Single Dose Study of the Effect of Formoterol Fumarate in Combination With Mometasone Furoate Inhaled Via a Pressurized Metered Dose Inhaler (pMDI) in Children Aged 5-11 Years Old With Persistent Asthma

Study Overview
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Brief Summary
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This study is being conducted to compare the pharmacodynamics (bronchodilation, onset and duration of action), of a single dose of formoterol fumarate in combination with mometasone furoate to placebo in children of 5-11 years with persistent asthma. The study will also assess the bronchodilatory effect of a single dose of formoterol fumarate alone and in combination with mometasone furoate delivered via a pressurized metered dose inhaler (pMDI) to the bronchodilatory effect of formoterol fumarate delivered via a dry powder inhaler (DPI). Furthermore, pharmacokinetic assessments of plasma and urine will also be conducted throughout the study to assess systemic exposure following administration of the study medication.

Official Title
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A Randomized, Double-blind, Double-dummy, Multi-centre, 4-way Cross-over Study to Compare the Single Dose Bronchodilatory Effect of Formoterol Fumarate in Combination With Mometasone Furoate Delivered Via Pressurized Metered Dose Inhaler (pMDI) to Placebo Delivered Via pMDI in Children Aged 5-11 Years Old With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Mometasone furoate/formoterol fumarate (MFF)
* Drug: Formoterol fumarate 12 μg pMDI (F12M)
* Drug: Formoterol fumarate 12 μg DPI (F12D)
* Drug: Placebo to F12D
* Drug: Placebo to F12M/MFF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 5 to 11 years of age of either sex and of any race A diagnosis (according to the Global Initiative for Asthma [GINA] guidelines) of persistent asthma for a period of at least 6 months prior to screening and must have been on a stable asthma regimen (daily dose unchanged) for at least 4 weeks prior to screening β2-agonist reversibility, defined as an increase in absolute FEV1 of ≥12% within 30 minutes after administration of 200μg of salbutamol without the use of a spacer or its equivalent in accordance with ATS/ERS standards A child must have an FEV1 of ≥ 60% and ≤ 90% of Polgar predicted when all restricted medications have been withheld for the appropriate intervals Exclusion Criteria: Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer. History of malignancy of any organ system within past 5 years. Pre-dose change (increase or decrease) in absolute FEV1 of 15% at Visit 2, compared with value at screening. Hospitalized or had an emergency room treatment for an acute asthma exacerbation in the 1 month prior to Visit 1, or who had a clinical deterioration of asthma between Visits 1 and 2 that resulted in emergency treatment, hospitalization, or treatment with excluded asthma medication. Significant medication condition or situation. QTc > 440 msec (boys) or > 450 msec (girls) on electrocardiogram(ECG) assessment at screening. Upper or lower respiratory tract infection within 4 weeks prior to screening. Chronic conditions affecting the respiratory tract or chronic lung diseases.

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F12M - PL - F12D - MFF<br>Participants received a single dose of each treatment in the following order, separated by a washout period of 6-7 days: Period 1: Formoterol fumarate 12 μg via pMDI + placebo to formoterol fumarate via DPI; Period 2: Placebo to formoterol fumarate / mometasone furoate via pMDI + placebo to formoterol fumarate via DPI; Period 3: Placebo to formoterol fumarate / mometasone furoate via pMDI + formoterol fumarate via DPI; Period 4: Formoterol fumarate / mometasone furoate 10 μg / 100 μg via pMDI + placebo to formoterol fumarate via DPI. Participants were allowed to continue their regular asthma maintenance inhaled corticosteroid medication throughout the study and were supplied with the short-acting β2-agonist (SABA) salbutamol as rescue medication. | Drug: Mometasone furoate/formoterol fumarate (MFF)<br>* Formoterol fumarate dihydrate / mometasone furoate combination product 10 μg / 100 μg delivered via Pressurized Metered Dose Inhaler (pMDI). One dose consisted of 2 puffs x 5 μg / 50 μg.<br>Drug: Formoterol fumarate 12 μg pMDI (F12M)<br>* Formoterol fumarate dihydrate 12 μg delivered via Pressurized Metered Dose Inhaler (pMDI) (1 dose = 2 puffs x 6 μg).<br>Drug: Formoterol fumarate 12 μg DPI (F12D)<br>* Formoterol fumarate dihydrate 12 μg delivered via Dry Powder Inhaler (DPI).<br>Drug: Placebo to F12D<br>* Placebo to formoterol fumarate DPI delivered via DPI<br>Drug: Placebo to F12M/MFF<br>* Placebo to formoterol fumarate pMDI and formoterol fumarate / mometasone furoate delivered via pMDI<br>|
| Experimental: F12D - F12M - MFF - PL<br>Participants received a single dose of each treatment in the following order, separated by a washout period of 6-7 days: Period 1: Placebo to formoterol fumarate / mometasone furoate via pMDI + formoterol fumarate via DPI; Period 2: Formoterol fumarate 12 μg via pMDI + placebo to formoterol fumarate via DPI; Period 3: Formoterol fumarate / mometasone furoate 10 μg / 100 μg via pMDI + placebo to formoterol fumarate via DPI; Period 4: Placebo to formoterol fumarate / mometasone furoate via pMDI + placebo to formoterol fumarate via DPI. Participants were allowed to continue their regular asthma maintenance inhaled corticosteroid medication throughout the study and were supplied with the short-acting β2-agonist (SABA) salbutamol as rescue medication. | Drug: Mometasone furoate/formoterol fumarate (MFF)<br>* Formoterol fumarate dihydrate / mometasone furoate combination product 10 μg / 100 μg delivered via Pressurized Metered Dose Inhaler (pMDI). One dose consisted of 2 puffs x 5 μg / 50 μg.<br>Drug: Formoterol fumarate 12 μg pMDI (F12M)<br>* Formoterol fumarate dihydrate 12 μg delivered via Pressurized Metered Dose Inhaler (pMDI) (1 dose = 2 puffs x 6 μg).<br>Drug: Formoterol fumarate 12 μg DPI (F12D)<br>* Formoterol fumarate dihydrate 12 μg delivered via Dry Powder Inhaler (DPI).<br>Drug: Placebo to F12D<br>* Placebo to formoterol fumarate DPI delivered via DPI<br>Drug: Placebo to F12M/MFF<br>* Placebo to formoterol fumarate pMDI and formoterol fumarate / mometasone furoate delivered via pMDI<br>|
| Experimental: MFF - F12D - PL - F12M<br>Participants received a single dose of each treatment in the following order, separated by a washout period of 6-7 days: Period 1: Formoterol fumarate / mometasone furoate 10 μg / 100 μg via pMDI + placebo to formoterol fumarate via DPI; Period 2: Placebo to formoterol fumarate / mometasone furoate via pMDI + formoterol fumarate via DPI; Period 3: Placebo to formoterol fumarate / mometasone furoate via pMDI + placebo to formoterol fumarate via DPI; Period 4: Formoterol fumarate 12 μg via pMDI + placebo to formoterol fumarate via DPI. Participants were allowed to continue their regular asthma maintenance inhaled corticosteroid medication throughout the study and were supplied with the short-acting β2-agonist (SABA) salbutamol as rescue medication. | Drug: Mometasone furoate/formoterol fumarate (MFF)<br>* Formoterol fumarate dihydrate / mometasone furoate combination product 10 μg / 100 μg delivered via Pressurized Metered Dose Inhaler (pMDI). One dose consisted of 2 puffs x 5 μg / 50 μg.<br>Drug: Formoterol fumarate 12 μg pMDI (F12M)<br>* Formoterol fumarate dihydrate 12 μg delivered via Pressurized Metered Dose Inhaler (pMDI) (1 dose = 2 puffs x 6 μg).<br>Drug: Formoterol fumarate 12 μg DPI (F12D)<br>* Formoterol fumarate dihydrate 12 μg delivered via Dry Powder Inhaler (DPI).<br>Drug: Placebo to F12D<br>* Placebo to formoterol fumarate DPI delivered via DPI<br>Drug: Placebo to F12M/MFF<br>* Placebo to formoterol fumarate pMDI and formoterol fumarate / mometasone furoate delivered via pMDI<br>|
| Experimental: PL - MFF - F12M - F12D<br>Participants received a single dose of each treatment in the following order, separated by a washout period of 6-7 days: Period 1: Placebo to formoterol fumarate / mometasone furoate via pMDI + placebo to formoterol fumarate via DPI; Period 2: Formoterol fumarate / mometasone furoate 10 μg / 100 μg via pMDI + placebo to formoterol fumarate via DPI; Period 3: Formoterol fumarate 12 μg via pMDI + placebo to formoterol fumarate via DPI; Period 4: Placebo to formoterol fumarate / mometasone furoate via pMDI + formoterol fumarate via DPI. Participants were allowed to continue their regular asthma maintenance inhaled corticosteroid medication throughout the study and were supplied with the short-acting β2-agonist (SABA) salbutamol as rescue medication. | Drug: Mometasone furoate/formoterol fumarate (MFF)<br>* Formoterol fumarate dihydrate / mometasone furoate combination product 10 μg / 100 μg delivered via Pressurized Metered Dose Inhaler (pMDI). One dose consisted of 2 puffs x 5 μg / 50 μg.<br>Drug: Formoterol fumarate 12 μg pMDI (F12M)<br>* Formoterol fumarate dihydrate 12 μg delivered via Pressurized Metered Dose Inhaler (pMDI) (1 dose = 2 puffs x 6 μg).<br>Drug: Formoterol fumarate 12 μg DPI (F12D)<br>* Formoterol fumarate dihydrate 12 μg delivered via Dry Powder Inhaler (DPI).<br>Drug: Placebo to F12D<br>* Placebo to formoterol fumarate DPI delivered via DPI<br>Drug: Placebo to F12M/MFF<br>* Placebo to formoterol fumarate pMDI and formoterol fumarate / mometasone furoate delivered via pMDI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Standardized Forced Expiratory Volume in 1 Second (FEV1) Using Area Under the Curve (AUC) From 0 to 12 Hours (0-12h) Post-dose by Treatment | For FEV1 AUC(0-12h) the trapezoidal rule was applied using planned time measurements to calculate the AUC up to and including the last measurement recorded before intake of rescue medication. The AUC was standardized by dividing by the length of time for which measurements of FEV1 were included in the calculation of the AUC thus adjusting for subjects who were unable to complete the measurements during the 12-hour observation period and without inhaling rescue medication. The unit of the AUC was in L, being a weighted average of the acceptable FEV1 measurements recorded over 12 hours post dose | From 0 to 12 Hours (0-12h) post-dose, after each treatment administered (approximately 1 treatment a week for 4 weeks of treatment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial FEV1 Measurement (i.e. at 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose) Following Inhalation of a Single Dose of Study Medication to Evaluate the Onset and Duration of the Bronchodilatory Effect | All efficacy evaluations were based on spirometry assessments of lung function. FEV1 is the maximum amount of air expired in one second. At Visits 2, 3, 4 and 5, spirometry assessments were performed in the clinic at predose and again at 5 and 30 minutes and 1, 2, 4, 8 and 12 hours post-dose within ± 5 minutes of the scheduled time for the time points up to and including 60 minutes post-dose and then within ± 10 minutes for all subsequent time points. Spirometry equipment and performance of spirometric testing were in accordance with the (ATS / ERS) standards. | 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose | 
| Serial Forced Vital Capacity (FVC) Measurement (i.e. at 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose) Following Inhalation of a Single Dose of Study Medication to Evaluate the Onset and Duration of the Bronchodilatory Effect | All efficacy evaluations were based on spirometry assessments of lung function. FVC is the volume (liters) of air that can forcibly be blown out after full inspiration. At Visits 2, 3, 4 and 5, spirometry assessments were performed in the clinic at predose and again at 5 and 30 minutes and 1, 2, 4, 8 and 12 hours post-dose within ± 5 minutes of the scheduled time for the time points up to and including 60 minutes post-dose and then within ± 10 minutes for all subsequent time points. Spirometry equipment and performance of spirometric testing were in accordance with the ATS / ERS standards. | 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose | 
| Serial Peak Expiratory Flow Rate (PEF) Measurement (i.e. at 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose) Following Inhalation of a Single Dose of Study Medication to Evaluate the Onset and Duration of the Bronchodilatory Effect | All efficacy evaluations were based on spirometry assessments of lung function. PEF is the greatest airflow rate achieved during forced exhalation with lungs fully inflated. At Visits 2, 3, 4 and 5, spirometry assessments were performed in the clinic at predose and again at 5 and 30 minutes and 1, 2, 4, 8 and 12 hours post-dose within ± 5 minutes of the scheduled time for the time points up to and including 60 minutes post-dose and then within ± 10 minutes for all subsequent time points. Spirometry equipment and performance of spirometric testing were in accordance with the ATS/ERS standards | 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose | 
| Plasma Formoterol Concentrations (Pmol/L) Following a Single Dose of Formoterol Fumarate Alone and in Combination With Mometasone Furoate Via the pMDI and Formoterol Fumarate Via the Dry Powder Inhaler (DPI) | Unchanged racemic formoterol in plasma was assayed by LC-MS/MS. The lower limit of quantification (LLOQ) for plasma was 1.45 pmol/L. No non-compartmental PK analysis was performed. | 5, 30 Minutes and 1, 2, 4, 8 and 12 Hours Post-dose | 
| Urinary Excretion of Formoterol Following a Single Dose of Formoterol Fumarate Alone and in Combination With Mometasone Furoate Via the pMDI and Formoterol Fumarate Via the Dry Powder Inhaler (DPI) | Unchanged racemic formoterol in urine was assayed by LC-MS/MS. The lower limit of quantification (LLOQ) for urine was 0.0174 nmol/L expressed as free base. The amounts of unchanged formoterol excreted in urine from 0 to 3 hours (Ae0-3) and from 0 to 12 hours post-dose (Ae0-12) were calculated from the formoterol concentrations in urine and the urine volumes using non-compartmental methods. | 0 to 3 hrs and 0-12 hrs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Children, Persistent asthma