Efficacy and Safety of Fluticasone Propionate(FP)/ Salmeterol Xinafoate (SLM) Hydro Fluoro Alkane (HFA) Metered Dose Inhaler (MDI) in Pediatric Patients With Bronchial Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: FP/ SLM HFA MDI 50/25 mcg; FP HFA MDI 50 mcg
Intervention description: Metered-dose aerosol product containing 50 mcg of fluticasone propionate and 25 mcg of salmeterol per inhalation; Metered-dose aerosol product containing 50 mcg of fluticasone propionate per inhalation
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 300.0
Sex: All
Minimum age: 6 Months
Maximum age: 4 Years
Healthy volunteers: No
Keywords: FP/SLM; Asthma; Infant; Efficacy; Safety

Summary:

      This study is a multicenter, stratified, randomized, active control, double-blinded,
      parallel-group comparative study with an open-label extension period. The study is designed
      to evaluate the efficacy and safety of FP/ SLM HFA MDI 50/25 microgram (mcg) one or two
      inhalation twice daily (BID) for 8 weeks in comparison with FP HFA MDI 50 mcg one or two
      inhalation BID, in 6-month to 4-year-old Japanese patients with bronchial asthma. The study
      is also designed to evaluate the safety of long-term treatment of FP/ SLM HFA MDI 50/25 mcg
      one or two BID for 16 weeks.

      The subjects meeting the eligibility criteria will enter the run-in period of 2 weeks and
      receive FP 50 mcg 1 or 2 inhalation bid (FP 100 or 200 mcg/day), before randomization. The
      subjects under 2 years of age at Visit 1 will receive only 1 inhalation bid during the run-in
      period. The subjects who meet the eligibility criteria for randomization will be stratified
      according to their age (<2 or >=2 year-old) at Visit 1 and randomized to one of the two
      treatment groups.

      The total duration of participation in the study will be 10 weeks for a comparison period
      completion and 27 weeks for a completion.
    

Eligibility criteria:

        Inclusion Criteria:

          -  The written informed consent must be obtained from his/her parent or legally
             acceptable representative. If the investigator can get the oral consent from the
             patient, the investigator should record so in the informed consent which is signed by
             his/her parent or legally acceptable representative.

          -  Ethnic origin is Japanese

          -  Aged >=6 months and <=4 years at Visit 1.

          -  Male and pre-menarchial female. Pre-menarchial females are defined as any female who
             has yet to begin menses.

          -  Patient: outpatient

          -  Diagnosis as a pediatric asthma has been made by reference to JPGL 2012 and the
             document which is of help as evidence should be kept as source document. As for <2
             years old, children are going to be diagnosed according to an instruction as follows
             in JPGL2012 as a reference. There are 3 or more episodes of marked expiratory
             wheezing, regardless of the presence of respiratory tract infection. It is also needed
             to confirm that there is asymptomatic period for about a week between each episode. In
             addition to this finding, if there is at least one of following findings, it is more
             helpful to diagnose infantile asthma: At least one of parents is diagnosed with
             bronchial asthma by a physician (including past history); Specific immunoglobulin E
             (IgE) antibody for inhalation antigen is detected in at least one of parents; Diseased
             child is diagnosed with atopic dermatitis by a physician (including past history);
             Specific IgE antibody for inhalation antigen is detected in diseased child; High serum
             IgE level in diseased child or his/her family (serum IgE level should be determined by
             considering age); Eosinophils and creola bodies found in sputum (examine nasal
             discharge eosinophilia and peripheral blood eosinophilia); Expiratory wheezing occurs
             when there is no airway infection; Expiratory wheezing and labored respiration or
             oxygen saturation are improved after beta-2 stimulant inhalation.

          -  A patient who needs to be treated with Inhaled corticosteroid (ICS)/ Long-acting beta
             2 agonist (LABA) and fulfill following all conditions: At least one documented
             exacerbation in that the patient treated with systemic glucocorticosteroids,
             aminophylline dose intravenous(d.i.v) or continuous isoproterenol inhalation in the 12
             months prior to Visit 1. Or a well-documented regular treatment with ICS (FP 200-400
             mcg daily or equivalent) continuous use in the 12 months prior to Visit 1; The patient
             has not received systemic glucocorticosteroids, aminophylline d.i.v., ICS (FP>200 mcg
             daily or equivalent) or continuous isoproterenol inhalation within 4 weeks prior to
             Visit 1.

        Exclusion Criteria:

          -  A patient who has suffered from upper and lower respiratory tract infection and then
             received medication within 2 weeks prior to Visit 1.

          -  A patient who is diagnosed upper and lower respiratory tract infection at Visit 1. Or
             a patient who has or is suspected to have deep-seated mycosis or infection to which no
             effective antibacterial agent is available. Or a patient who is suspected to have
             respiratory syncytial (RS) virus infection and cannot be identified to be negative for
             RS virus antigen.

          -  A patient who has respiratory disorder other than bronchial asthma, and the
             investigator judges the respiratory disorder affect the assessment of efficacy in this
             study.

          -  A patient who has unstable liver disease or chronic stable hepatitis B receiving
             significant immunosuppressive agents due to risk of hepatitis B reactivation.

          -  A patient who has malformation/foreign particle lodged in an airway. Or subjects who
             have known, pre-existing, clinically significant gastroesophageal reflux disease ,
             endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic,
             haematological or any other system abnormalities that are uncontrolled with standard
             treatment.

          -  A patient who has or is suspected to have hypersensitivity to study medications, the
             rescue medication or any ingredients of them.

          -  A patient who has been treated with another investigational product within 1 months
             prior to Visit 1 or within five half-lives (t-half) of the prior investigational study
             (whichever is the longer of the two).

          -  As for the patients who has evaluable ECG data at Visit 1, QT interval corrected
             (Fridericia) for heart rate (QTc[F])>=450 milliseconds (msec). The QT interval
             corrected for heart rate (QTc) should be based on averaged QTc values of triplicate
             electrocardiograms (ECGs) obtained over a brief recording period. As for the patients
             who don't has evaluable ECG data at Visit 1, if the patient has known prolonged
             QTc>=450 msec (any correction is valid), the patient will be excluded.

          -  A patient who is child in care (including foster parent system), or whom the
             investigator judges inappropriate for the study.

        Randomization Inclusion Criterion :

          -  A patient who has asthma symptoms scores (total of daytime and night-time) both over
             >=6 in total and >=1 per day for >=3 days at the last 7 consecutive days of the run-in
             period (excluding the day of Visit 2). Completion of symptom scores (daytime and
             night-time) on 5 or more days out of the last 7 consecutive days during the run-in
             period is required.

        Randomization Exclusion Criteria :

          -  A patient who has received systemic steroids during run-in period.

          -  A patient who has suffered from or is suspected to have upper and lower respiratory
             tract infection that may affect the assessment of the efficacy during the run-in
             period. Or a patient who has or is suspected to have deep-seated mycosis or infection
             to which no effective antibacterial agent is available during the run-in period. Or a
             patient who is suspected to have RS virus infection and cannot be identified to be
             negative for RS virus antigen during run-in period.

          -  A patient who has no evaluable ECG data during the run-in period. As for the patients
             who has evaluable ECG data during the run-in period, QTc(F) >=450 msec. The QTc should
             be based on averaged QTc values of triplicate electrocardiograms (ECGs) obtained over
             a brief recording period.

          -  A patient who has not been able to appropriately record patient diary or inhale FP
             appropriately during the run-in period, in the opinion of the investigator.