Efficacy and Safety Study of Fluticasone Proponate Inhalation Solution in Adult and Adolescent Asthma
Efficacy and Safety Study of Fluticasone Proponate Inhalation Solution in Adult and Adolescent Asthma
This is a multicentre, randomized, single-blind, active-controlled, parallel-group phase III
 local registration study for a treatment period of 12 weeks. This study aims to assess the
 effectiveness and safety of fluticasone propionate 1mg via nebulizer BID in treatment of
 Chinese adult and adolescent patients with severe persistent asthma for a treatment period of
 12 weeks versus budesonide 2mg via nebulizer BID. The steady-state plasma pharmacokinetics of
 fluticasone propionate inhalation solution will also be assessed.
Male or female subjects between 17 to 70 (inclusive) years of age with severe persistent
 asthma meeting the inclusion criteria and having completed the screening period of 2 weeks
 will, in a proportion of 1:1, randomly receive fluticasone propionate 1mg via nebulizer BID
 or budesonide 2mg via nebulizer BID for a treatment period of 12 weeks. The clinic visit will
 be arranged at 2 weeks, 4 weeks, 8 weeks and 12 weeks during study treatment. If the subjects
 meet the criteria of pre-defined asthma control at treatment 4 weeks or 8 weeks, they will
 have one chance to be treated with the half dose of study drug. 2 weeks after completion of
 study treatment or after early withdrawal from study, the follow-up visit will be performed
 to assess the post-treatment adverse events. The primary endpoint is the mean change from
 baseline in morning peak expiratory flow (PEF) over the 12 week treatment period. Safety
 assessments include adverse events, vital signs, oral and oropharyngeal candidiasis,
 hematological, biochemical tests), 24-hour urinary cortisol and 12-lead ECG. The steady-state
 plasma pharmacokinetics of fluticasone propionate inhalation solution will also be assessed.
Inclusion Criteria:

 -  Chinese male or female outpatients aged >=17 years and <=70 years

 -  A female is eligible to enter and participate in this study if she is:

 Non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including
 any female who is pre-menarchal, post-menopausal), or Child-bearing potential, has a
 negative urinary pregnancy test at screening and agrees to take contraceptive precautions
 (including abstinence) (referring to appendix 1: Highly Effective Methods For Avoidance Of
 Pregnancy In Women Of Childbearing Potential) which, in the opinion of the investigator are
 adequate to prevent pregnancy during the study.

 -  A documented clinical history of asthma for a period of at least 12 weeks prior to
 Visit 1 based on the Guidance of Asthma Management and Prevention 2008 in China (refer
 to appendix 2).

 -  Demonstrated >=12% and >=200mL reversibility of FEV1 within 15-30minutes following
 inhalation of 200-400ug of salbutamol aerosol within 12 months prior to visit 1 or at
 the Screening Visit.

 -  Subjects have pre-bronchodilator FEV1% predicted between >=40% and <80% at visit 1.

 -  Subjects on a stable dose at least 2 weeks with high dose ICS (eg. Fluticasone
 Propionate 500ug twice daily or other ICS with equivalence doses, refer to Appendix 3)
 or moderate dose ICS plus LABA (eg. Fluticasone Propionate/Salmoterol 250/50ug , twice
 daily; or Budesonide/Formoterol Fumarate in maintainance160/4.5ug, two inhalation,
 twice daily; or other product equivalence doses).

 -  Subjects and/or their legally acceptable representative (if applicable) is willing to
 give informed consent to participate in the study, and having ability to comply with
 study procedures (including patients can use Nebulizer correctly, be able to
 understand and complete the diary cards and be able to record their PEF using a peak
 flow meter). The subjects and/or their legally acceptable representative (if
 applicable) will need to give additional informed consent to be eligible for blood
 pharmacokinetic samplings.

 Exclusion Criteria:

 -  History of Life-threatening asthma: Defined for this protocol as an asthma episode
 that required intubation and/or was associated with hypercapnea, respiratory arrest or
 hypoxic seizures.

 -  Bacterial or viral infection of the upper or lower respiratory tract, sinus or middle
 ear that is not resolved within 4 weeks of visit 1 and led to a change in asthma
 management or, 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.

 -  A subject must not have current evidence of pneumonia, pneumothorax, atelectasis,
 pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema,
 chronic obstructive pulmonary disease, or other respiratory abnormalities other than
 asthma.

 -  Subjects have any clinically significant, uncontrolled condition or disease state
 that, in the opinion of the investigator, would put the safety of the patient at risk
 through study participation or would confound the interpretation of the efficacy
 results if the condition/disease exacerbated during the study.

 -  Subjects will not b eligible for the run-in if he/she has clinical visual evidence of
 candidias at visit 1.

 -  Current smoker or a smoking history of 10 pack years or more. A subject may not have
 used inhaled tobacco products (i.e., cigarettes, cigars or pipe tobacco) within the
 past 3 months.

 -  Patients who are pregnant or lactating.

 -  Patients having any known or suspected hypersensitivity to corticosteroids or the
 excipients of study drug, including Polysorbate 20, Sorbitan monolaurate, Monosodium
 phosphate dehydrate, Dibasic sodium phosphate anhydrous, Sodium Chloride and Water for
 Injection.

 -  Patients who have evidence of alcohol abuse.

 -  Patients who will have a pre-planned surgery operation in 6 months.

 -  Liver function tests: aspartate aminotransferase (AST) / alanine aminotransferase
 (ALT) >= 2 × upper limit of normal (ULN) or alkaline phosphatase (ALP) / bilirubin
 >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated
 and direct bilirubin <35%).

 -  Has QTc >= 450 msec or >= 480 msec for patients with bundle branch block at the time
 of screening.

 -  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.

 -  No subject is permitted to perform night shift work from Visit 1 until completion of
 the study treatment period.

 -  Use of the following medications within the following time intervals prior to visit 1
 or during the study: Medication / No use within the following time intervals prior to
 Screening (Visit 1) or at any time during the study Systemic or oral corticosteroids /
 2 weeks Depot corticosteroids /12 weeks Anti-IgE (e.g. Xolair)/ 12 weeks Oral
 long-acting beta2-agonists (e.g. bambuterol) and inhaled long-acting beta2-agonists
 (e.g. salmeterol, formoterol) or combination products containing inhaled long-acting
 beta2-agonists (e.g. Seretide, Symbicort) / 12 hours (the stable dose of ICS/LABA
 combination within 2 weeks prior to Visit 1 could be continued during the run-in
 period) Theophyllines, slow-release bronchodilators, anticholinergics, ketotifen,
 nedocromil sodium, sodium cromoglycate, Anti-leukotrienes including suppressors of
 leukotriene production and antagonists / 1 day Inhaled short-acting beta2-agonist / 4
 hours (salbutamol will be supplied for rescue during the study) Potent Cytochrome P450
 3A4 inhibitors(e.g. ritonavir, ketoconazole, itraconzole) / 4 weeks Prescription or
 over the counter medication that would significantly affect the course of asthma, or
 interact with sympathomimetic amines, such as: anticonvulsants (barbiturates,
 hydantoins, carbamazepine); polycyclic antidepressants; beta-adrenergic blocking
 agents; phenothiazines and monoamine oxidase (MAO) inhibitors /1 day Chinese
 traditional medicines used for treatment of asthma and other allergic diseases / 1
 week Any other investigational drug / 30 days or within 5 half lives, whichever is
 longer