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

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

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

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.

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.

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.

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.

Rate of asthma exacerbations per year is equal to total number of asthma exacerbations during treatment/time on treatment (year).

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.

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.

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.

PEF is the maximum speed of expiration. Spirometry was used for assessment of PEF. A positive change from Baseline indicates improvement.

Diurnal PEF Fluctuation is equal to [(Higher PEF - Lower PEF)/0.5*(Higher PEF + Lower PEF)] * 100%. A positive change from Baseline indicates improvement.

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.

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.

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).

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).

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.

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.

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.

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.

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