Review 2 Clinical Trials of Mometasone Furoate/ Formoterol Fumarate


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Review 2 Clinical Trials of Mometasone Furoate/ Formoterol Fumarate

Presented by Sadudee Boonmee, MD.

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  • Patients were randomized 1:1:1:1 to receive two inhalations/dose of MF/F 200/10 g(100/5 g/inhalation), MF 200 g (100 g/inhalation),F 10 g (5 g/inhalation), or placebo (
  • Patients were randomized 1:1:1:1 to receive two inhalations/dose of MF/F 200/10 g(100/5 g/inhalation), MF 200 g (100 g/inhalation),F 10 g (5 g/inhalation), or placebo (
  • (2 consecutive days of ≥ 8 puff of any combination of SABA or NB Tx(one nebulizer treatment wasequivalent to 6 puffs of SABA).)
  • provide a better opportunity to characterizethe treatment response, because patients onICS/LABA combinations before the screening visitwere likely to show higher forced expiratory volume in1 second (FEV1) and lower reversibility at screening
  • (ACQ) total score14 (scores range from 0 to 6; high scores indicate poorer asthma control)AQLQ(s) total score15 (scores range from 1 to 7; high scoresindicate less impairment)
  • Impaired lung functionUncontrol asthma But relatively high AQLQ(s) 4.9 in population with severe asthma
  • Baseline defined as mean of two predose measurements (30 min before dosing and immediately before dosing) on day 1.#p 0.001 compared with MF 400 g
  • Review 2 Clinical Trials of Mometasone Furoate/ Formoterol Fumarate

    1. 1. Review 2 Clinical Trials of Mometasone Furoate/formoterol fumarate (FDC) Sadudee Boonmee , MD
    2. 2. Introduction• Mometasone Furoate (MF) is a potent ICS with high affinity for glucocorticoid receptors, low systemic bioavailability, and clinical efficacy in patients with asthma.• MF reduces the frequency and severity of asthma deteriorations in children and adults• Formoterol (F)is known to rapidly increase lung function and maintain bronchodilation over 24 hours when administered at 10 mcg twice daily (b.i.d.).
    3. 3. • The efficacy of mometasone furoate and formoterol fumarate was mainly assessed in 2 multicenter, randomized, double-blind, parallel group clinical trials• Mometasone furoate and formoterol fumarate dihydrate 100 µg/5 µg and 200 µg/5 µg for inhalation was approved by FDA in June 2010 for the treatment of asthma in patients ≥12 years of age
    4. 4. Robert A. Nathan, M.D., Hendrik Nolte, M.D., Ph.D., and David S. Pearlman, M. Allergy Asthma Proc 31:269–279, 2010
    5. 5. Methods• Study Design• 26-week, randomized, multicenter, double- blind,double-dummy, placebo-controlled, parallel-group study in 152 sites across North America, Latin America, Europe, and Asia• Screening was followed by a 2- to 3-week, open label, run-in period with MF metered- dose inhaler, 200 mcg, twice daily (b.i.d.)
    6. 6. Methods• monitored for asthma deteriorations throughout the study• provided asthma action plan, immediate access to rescue medication (oral steroids and short-acting 2-agonists [SABA])• regular office visits and 24-hour access to physician contact
    7. 7. Methods• Inclusion criteria• aged ≥ 12 years with history of asthma for 12 months on a stable asthma regimen (daily dose unchanged) for 2 weeks at screening• history of medium-dose ICS use ( = daily dose of 400 g of BDP) for 12 weeks, with or without additional LABA
    8. 8. Methods• Fulfil one of the following criteria - increase FEV1 of ≥ 12% or a volume increase of ≥ 200 mL after 15–20 minutes of albuterol/salbutamol administration or of a nebulized SABA - PEF variability of 20% - diurnal variation PEF of 20% - At screening, patients’ FEV1 was 60% - 90% of predicted - At baseline, patients’ FEV1 was 60 - 85% of predicted,when all restricted medications had been withheld for 4 hours
    9. 9. Methods• Exclusion criteria - unstable asthma (screening and baseline) - emergency room treatment for an asthma deterioration (systemic corticosteroid therapy or hospitalization within the 3 mo before baseline - concomitant asthma medication - history of current or past smoking (10 pack years) - significant abnormal vital sign - visible oropharyngeal candidiasis at baseline or earlier.
    10. 10. Methods• Clinical visit at - screening - prebaseline (D1) - week 1, 4, 8, 16, 20, 26 and or end of treatment (EOT)• Efficacy evaluated by - PFT at all visit - serial spirometer at baseline and wk 1, 12, and 26 and/or EOT visit
    11. 11. Methods• Patient record - SABA usage - oral prednisolone/prednisolone use - number of nocturnal awakenings requiring SABA - PEF measurement - A.M. and P.M. asthma symptom score daily record in e-diaries• The Asthma Quality of Life Questionaire with standard activities (AQLQs) and Asthma Control Questionaire (ACQ) complete at baseline, wk 4, 12, and 26 ; and/or EOT
    12. 12. Study End Points• Coprimary end point : inflammatory and respiratory aspect - time to first asthma deterioration for MF/F versus F - bronchodilatory effect of MF/F versus MF• Secondary end points - change from baseline to wk 26 in 1) AQLQ(s) total score for MF/F vs placebo 2) ACQ total score for MF/F vs placebo 3) proportion of nocturnal awakenings due to asthma requiring SABA 4) trough FEV1 (evaluate the end points of the dosing interval )
    13. 13. Study End Points• Secondary end points (cont.) 5) change from baseline in A.M. PEF and symptom scores 6) total 24 hr SABA usage 7) time to moderate asthma exacerbation ( detail in slide 32 )
    14. 14. Results
    15. 15. Results• Reduction in Asthma Deterioration 341 patients experienced asthma deterioration at some point during the study • MF/F and MF delay time to first asthma deterioration compared with F and placebo ( P‹ 0.001) • Medial time to first asthma deterioration in F and placebo were 92 and 131 day respectively • ‹ 50% of the patients in the MF/F and MF experienced asthma deterioration, median times to first asthma deterioration could not be determined
    16. 16. Results Significantly fewer patients receiving MF/F and MF compared with F and placebo experienced an asthma deterioration (all p < 0.001)
    17. 17. Results• Improvement in Lung Function
    18. 18. Results• Improvement in Lung Function
    19. 19. Results• Trough FEV1 measured before inhalation of the A.M.dose• Treatment with MF/F was significantly better than treatment with F after week 1 (p 0.001) and placebo at all time points (p ≤ 0.006). Treatment with MF/F was also statistically better than treatment with MF at several time points, including week 26 (p = 0.023).
    20. 20. Results -A.M. PEF of MF/F group improved by wk 1 compared with placebo (P < 0.001) and sustained throughout study -EOT change from baseline in A.M. PEF significant greater in MF/F group than placebo ( P ≤ 0.008) - MF alone statistic significant vs Placebo (P < 0.001 )
    21. 21. • Effect of MF/F on asthma control and QoL
    22. 22. • statistically significant and clinically• important improvement in asthma control (ACQ total scores) for patients treated with MF/F• MF/F (- 0.52) versus F (-0.20) or versus placebo (- 0.22; p < 0.001 for both)• The MF/F group showed improved asthma control, with ACQ scores approaching the “well-controlled” threshold (ACQ score, ≤ 1.0)
    23. 23. • MF group showed numerical improvements in asthma control versus F and versus placebo at week 26• F monotherapy did not show significantly improved asthma control versus placebo at any time point
    24. 24. Discussion• MF/F on asthma deteriorations was assessed - Asthma deteriorations ( diminished lung function,PEF for at least 2 days, FEV1) - Clinically judge deteriorations (hospitalization, emergency department visit, or treatment with systemic steroids for asthma)• Treatment with MF/F compared with F monotherapy and placebo reduced asthma deteriorations• Contribution of F shown superior of MF/F vs MF on lung function
    25. 25. Discussion• Mometasone have an additive and stabilizing effect on FEV1 and daily PEF compared with F alone as noted by a significant drop in lung• Patients receiving MF/F reported improvements in asthma control with ACQ scores,improvements in day and nighttime symptoms, QoL, and reduced requirement for rescue medication compared with other treatment groups• MF/F were well tolerated, no new safety signals was detected
    26. 26. Conclusion• Mometasone furoate/Formoterol fumarate (MF/F) show more effective than monocomponent in controlling asthma and reducing the risk of asthma deterioration in patient with persistent asthma uncontrolled on medium- dose ICS• MF/F 200/10 mcg improved lung function more than treatment with either of individual constitue compounds
    27. 27. • moderate asthma exacerbation defined as any of the following - 2 consecutive nights with one or more nocturnal awakenings due to asthma symptom require SABA - decrease in A.M. or P.M. PEF ≥ 25% on 2 consecutive days of treatment - increase short acting bronchodilator
    28. 28. Steven F. Weinstein, M.D., Jonathan Corren, M.D., Kevin Murphy, M.D., Hendrik Nolte, M.D., and Martha White, M.D. Allergy Asthma Proc 31:280 –289, 2010
    29. 29. Methods• Study design - 12-week, randomized, multicenter, double- blind, parallel-group study conducted in 115 clinical center in North America, Latin America, Russia, Ukraine, and Europe (according with Good Clinical Practice) - Visit schedule at screening, prebaseline baseline (day 1), and at weeks 1, 4, 8, and 12
    30. 30. Methods• Pt. severe asthma completed a 2- to 3-week open-label run-in period with MDI- administered MF 400 mcg b.i.d(to standardize treatment before randomization)• At baseline eligible Pt. were randomized in a 1:1:1 ratio to receive MDI MF/F 200/10 mcg MF/F 400/10 mcg b.i.d. for 12 weeks MF 400 mcg
    31. 31. Methods• Study Population Inclusion criteria - Pt. ≥ 12 years with a diagnosis of asthma of 12 months duration - History of asthma deteriorations within 2–12 months of screening requiring treatment with oral glucocorticoid steroids - Receiving a high daily dose of ICS (= 1000 mcg of beclomethasone) with or without a LABA for 12 weeks before screening - On a stable asthma treatment regimen (daily dose unchanged) for 2 weeks at screening
    32. 32. MethodsAsthma-related inclusion criteria- Prebronchodilator FEV1 of 50–85% ofpredicted atbaseline- β2- agonist reversibility after 4 inhalations ofalbuterol ( ≥ 12% and ≥ 200 mL of FEV1)- 20% diurnal variation of PEF between A.M.predose PEF and postdose PEF from theprevious evening (P.M.)
    33. 33. MethodsExclusion criteria- unstable asthma between screening andbaseline (emergency treatment orhospitalization, treatment with systemiccorticosteroids)- ventilator support for respiratory failuresecondary to asthma- upper or lower respiratory tract infection(viral or bacterial) within 2 weeks before thescreening and baseline visits.
    34. 34. MethodsExclusion criteria - Concomitant asthma medication - Current smoking or a history of smoking 10 pack-years - Women breast-feeding, pregnant, or intended to become pregnant during the study period - Abnormal electrocardiogram (ECG)
    35. 35. Study End Pointsprimary end point Assessment of the bronchodilatory effect of MDI MF/F 400/10 mcg b.i.d. compared with MF 400 mcg b.i.d. by the mean change from baseline to week 12 in FEV1 AUC 0–12h measured by serial spirometry over 12 hours
    36. 36. Secondary End points 1) change from baseline to week 12 in the Asthma Control Questionnaire 2) change from baseline to week 12 in the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) 3) change from baseline in the proportion of nocturnal awakenings requiring SABA rescue medication 4) trough FEV1 (evaluate the end points of the dosing interval )
    37. 37. • Secondary End points 5) Number of asthma deterioration Asthma deterioration defined by any one of three following criteria - FEV1 decrease below 80% of baseline - PEF decrease below 70% of baseline for at least 2 consecutive days - Clinically judged deterioration (ER treatment, Hospitalization, treat with additional asthma medication : steroid)• Spirometry measure at baseline, wk.1 and wk 12• ACQ and AQLQ(s) assessed at baseline, wk 4, 8, 12
    38. 38. ResultsTotal 643 pt ( 88.3%) complete study
    39. 39. Results
    40. 40. Resultsprimary end point• FEV1 AUC 0–12h between baseline and week 12 for both MF/F 200/10 mcg and MF/F 400/10 mcg treatment groups ( # p < 0.001)• Tx with MF/F 400/10 mcg greater change in FEV1 AUC 0–12h than MF/F 200/10 mcg all time point
    41. 41. Results• primary end point : serial spirometry Both MF/F significant superior to MF alone (P < 0.001) as early as 5 min at Day 1 and at week 12 Day 1 Wk 12
    42. 42. ResultsSecondary end points• Trough FEV1 - week 12 MF/F 400/10 mcg significantly superior to MF 400 mcg (p = 0.006) and at all other time points (p ≤ 0.04) - MF/F 200/10 mcg was statistically superior to MF 400 mcg only at week 4 (p = 0.027)
    43. 43. Results• Secondary end points Predose A.M. PEF significant improve in both MF/F group - Wk 1 P < 0.001 - Wk 12 P ≤ 0.003
    44. 44. Results• Secondary end points Compared with MF alone, both doses of MF/F reduced the proportion of nocturnal awakenings requiring SABA rescue medication (p ≤ 0.006)
    45. 45. Results• Secondary end points Both doses of MF/F reduced mean total asthma symptom scores more than MF alone (p ≤0.001)
    46. 46. Results• Secondary end points Both doses of MF/F combination therapy were significantly superior to MF alone in improving ACQ total scores at week 12 p ≤ 0.014
    47. 47. Results• Secondary end points• Mean AQLQ(s) baseline were high in all treatment group.• Mean change from baseline to wk 12 were similar between treatment groups: 0.50, 0.61, and 0.51 for MF 400 g, MF/F 200/10 g, and MF/F 400/10 g, respectively.• small clinically meaningful improvement in patients’ quality of life
    48. 48. Results• Safety
    49. 49. Results• The majority of patients had AEs were mild or moderate in intensity and unrelated to study medication• Patients reporting AEs related to the study drug was 4.8% - oral candidiasis (0.7%) - cough (0.5%) - dysphonia (0.5%)
    50. 50. Discussion• Lung function improvements were significantly more rapid with both strengths of MF/F compared with MF alone.• The statistical superiority of MF/F treatments over MF was maintained over time as determined by FEV1 AUC0–12h outcomes at week 12
    51. 51. Discussion• clinically significant contribution of F to the MF/F in additional improvement in lung function in Pt. with severe asthma who were receiving MF 400 g during the run-in period without a washout before receiving the study medication
    52. 52. Discussion• Improved bronchodilation, both doses of MF/F induced superior asthma control compared with MF alone ( Measure asthma control : trough FEV1, nocturnal awakenings requiring rescue medication, total asthma symptom scores, SABA use, and A.M. and P.M. PEF, statistically favored both doses of MF/F compared with MF alone)
    53. 53. Conclusion• Measurements of both the bronchodilatory and the anti- inflammatory effects demonstrated superiority of MF/F compared with MF alone• Addition of F significantly contributes to the efficacy of MF/F for rapid and sustained improvement in lung function, control of asthma symptoms, and reduction of asthma deteriorations in patients with severe asthma.• Both strengths of MF/F combination therapy (200/10 g b.i.d. and 400/10 g b.i.d.) were found to be safe and effective in treatment of severe, poorly control asthma.
    54. 54. Dosing was approved by FDA as 2 inhalationstwice daily at either the 100 µg/5 µg or 200µg/5 µg dose Clin.Pharm. Review
    55. 55. Thank You