Study of Efficacy and Long-Term Safety of Mometasone Furoate in Combination With Formoterol Fumarate Versus Mometasone Furoate in Children (5 to 11 Years of Age) With Persistent Asthma (MK-0887A-087)

Study Overview
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Brief Summary
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This study compares the 12-week efficacy and 24-week safety of mometasone furoate/formoterol fumarate (MF/F) 100/10 mcg and mometasone furate (MF) 100 mcg, both administered twice daily (BID) via metered-dose inhaler (MDI) in children aged 5 to 11 years with persistent asthma.

Official Title
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A Phase III, Randomized, Active-Controlled, Parallel-Group Clinical Trial to Study the Efficacy and Long-Term Safety of Mometasone Furoate/Formoterol Fumarate (MF/F, MK-0887A [SCH418131]), Compared With Mometasone Furoate (MF, MK-0887 [SCH032088]), in Children With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: MF MDI 100 mcg BID (Open Label)
* Drug: MF/F MDI 100/10 mcg BID
* Drug: MF MDI 100 mcg BID
* Drug: Albuterol/Salbutamol PRN
* Drug: Prednisone/Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of asthma of ≥ 6-months duration according to the Global Initiative for Asthma (GINA) guidelines Has asthma that is adequately controlled on a stable dose of inhaled corticosteroid (ICS) combined with long-acting beta-agonist (LABA) ≥ 4 weeks Is able to demonstrate an FEV1 >60% and ≤90% predicted Is able to demonstrate an increase in absolute FEV1 of at least 12% within 30 minutes after administration of albuterol/salbutamol. Is able to use an MDI (without spacer), use a peak flow meter, and perform spirometry correctly. Is willing (with consent of their parent(s)/guardian) to discontinue previously prescribed asthma medication, if there is no inherent harm in changing the participant's current asthma therapy. Has laboratory tests that are clinically acceptable to the investigator. Exclusion Criteria: Requires >8 inhalations per day of albuterol (100 mcg per actuation), and/or >2 nebulized treatments per day of 2.5 mg albuterol on any 2 consecutive days Has a clinical worsening of asthma that results in emergency room visit (for an asthma exacerbation), hospitalization due to asthma, or treatment with additional, excluded asthma medication (other than SABA) between the Screening and Baseline visits. Is considered by the investigator to have unstable asthma at the end of the run-in period Has had > 4 asthma exacerbations (defined as a worsening of asthma requiring systemic corticosteroid use and/or ≥ 24-hour stay in an emergency department, urgent care center, or hospital) within 1 year prior to visit 1 Has had a history of life-threatening asthma Has a clinically significant condition or situation, other than the condition being studied which may interfere with trial evaluations, participant safety, or optimal participation in the trial

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MF/F MDI 100/10 mcg BID<br>Eligible participants will be assigned randomly to receive double-blinded MF/F MDI 100/10 mcg BID for 24 weeks. | Drug: MF MDI 100 mcg BID (Open Label)<br>* Eligible participants will receive open-label MF MDI 100 mcg BID during a 2-week run-in period.<br>* Other names: SCH 032088 (MK-0887);Drug: MF/F MDI 100/10 mcg BID<br>* After a 2 week run-in on open-label MF MDI 100 mcg BID, eligible participants will receive double-blinded treatment with MF/F MDI 100/10 mcg BID.<br>* Other names: SCH 418131 (MK-0887A);Drug: Albuterol/Salbutamol PRN<br>* Participants may use study-provided short-acting beta agonist (SABA), albuterol/salbutamol, as needed (PRN) for the relief of asthma symptoms.<br>Drug: Prednisone/Prednisolone<br>* Participants may use a systemic corticosteroid (prednisone/prednisolone) for acute asthma worsening per investigator discretion.<br>|
| Active Comparator: MF MDI 100 mcg BID<br>Eligible participants will be assigned randomly to receive double-blinded MF MDI 100 mcg BID for 24 weeks. | Drug: MF MDI 100 mcg BID (Open Label)<br>* Eligible participants will receive open-label MF MDI 100 mcg BID during a 2-week run-in period.<br>* Other names: SCH 032088 (MK-0887);Drug: MF MDI 100 mcg BID<br>* After a 2 week run-in on open-label MF MDI 100 mcg BID, eligible participants will receive double-blinded treatment with MF MDI 100 mcg BID.<br>* Other names: SCH 032088 (MK-0887);Drug: Albuterol/Salbutamol PRN<br>* Participants may use study-provided short-acting beta agonist (SABA), albuterol/salbutamol, as needed (PRN) for the relief of asthma symptoms.<br>Drug: Prednisone/Prednisolone<br>* Participants may use a systemic corticosteroid (prednisone/prednisolone) for acute asthma worsening per investigator discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Morning (AM) Post-Dose % Predicted Forced Expiratory Volume in One Second (FEV1) in the Area Under the Curve (AUC)0-60 | This endpoint reflects changes in lung function data (forced expiratory volume in 1 second) measured across 0 to 60 minutes post-dose (at 0, 5, 15, 30 and 60 minutes) and averaged across study visits in the Treatment Period (Day 1, Week 1, Week 4, Week 8 and Week 12) compared to Baseline. Baseline was the average of % predicted FEV1 values at 30 min and 0 min pre-dose. At each visit, the area under the curve is calculated over the post-dose timepoints. Units are standardized to percent predicted FEV1 by dividing the AUC calculation by the duration of the observed AUC. | Baseline, and average of Day 1, Weeks 1, 4, 8, and 12 | 
| Count (Percentage) of Participants Experiencing At Least One Adverse Event (AE) | An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition temporally associated with the use of the Sponsor's product, is also an AE. | Up to 26 weeks | 
| Count (Percentage) of Participants Discontinuing From Study Medication Due to An AE | An Adverse Event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition temporally associated with the use of the Sponsor's product, is also an AE. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline AM Post-Dose Percent Predicted FEV1 on Day 1 of Treatment | The key secondary objective was to determine the onset of action for the efficacy of MF/F MDI 100/10 mcg BID, compared with MF MDI 100 mcg BID. The post-dose AM % predicted FEV1 was averaged sequentially, and the change from baseline on Day 1 was assessed. This key secondary endpoint was controlled for multiplicity in a step-down fashion, based on trial success defined as a statistically significant improvement in the primary endpoint for MF/F vs MF. Missing data were imputed using control-based multiple imputations with the cLDA model. | Baseline and Day 1, measured at 4 hr, 2 hr and 60, 30, 15, and 5 min, post-dose time points | 
| Change From Baseline AM Post-Dose % Predicted FEV1 AUC 0-4 Hours on Day 1 and Week 12 of Treatment | This endpoint reflects changes in lung function data (forced expiratory volume in 1 second) measured across 0 to 4 hours post-dose on Day 1 and Week 12 compared to Baseline. Baseline was the average of 30 and 0 minutes pre-dose % predicted FEV1 values. The AUC was calculated over the scheduled timepoints of 0 min, 5 min, 15 min, 30 min, 60 min, 2 hr and 4 hr post-dose. Units are standardized to percent predicted FEV1 by dividing the AUC calculation by the duration of the observed AUC. | Baseline, Day 1 and Week 12 | 
| Change From Baseline in AM Pre-Dose % Predicted FEV1 With MF/F MDI 100/10 mcg BID or MF MDI 100 mcg BID Over the First 12 Weeks of Treatment | The change from baseline in AM pre-dose % predicted FEV1 with MF/F MDI 100/10 mcg BID vs MF MDI 100 mcg BID averaged over 12 weeks treatment was assessed. This secondary analysis of the change from baseline used the cLDA method without multiple imputation. A model-based MAR approach was used for missing data. | Baseline and Weeks 4, 8, and 12 (Averaged) | 
| Mean Change From Baseline in Total Daily Use of Short-Acting Beta-Agonist (SABA) Rescue Medication With MF/F MDI 100/10 mcg BID or MF MDI 100 mcg BID Over the First 12 Weeks of Treatment | To evaluate the efficacy of MF/F MDI 100/10 mcg BID compared with MF MDI 100 mcg BID, the change from baseline in total daily short-acting beta-agonist (SABA) use (puffs per day) was averaged and assessed. All participants received SABA MDIs (albuterol 90 mcg or salbutamol 100 mcg) for as-needed relief of asthma symptoms. This secondary analysis of the change from baseline used the cLDA method without multiple imputation.A model-based MAR approach was used for missing data. | Baseline and Weeks 1-12 (Averaged) | 
| Participants Using SABA Rescue Medication Across Weeks 1-12 of the Treatment Period | To evaluate the efficacy of MF/F MDI 100/10 mcg BID compared with MF MDI 100 mcg BID, the number of participants using SABA rescue medication in Weeks 1-12 (individually) of the double-blind treatment period was assessed. All participants received SABA MDIs (albuterol 90 mcg or salbutamol 100 mcg) for as-needed relief of asthma symptoms. | Baseline and Weeks 1-12 (Averaged) | 
| Participants Whose SABA Rescue Medication Use Increased Across Weeks 1-12 of the Treatment Period | To evaluate the efficacy of MF/F MDI 100/10 mcg BID compared with MF MDI 100 mcg BID, the number of participants whose use of SABA rescue medication increased in Weeks 1-12 (individually) of the double-blind treatment period was assessed. All participants received SABA MDIs (albuterol 90 mcg or salbutamol 100 mcg) for relief of asthma symptoms. | Weeks 1-12 (Averaged) | 
| Area Under the Plasma Concentration-Time Curve of Mometasone Furoate From Time 0 to 12 Hours (AUC0-12) | Blood samples were collected predose, and 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 in a subset of participants who consented to take part in a PK sub-trial. Per protocol, descriptive MF pharmacokinetics were summarized without regard to treatment assignment. | Predose, 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 | 
| Area Under the Plasma Concentration-Time Curve of Mometasone Furoate From Time 0 to Time of Last Measurable Concentration (AUC0-last) | Blood samples were collected predose, and 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 in a subset of participants who consented to take part in a PK sub-trial. Per protocol, descriptive MF pharmacokinetics were summarized without regard to treatment assignment. | Predose, 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 | 
| Maximum Plasma Concentration (Cmax) of Mometsone Furoate | Blood samples were collected predose, and 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 in a subset of participants who consented to take part in a PK sub-trial. Per protocol, descriptive MF pharmacokinetics were summarized without regard to treatment assignment. | Predose, 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 | 
| Time to Maximum Plasma Concentration (Tmax) of Mometsone Furoate | Blood samples were collected predose, and 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 in a subset of participants who consented to take part in a PK sub-trial. Per protocol, descriptive MF pharmacokinetics were summarized without regard to treatment assignment. | Predose, 0.75, 1.5, 3, 8, and 12 hours postdose at Week 12 |