Efficacy of Ciclesonide Inhaled Once Daily Versus Other Corticosteroids Used for Treatment of Mild Asthma in Children (4 to 11 Years) (BY9010/CA-101)

Study Overview
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Brief Summary
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The aim of this study is to compare the efficacy of ciclesonide with respect to reduction of the number of asthma exacerbations in children with mild persistent asthma. Treatment medication will be administered as follows: ciclesonide will be inhaled once daily, using one of the two dose levels versus placebo together with other corticosteroids used as intermittent treatment. The study duration consists of a baseline period (3 to 4 weeks) and a treatment period (12 months). The study will provide further data on safety and tolerability of ciclesonide.

Detailed Description
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The drug being tested in this study is called ciclesonide. Ciclesonide is being tested to treat children who have mild asthma. The study enrolled 240 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): Ciclesonide 100 µg Ciclesonide 200 µg Placebo (dummy inactive inhalation) - this is a metered-dose inhaler that looks like the study drug but has no active ingredient. All participants were asked to take two puffs from a metered-dose inhaler once daily, in the evening, for up to 12 months. This multi-center trial was conducted in Canada, Hungary and South Africa. The overall time to participate in this study was 12 months preceded by a baseline washout period of 3 to 4 weeks. Participants made multiple visits to the clinic including a safety follow-up visit within 30 days of the last treatment.

Official Title
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Effect of Low Dose Continuous Treatment With Ciclesonide Over One Year on the Time to First Exacerbation in Children With Mild Asthma Versus Intermittent Treatment for Exacerbations

Conditions
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Asthma

Intervention / Treatment
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* Drug: Ciclesonide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Outpatients Symptoms consistent with the diagnosis of asthma for at least 12 months Forced Expiratory Volume in one Second (FEV) at least 80% of predicted Participants who have a history of reversible airway obstruction Good health with the exception of asthma Main Exclusion Criteria: History of life-threatening asthma A hospitalization for asthma within the last 3 months, or more than two hospitalizations for asthma within the last year Concomitant severe diseases or diseases which are contraindications for the use of inhaled steroids Participants suffering from relevant lung diseases causing alternating impairment in lung function (e.g. chronic bronchitis or emphysema) Prematurely born children (<36 weeks of gestation) Smokers Pregnancy (or intention to become pregnant during the course of the trial), breast feeding or lack of safe contraception by female of child-bearing potential

Ages Eligible for Study
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Minimum Age: 4 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 |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Ciclesonide placebo-matching metered-dose inhaler<br>|
| Active Comparator: Ciclesonide 100 µg<br>Ciclesonide 100 µg, metered-dose inhaler, two puffs once daily, in the evening, for up to 12 months. | Drug: Ciclesonide<br>* Ciclesonide metered-dose inhaler<br>* Other names: Alvesco®;|
| Active Comparator: Ciclesonide 200 µg<br>Ciclesonide 200 µg, metered-dose inhaler, two puffs once daily, in the evening, for up to 12 months. | Drug: Ciclesonide<br>* Ciclesonide metered-dose inhaler<br>* Other names: Alvesco®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Asthma Exacerbation | Time to first asthma exacerbation is defined as the time in days until the first asthma exacerbation, or to the end of treatment visit. In the absence of an exacerbation, an early treatment discontinuation is treated as a censored observation on the day following the last use of study drug. | Up to 12 months | 
| Exacerbations (Post-hoc Analysis of Annual Rates) | A model-based analysis of asthma exacerbation was performed to adjust to important covariables. The distribution of the data suggested a Poisson regression modeling (zero inflated) strategy. After a variable selection process considering also variable-by-treatment interactions, the variables centre, age [years] and race were identified to be important beside treatment. The parameters centre and age [years] were allocated to zero-model part and the variables treatment and race to the Poisson model part. The estimates of the per-treatment rates are based on a negative-binomial distribution. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth Velocity as Assessed by Stadiometric Height Measurement | Standing height measured in millimeters (mm) with a wall-mounted stadiometer. | Up to 12 months | 
| Mean Rate of Asthma Exacerbations Per Year | Rate of asthma exacerbations per year is equal to total number of asthma exacerbations during treatment/time on treatment (year). | Up to 12 months | 
| Duration of Exacerbations | Duration of exacerbation was defined as the time in days when the criteria for an exacerbation were met to the time when peak flow measurements returned to baseline. | Up to 12 months | 
| Number of Exacerbations Per Participant | The mean number of asthma exacerbations per participant is reported. | Up to 12 months | 
| Percentage of Participants Who Dropped-out Due to Asthma Exacerbation |  | Up to 12 months | 
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) (Absolute Value) | FEV1 is the maximal amount of air forcefully exhaled from the lungs in one second. Spirometry was used for assessment of FEV1. A positive change from Baseline indicates improvement. | Baseline and Months 1, 2, 4, 6, 8, 10 and 12 | 
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) (Percent Predicted) | FEV1 is the maximal amount of air forcefully exhaled from the lungs in one second. Spirometry was used for assessment of FEV1. A positive change from Baseline indicates improvement. | Baseline and Months 1, 2, 4, 6, 8, 10 and 12 | 
| Morning and Evening Peak Expiratory Flow (PEF) Measurements by Diary Entries | PEF is the maximum speed of expiration. Spirometry was used for assessment of PEF. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Change From Baseline in PEF by Diary Entries | PEF is the maximum speed of expiration. Spirometry was used for assessment of PEF. A positive change from Baseline indicates improvement. | Baseline and Months 1, 2, 4, 6, 8, 10 and 12 | 
| Change From Baseline in Diurnal PEF Fluctuation | Diurnal PEF Fluctuation is equal to [(Higher PEF - Lower PEF)/0.5*(Higher PEF + Lower PEF)] * 100%. A positive change from Baseline indicates improvement. | Baseline and Months 1, 2, 4, 6, 8, 10 and 12 | 
| Total Asthma Symptom Score by Diary Entries | Total Asthma Score = daytime asthma score + night-time asthma score, where higher score indicates worsening of disease. Night-time asthma score is assessed on a 5 point scale where 0=No symptoms, slept through the night, 1=Slept well but some complaints in the morning, 2=Woke up once because of asthma (including early wakening), 3=Woke up several times because of asthma (including early wakening) and 4=Bad night, awake most of the night because of asthma. Day-time asthma score is assessed on a 5 point scale where 0= Very well, no symptoms, 1= One episode of wheezing, cough or breathlessness, 2= More than one episode of wheezing, cough or breathlessness without interfering with normal activities, 3= Wheezing, cough or shortness of breath most of the day which interfered to some extent with normal activities and 4= Asthma very bad. Unable to carry out daily activities as usual. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Percentage of Nights With Nocturnal Awakenings Due to Asthma Symptoms | Nocturnal awakenings due to asthma symptoms were recorded in the participant's diary. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Rescue Medication Use Per Day | Salbutamol (100 μg/puff) was used as rescue medication according to the individual needs of the participant. Each use was documented in the participant's diary. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Percentage of Rescue Medication Free Days | Days without use of rescue medication documented in the participant's diary were reported. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Percentage of Asthma Symptom Free Days | Days without Asthma Symptom documented in the participant's diary were reported. | Months 1, 2, 4, 6, 8, 10 and 12 | 
| Quality of Life Assessments as Per Paediatric Asthma Quality of Life Questionnaire, Standardized (PAQLQ[S]) | The PAQLQ(S) consists of 23 items divided into three domains: Activity limitations (items 1-3, 19, 22); Symptoms (items 4, 6, 8, 10, 12, 14, 16, 18, 20, 23) and Emotional function (items 5, 7, 9, 11, 13, 15, 17, 21). Participants were asked to answer each question using a seven-point scale (where 1 indicated maximum impairment and 7 indicated no impairment) and recall their experience during the previous week. Overall PAQLQ score is equal to the mean of all 23 items for a total possible score 1 (worst) to 7 (best). | Months 2, 6 and 12 | 
| Quality of Life Assessments as Per Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ) | The PACQLQ consists of 13 items divided into two domains: Activity limitations (items 2, 4, 6, 8) and Emotional function (items 1, 3, 5, 7, 9, 10, 11, 12, 13). Caregivers answered each question using a seven-point scale (whereby 1 indicated maximum impairment and 7 indicated no impairment) and recalled their experiences during the previous week. Overall PACQLQ score is equal to the mean of all 13 items for a total possible score of 1 (worst) to 7 (best). | Months 2, 6 and 12 | 
| Number of Participants With Clinically Significant Vital Signs Findings | Vital signs included body temperature, systolic and diastolic blood pressure and heart rate in beats per minute (bpm). The investigator determined if the result was clinically significant based on the following criteria: Systolic Blood Pressure >130 mmHg or <80 mmHg or a >20 mmHg difference from Baseline; Diastolic Blood Pressure > 85 mmHg; and Resting Heart Rate >140 bpm or <60 bpm or a >30 bpm difference from Baseline. | Up to 12 months | 
| Number of Participants With Clinically Significant Physical Examination Findings | A thorough physical examination was performed consisting of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) lungs/thorax; (4) heart/cardiovascular system; (5) abdomen; (6) skin and mucosae; (7) nervous system; (8) lymph nodes; (9) musculo-skeletal system; (10) physical examinations other than body systems described in (1) to (9). The investigator determined if any of the findings were clinically significant. | Up to 12 months | 
| Number of Participants With Clinically Significant Laboratory Values | Clinically significant laboratory values were hematology and chemistry tests determined by the investigator to be clinically significant based on the following criteria: Hemoglobin <9.5 g/dL; Erythrocytes <3.0 x 10^6/μL or >6.5 x 10^6/μL; White Blood Count <3000/mm^3 or >20000/mm^3; serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (GGT), Total Bilirubin and Glucose >2 times Upper limit of Normal Range (ULNR); Alkaline Phosphatase and Creatine Kinase >3 times ULNR; Creatinine >1.5 times ULN; Potassium >5.0 mmol/L or <3.0 mmol/L; and Sodium >150 mmol/L or 130 mmol/L. | Up to 12 months | 
| Number of Participants With Adverse Events and Serious Adverse Events | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly/birth defect or any other important medical condition considered serious based on medical and scientific judgement. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Ciclesonide, Exacerbation