SAS115358, a 6-month safety and benefit study of inhaled fluticasone
propionate/ salmeterol combination versus inhaled fluticasone
propionate in the treatment of 6,200 pediatric subjects 4-11 years
old with persistent asthma.

1. Informed consent
• Subject*s legal guardian must be able and willing to give written informed consent to take part in the study. If applicable, subject must be able and willing to give assent to take part in the study according to the local requirement.
• Subject and their legal guardian understand that the study requires them to be treated on an outpatient basis.
• Subject and their legal guardian understand that they must comply with study medication and study assessments including recording of symptom scores and rescue albuterol/salbutamol use, attending scheduled study visits, and being accessible by a telephone call.
2. Age: 4-11 years of age at Visit 1
3. Gender: Male or eligible female
Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. All females of childbearing potential must have a negative urine pregnancy test result prior to randomization to continue in the study. Females who become pregnant during the course of the study will be discontinued and the pregnancy outcome followed (see Section 6.2.5)
Females of childbearing potential are
• Females, regardless of their age, with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility
• This category includes young females who have begun to menstruate, females with oligomenorrhea, and females who are perimenopausal.
4. Asthma diagnosis: Asthma, defined by the regional asthma guidelines (i.e., NIH, GINA, etc.), for at least 6 months prior to Visit 1.
Asthma is defined as a chronic inflammatory disorder associated with airway hyperresponsiveness and reversible airways obstruction that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.
If the subject is naïve to the study site, the subject/guardian must self-report a physician diagnosis of asthma and the investigator must confirm by review of medical history with the subject/guardian.
5. Ability to answer questions regarding asthma control (with assistance of his/her parents [guardians], if needed), and use a metered-dose inhaler (MDI) and DISKUS effectively.
6. In countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids (refer to the local product labels for varicella vaccine, ADVAIR DISKUS, and FLOVENT DISKUS) and/or varicella immunization is recommended for the age group, the subject must have a history of clinical varicella infection or recipient of a varicella vaccine before receiving any study drug. In those countries, subjects without a history of clinical varicella disease must receive varicella vaccine prior to randomization, and should follow standard guidelines regarding timing of second dose, if indicated.
7. Subject must have history of at least one occurrence (self-report by subject/guardian) of treatment with systemic corticosteroid [3 or more days of oral corticosteroid (OCS) or an equivalent depot corticosteroid injection] for an asthma exacerbation within the prior 12 months, excluding the 4 weeks immediately preceding Visit 1 (see Section 4.3, Exclusion Criteria #7).
8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks from Visit 1 and Subjects must meet one of the following pre-study asthma medication, impairment domain (Childhood Asthma Control Test) and risk domain (asthma exacerbations) criteria to be eligible for enrolment (Table 1).
• Subjects on SABA alone, LTRA, theophylline, or cromolyn as monotherapy with Childhood Asthma Control Test score *19 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or
• Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score *20 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or
• Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score *19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score *20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score *19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score *20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score *19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score *20 at Visit 1 and have had only 1 asthma exacerbation in the previous year.
Note:
• Subjects receiving SABA only, LTRA, theophylline or cromolyn as monotherapy with Childhood Asthma Control Test >=20 are not eligible.
• Subjects receiving medium-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score <=19 at Visit 1 are not eligible.
• To be eligible, subjects should not present signs of unstable asthma as described in Section 4.30, Exclusion Criterion #2.
• Subjects who are currently on high-dose ICS or high-dose ICS/LABA are not eligible for the study (Section 4.3 Exclusion Criterion #3).
• Subjects who had an asthma exacerbation within 4 weeks of Visit 1 or more than 4 asthma exacerbations in the last 12 months from Visit 1 are not eligible (Section 4.3, Exclusion Criterion #7).

1. History of life-threatening asthma: Defined for this protocol as an asthma episode that required intubation, hypercapnea requiring non-invasive ventilatory support, respiratory arrest, hypoxic seizures or asthma-related syncopal episode(s).
2. Unstable asthma at Visit 1. Signs of unstable asthma include:
• Daily use of > 4 puffs of albuterol/salbutamol (other than pre-exercise treatment), >=8 puffs of albuterol/salbutamol for 2 or more consecutive 24-hour periods in the 7 days preceding Visit 1,
• >=2 nighttime awakenings due to asthma symptoms in the 7 days preceding Visit 1, or
• Investigator*s discretion (reason should be recorded in source documents).
3. Subjects who are currently receiving high-dose ICS or ICS/LABA therapy to treat asthma symptoms.
4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.
5. Respiratory infection: Bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear (either culture-documented or suspected) that is not resolved at Visit 1 and that in the opinion of the investigator is expected to affect the subject*s asthma status or the subject*s ability to participate in the study.
6. Subjects with only exercise-induced asthma are excluded from participation in this study.
7. Asthma exacerbation: An asthma exacerbation requiring systemic (tablets, suspension or injection) corticosteroids within 4 weeks of Visit 1 or more than 4 separate exacerbations in the last 12 months from Visit 1.
These include asthma exacerbations resulting from poor compliance with asthma medications.
Each asthma exacerbation must be separated by >7 days from the discontinuation of OCS to be considered an individual event.
8. Asthma hospitalization: Hospitalization for asthma within 4 weeks of Visit 1 or more than 2 hospitalizations (defined as overnight admission) for asthma in the last 12 months from Visit 1. Each hospitalization must be separated by >7 days to be considered an individual event (ED visits < 24 hours in duration are not considered hospitalizations).
9. Other current evidence of clinically significant uncontrolled diseases/conditions of any body or organ system. Excluded diseases/conditions includes, but are not limited to the following:
Uncontrolled hypertension1 Uncontrolled hematologic, hepatic, neurologic, or renal disease
Uncontrolled gastroesophageal reflux disease Immunologic compromise
Cardiac arrhythmias Tuberculosis (current or untreated)2
Congestive heart failure Cushing*s disease
Coronary artery disease Addison*s disease
Current malignancy Uncontrolled eosinophilic esophagitis
Uncontrolled diabetes mellitus Uncontrolled thyroid disorder
1. Two or more measurements with systolic or diastolic BP above the 95% percentile reference value for the subjects height and weight
2. Subjects with a history of tuberculosis infection who have completed an appropriate course of anti-tuberculosis treatment may be suitable for study entry provided that there is no clinical suspicion of active or recurrent disease;Significant is defined as any disease/condition that, in the opinion of the investigator, would put the safety of the subject at risk through study participation, or which would confound the interpretation of the study results if the disease/condition exacerbated during the study.
10. Neurological or psychiatric disease or history of drug or alcohol abuse (of a subject or his/her guardian) which in the opinion of the investigator could interfere with the subject*s proper completion of the protocol requirements excludes study participation.
11. Investigational medications: A subject must not have participated in an interventional study or used any investigational drug for any disease state within 30 days prior to Visit 1.
12.Drug allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medications.
13. Severe hypersensitivity to cow*s milk proteins. Any immediate hypersensitivity reaction such as urticaria, angioedema, rash, or bronchospasm to milk proteins.
14. Concomitant medications: Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase (MAO) inhibitors, or diuretics.
15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors: A subject is not eligible if he/she is receiving potent CYP34A inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconzole).
16. Affiliation with investigator*s site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
17. Children in Care: A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible Institutional Review Board (IRB)/Independent Ethics Committee (IEC).