-needed inh. -1.2 -1.3 P=0.36 As-needed inh.- free days, % 47 46 P=0.56 Awakenings, % -19 -20 P=0.11 Asthma control days, % 38 37 P=0.37 Morning PEF, L/min 28 27 P=0.67 Evening PEF, L/min 22 23 P=0.42

  17. Inhalations/24h 2.4 SMART Flu/salm + SABA 2.0 1.6 1.2 P=NS 0.8 0.4 0 20 40 60 80 100 120 140 160 180 Days since randomization Daily Mean Use of As-needed Inhalations

  18. Flu/salm + SABA SMART Percentage of Days with Different Levels of As-needed Use Mean % of days 60 No as-needed use on 59% of days in both groups 50 40 30 20 >4 inh. as needed: Flu/salm + SABA: 3.6 % SMART: 2.7 % 10 0 0 1 2 3 4 5 6 7 8 >8 As-needed inhalations

  19. Distribution of Average Daily Reliever Use Average daily no. of as-needed inh. 4 Percentiles 90th 3 75th Median 25th 10th 2 50% of patients in both groups used < 0.51 inh./day as-needed 25% of patients in both groups used <1 inh./week as-needed 1 0.51 0.51 0 Flu/salm + SABA SMART

  20. Corticosteroid Load Level of use Flu/salm + SABA n=1153 SMART n=1151 Mean ICS dose, maintenance plus as needed (mg/day) Not adjusted (FP vs. BUD) 1000 792 Adjusted (BDP equivalent)* 2000 1238 Oral corticosteroid use/group No. of courses 139 106 *Adapted from GINA 2006, page 29

  21. Distribution of Mean Daily Budesonide Dose in the SMART Group Patients (%) 70 <1 inh./day prn 60 50 40 30 <2 inh./day prn 20 <3 inh./day prn No extra prn <4 inh./day prn 10 >4 inh./day prn 0 640 641-800 801-960 961-1120 1121-1280 >1281 Mean budesonide dose (µg/day)

  22. Distribution of Mean Daily ICS Dose in BDP Equivalents* vs. Fluticasone/Salmeterol Group Patients (%) Mean daily inhaled ICS dose (BDP equiv. µg/day) 70 60 50 40 Flu/salm 1000/daily = 2000µg/daily BDP equivalents >90% of SMART patients use a lower daily ICS dose vs. the prescribed dose of flu/salm 30 20 10 0 1000 >2000 1001- 1250 1251- 1500 1501- 1750 1751- 2000 *Adapted from GINA 2006, page 29

  23. Summary of Adverse Events AE = adverse event; SAE = serious adverse event; DAE = discontinuation due to adverse event *Includes one death due to typhoid fever

  24. The COSMOS Study

  25. Seretide 2 inh. 50/500 µg + salbutamol as needed Seretide 2 inh. 50/250 µg + salbutamol as needed Seretide 2 inh. 50/100 µg + salbutamol as needed COSMOS Study Design Randomized, open-label effectiveness study (N=2,143) Run-in: 2 weeks R ICS 500 µg/day  LABA Symbicort 4 inh. 160/4.5 µg + Symbicort as needed Symbicort 2 inh. 160/4.5 µg + Symbicort as needed Weeks 0 4 12 26 52 Dose titration phase (at scheduled or unscheduled visits) Inh.=inhalations; Seretide=fluticasone/salmeterol (flu/salm); Symbicort=budesonide/formoterol (bud/form) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  26. Salbutamol prn (patient) Bud/form prn (patient) 2 inh. 50/500 µg Titration (doctor) 4 inh. 160/4.5 µg 2 inh. 50/250 µg Titration (doctor) 2 inh. 50/100 µg 2 inh. 160/4.5 µg COSMOS Examined Two Treatment Concepts Daily asthma medication Bud/form group Flu/salm group (1 inhaler) (up to 4 different inhalers) prn=as-needed use Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  27. Males, n (%) 429 (40) 451 (42) Mean age, years (range) 45 (12-84) 45 (12-80) 73 73 12.5 12.5 Mean reversibility in FEV1, % Mean ICS at entry, mg/day 881 888 Long-acting b2-agonists, % 38 38 Mean SABA use, inh./day 2.7 2.6 Smoking pack-years 5 5 Patient Characteristics Flu/salm+SABA SMART Characteristic (n=1076) (n=1067) Mean FEV1, % predicted* SMART=Symbicort Maintenance And Reliever Therapy *Pre-bronchodilator Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  28. Flu/salm:1076 Bud/form:1067 Completed on treatment: 907 (84%) 930 (87%) Patient Flow Enrolled: 2509 Randomized: 2143 Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  29. Risk of Having a First Severe Exacerbation Patients with exacerbation (%) 25 Risk reduction: 25% (CI: 7, 39%) Flu/salm+SABA 20 SMART 15 P=0.01 10 5 0 Time (days) 0 80 240 160 320 Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  30. Cumulative Rate of Severe Exacerbations Event rate Flu/salm 0.31 SMART 0.24 Events/patient/year 0.32 NNT=14 Flu/salm+SABA SMART 0.24 0.16 Decrease in rate: 22% (CI: 9, 44%) P<0.01 0.08 Time (days) 0 80 240 160 320 Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28. Titration phase

  31. COSMOS: ICS Dose and Exacerbation Rate Total ICS dose mg/day (BDP equivalents) Cumulative exacerbation rate 1500 0.32 1250 0.24 1000 750 0.16 Difference in rate= 0.24 vs 0.31 500 Flu/salm Bud/form maintenance + as needed 0.08 Difference in rate= 0.03 vs 0.04 Bud/form maintenance only 250 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Titration phase Titration phase Time post-randomization (days) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  32. Severe Exacerbations Flu/salm+SABA SMART P<0.01* Exacerbation subtypes 400 329 300 255 280 70 70 62 217 50 50 200 50 42 200 174 39 30 30 120 100 10 10 40 0 Oral steroidcourses without hospital/ER visits Unscheduled visits only Hospitalizations/ ER visits Total exacerbations *Poisson regression analysis Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  33. 16% 24% 34% 37% * Flu/salm (7.2 days/event) vs. SMART (5.9 days/event) Exacerbation Burden (descriptive statistics) Reduction (%) with SMART vs. Flu/salm+SABA 10 Unscheduled visits Oral steroid days Hospital days ER visits 0 154 to 117 2978 to 1980 45 to 38 94 to 59* -10 -20 -30 -40 Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  34. P<0.05 (post-terbutaline) Both Regimens Provide Sustained Increases inPre- and Post-bronchodilator FEV1 Mean FEV1 (L) 2.65 2.55 P=0.07 (pre-terbutaline) 2.45 Flu/salm+SABA 2.35 SMART 2.25 Weeks 0 4 12 26 52 Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  35. Self-reported Relief Medication Use (estimated for two weeks prior to each visit) Reliever use (mean inh./day) 1.2 Flu/salm (as-needed salbutamol) 0.8 P<0.001 SMART 0.4 0 Weeks 0 4 12 26 52 Treatment Flu/salm: 0.9 inh./day Bud/form: 0.6 inh./day Baseline Flu/salm: 2.7 inh./day Bud/form: 2.6 inh./day Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  36. COSMOS: ICS Dose and Rescue Use As-needed rescue (inh./day) Total ICS dose mg/day (BDP equivalents) 1500 1.0 1250 Difference overall 38% P>0.001 0.75 1000 750 0.50 500 Flu/salm Bud/form maintenance + as needed 0.25 Bud/form maintenance only 250 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Titration phase Titration phase Time post-randomization (days) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  37. Patients with Low As-needed Use at 12 Months Odds of being well-controlled were increased by 68% with SMART (P<0.01) Patients (%) (n=787) 76% 80 (n=688) 66% 60 (n=350) 40 34% (n=247) 24% 20 0 Flu/salm Flu/salm SMART SMART Well-controlled (<4 inh./week as needed)* Not well-controlled (>4 inh./week as needed)* *A criterion for well-controlled asthma in the GOAL study (Bateman et al. Am J Respir Crit Care Med 2004;170(8):836-44) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  38. Maintenance & As-needed Use (Assessed at the final visit) Patients (%) Maintenance ICS level* High 80 Medium Low 60 40 20 0 Flu/salm Flu/salm SMART SMART Well-controlled (<4 inh./week as needed) Not well-controlled (>4 inh./week as needed) *As defined by GINA 2002 Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  39. Symptom Control Questionnaire ACQ5 overall score (0–6) 2.0 1.8 Flu/salm+SABA 1.6 SMART 1.4 P=0.07 1.2 1.0 Weeks 0 4 12 26 52 Titration phase ACQ5 was a short form of the asthma control questionnaire used to assess symptoms. The ACQ5 excluded control measures related to as-needed medication use and lung function. Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  40. Mean Total ICS Dose Over Time BDP equivalent total daily ICS dose (µg) Flu/salm Bud/form (maintenance + as needed) 1400 Bud/form (maintenance only) 1200 1000 800 600 400 200 0 0 60 120 180 240 300 360 Titration phase Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  41. Final Prescribed Maintenance ICS Dose (% of patients ondose) Flu/salm SMART 70 70 68% 58% 50 50 30 30 31% 27% 14% 10 10 (FP mg/day) 200 Low* 500 Medium* 1000 High* 320 Low* (BUD mg/day) 640 Medium* *As defined by GINA 2002 ~1-2% of subjects in both groups used a non-protocolled dose (not shown) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  42. BUD 653 mg/day FP 583mg/day 91 mg prn 562 mg regular Overall Steroid Load Inhaled dose in micrograms (mg/day) Days with oral steroid use* 3500 700 2978 2500 500 1980 1500 300 100 500 0 Flu/salm SMART Flu/salm SMART aDue to asthma exacerbation Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  43. Total Inhaler Prescriptions(Mean number of prescribed study inhalers/patient/year) 20 16.6 Flu/salm (100/250/500 strengths) + albuterol prn 16 5.0 12.7 SMART (160/4.5 strength) for maintenance + as needed 12 11.6 8 4 0 Flu/salm + albuterol SMART Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  44. Health-related Quality of Life Adjusted mean change in AQLQs scores Flu/salm+SABA SMART 0.8 0.6 0.4 0.2 0 Symptoms Activity Emotional Environmental Overall Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  45. Cost Difference SMART vs. Flu/salm+SABA GERMANYa FRANCE ITALY UKb 40 21 Cost increase with SMART 8 0 -1 -15 Cost difference/patient-year (€) -40 Cost decrease with SMART -50 -80 -73 -92 Direct costs Total costs -120 -118 aDifferences in direct and total costs were statistically significant only in Germany b1 £=1.45 Euro (Dec 2004) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  46. Overview of Exposure SMART (n=1064) Flu/salm+SABA (n=1071) Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  47. Number of Patients with the Most Frequently Reported Adverse Events (>3%) SMART (n=1064)n (%) Flu/salm+SABA (n=1071)n (%) Preferred term Adapted from Vogelmeier et al. Eur Respir J 2005;26:819-28.

  48. The COMPASS Study

  49. Study Objective • To compare the efficacy and safety of budesonide/formoterol (bud/form) maintenance and reliever therapy (SMART) with: • Double maintenance dose of bud/form • Fluticasone/salmeterol (flu/salm) at its most frequently prescribed dose SMART = Symbicort Maintenance And Reliever Therapy Adapted from Kuna et al. Int J ClinPract2007;61(5):725-36.

  50. COMPASS: Study Design Six-month, double-blind, double-dummy Flu/salm 25/125 µg 2 inh. bd + Bricanyl as reliever (n=1123) Run-in Regular ICS ≥500 µg Bud/form320/9 µg 1 inh. bd + terbutalineas reliever (n=1105) R Enrolled: n=4399 Randomized: n=3335 Bud/form 160/4.5 µg 1 inhalation bd + bud/formas reliever (SMART) (n=1107) Visit: 1 2 3 4 5 Week: -2 0 8 16 24 Adapted from Kuna et al. Int J Clin Pract 2007;61(5):725-36.

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