Review 2 Clinical Trials of Mometasone Furoate/ Formoterol Fumarate Presented by Sadudee Boonmee, MD.

1. Review 2 Clinical Trials of
Mometasone Furoate/
formoterol fumarate (FDC)
Sadudee Boonmee , MD

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. • 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. Robert A. Nathan, M.D., Hendrik Nolte, M.D., Ph.D., and
David S. Pearlman, M.
Allergy Asthma Proc 31:269–279, 2010

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.)

7. 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

8. 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

9. 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

10. 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.

11. 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

12. 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

13. 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 )

14. 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 )

15. Results

18. 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

19. Results
Significantly fewer patients
receiving MF/F and MF
compared with F and
placebo experienced an
asthma deterioration
(all p < 0.001)

20. Results
• Improvement in Lung Function

21. Results
• Improvement in Lung Function

23. 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).

24. 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 )

25. • Effect of MF/F on asthma control and QoL

26. • 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)

27. • 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

29. 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

30. 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

31. 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

32. • 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

33. 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

34. 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

35. 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

36. 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

37. Methods
Asthma-related inclusion criteria
- Prebronchodilator FEV1 of 50–85% of
predicted atbaseline
- β2- agonist reversibility after 4 inhalations of
albuterol ( ≥ 12% and ≥ 200 mL of FEV1)
- 20% diurnal variation of PEF between A.M.
predose PEF and postdose PEF from the
previous evening (P.M.)

38. Methods
Exclusion criteria
- unstable asthma between screening and
baseline (emergency treatment or
hospitalization, treatment with systemic
corticosteroids)
- ventilator support for respiratory failure
secondary to asthma
- upper or lower respiratory tract infection
(viral or bacterial) within 2 weeks before the
screening and baseline visits.

39. Methods
Exclusion 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)

40. Study End Points
primary 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

41. 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 )

42. • 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

43. Results
Total 643 pt ( 88.3%) complete study

44. Results

45. Results
primary 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

46. 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

47. Results
Secondary 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)

48. 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

49. 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)

50. Results
• Secondary end points
Both doses of MF/F reduced
mean total asthma symptom
scores more than MF alone
(p ≤0.001)

51. 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

52. 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

53. Results
• Safety

54. 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%)

55. 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

56. 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

57. 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)

58. 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.

59. Dosing was approved by FDA as 2 inhalations
twice daily at either the 100 µg/5 µg or 200
µg/5 µg dose
Clin.Pharm. Review

60. Thank You