Review 2 Clinical Trials of Mometasone Furoate/ formoterol fumarate (FDC)

Sadudee Boonmee , MD

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.).

• 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

Robert A. Nathan, M.D., Hendrik Nolte, M.D., Ph.D., and David S. Pearlman, M.

Allergy Asthma Proc 31:269–279, 2010

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.)

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

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

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

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.

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

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

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 )

Study End Points

• Secondary end points (cont.)5) change from baseline in A.M. PEF and symptom scores6) total 24 hr SABA usage7) time to moderate asthma exacerbation

( detail in slide 32 )

Results

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, mediantimes to first asthma deterioration could not bedetermined

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

Results• Improvement in Lung Function

Results• Improvement in Lung Function

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).

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 )

• Effect of MF/F on asthma control and QoL

• 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)

• 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

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

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 newsafety signals was detected

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

• 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

Allergy Asthma Proc 31:280 –289, 2010

Steven F. Weinstein, M.D., Jonathan Corren, M.D., Kevin Murphy, M.D., Hendrik Nolte, M.D.,

and Martha White, M.D.

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, prebaselinebaseline (day 1), and at weeks 1, 4, 8, and 12

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 receiveMDI MF/F 200/10 mcgMF/F 400/10 mcgMF 400 mcg

b.i.d. for 12 weeks

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

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.)

MethodsExclusion 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.

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)

Study End Points

primary end pointAssessment 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

Secondary End points 1) change from baseline to week 12 in the Asthma Control Questionnaire2) 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 medication4) trough FEV1 (evaluate the end points of the dosing interval )

• 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

Results

Total 643 pt ( 88.3%) complete study

Results

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

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

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)

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

Results

• Secondary end points

Compared with MFalone, both doses of MF/F reduced the proportion ofnocturnal awakeningsrequiring SABA rescue medication (p ≤ 0.006)

Results• Secondary end points

Both doses of MF/F reduced mean total asthma symptomscores more than MF alone (p ≤0.001)

Results• Secondary end points

Both doses ofMF/F combination therapy were significantly superiorto MF alone in improving ACQ total scores at week 12 p ≤ 0.014

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

Results• Safety

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%)

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

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

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)

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.

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

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