A Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Combination Dry Powder of Fluticasone Propionate and Salmeterol (FSC) 250/50 Microgram (mcg) Twice Daily (BID) in Adults and Adolescents With Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: FSC; Placebo
Intervention description: Subject will be administered FSC 250 mcg/50 mcg via dry powder inhalation device or multi-dose dry powder inhalation device BID for each treatment period; Subject will be administered placebo via dry powder inhalation device or multi-dose dry powder inhalation device BID for each treatment period
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 124.0
Sex: All
Minimum age: 12 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Multi-Dose Inhaler; safety; Asthma; efficacy; pharmacodynamics; fluticasone propionate/salmeterol (FSC) 250/50 mcg; tolerability; Capsule-Based Inhaler

Summary:

      This is a multi-centre, randomised, double-blind, double-dummy, two way cross-over, 12 week
      non inferiority study to evaluate the efficacy, safety, and tolerability of FSC 250/50 mcg
      capsule-based inhaler and FSC 250/50 mcg multi-dose inhaler each administered BID in adults
      and adolescents with asthma. The primary objective of this study is to demonstrate that FSC
      250/50 mcg administered BID by capsule-based inhaler is non-inferior compared to FSC 250/50
      mcg administered BID by multi-dose inhaler . The study consists of six phases: Pre-screening,
      Screening/Run-in (3 weeks), Treatment Period 1 (12 weeks), Washout (minimum 3 weeks),
      Treatment Period 2 (12 weeks) and Follow-up (1 week). The total duration of the study for
      each subject will be at least 31 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female >=12 and <=80 years of age at the time of signing the informed consent

          -  A female subject is eligible to participate if she is of:

          -  Non-childbearing potential defined as premenopausal females with a documented tubal
             ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous
             amenorrhea (in questionable cases a blood sample with simultaneous follicle
             stimulating hormone >40 milli international unit per milliliter (mIU/mL) and
             oestradiol <40 picogram (pg)/mL [<147 picomole per liter (pmol/L)] is confirmatory);
             Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt
             will be required to use one of the contraception methods (i.e., in accordance with the
             approved product label and the instructions of the physician for the duration of the
             study from Screening to follow-up contact) if they wish to continue their HRT during
             the study. Otherwise, they must discontinue HRT to allow confirmation of
             postmenopausal status before study enrolment. For most forms of HRT, at least 2 to 4
             weeks should elapse between the cessation of therapy and the blood draw; this interval
             depends on the type and dosage of HRT. After confirmation of their postmenopausal
             status, they can resume use of HRT during the study without use of a contraceptive
             method; child-bearing potential and is abstinent or agrees to use one of the
             contraception methods for an appropriate period of time (as determined by the product
             label or investigator) before the start of dosing to sufficiently minimise the risk of
             pregnancy at that point. Female subjects must agree to use contraception until at
             least 2 days post the last dose of study treatment; abstinence from penile-vaginal
             intercourse must be consistent with the preferred and usual lifestyle of the subject.

          -  Severity of disease: A best prebronchodilator FEV1 of >=40% to <=85% of the predicted
             normal value at Visit 1 (Screening and Run-in Visit). Predicted values will be based
             upon National Health and Nutrition Examination Survey (NHANES) III. If a subject is
             recorded as having Hispanic or Latino ethnicity, then the Mexican-American equations
             will be used (irrespective of race). If a subject is recorded as being of
             African-American/African heritage race, then the African American equations will be
             used. If a subject is recorded as being of Asian race, then the Asian adjustment will
             be used. Otherwise, the Caucasian equations will be used.

          -  Reversibility of disease: Demonstrated >=12% and >=200 mL reversibility of FEV1 within
             10 to 40 minutes after 2 to 4 inhalations of salbutamol inhalation aerosol (or
             equivalent nebulised treatment with salbutamol solution) at Visit 1 (Screening and
             Run-in Visit).

          -  Current anti-asthma therapy: All subjects must be using an Inhaled Corticosteroid
             (ICS) with or without long-acting beta-adrenergic agonist (LABA) for at least 8 weeks
             and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit).
             Two populations are eligible for enrolment: - Subjects maintained on ICS monotherapy
             (FP 100 mcg to 250 mcg BID or equivalent) for at least 8 weeks and a stable dose for
             at least 4 weeks before Visit 1 (Screening and Run-in Visit) or Subjects maintained on
             an ICS/LABA combination product (e.g., Fluticasone propionate/salmeterol 100/50 or
             250/50 mcg BID or equivalent by other combination products or by separate inhalers)
             for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening
             and Run-in Visit). Subjects taking budesonide/formoterol or beclomethasone/formoterol
             as needed must switch to budesonide/formoterol maintenance dosing (excluding the
             highest dose) with use of a SABA for symptom relief at least 8 weeks and a stable dose
             for at least 4 weeks before Visit 1 (Screening and Run-in Visit). NOTE: Subjects on
             low dose ICS monotherapy should only be enrolled, if, in the opinion of the
             investigator, after review of their medical history and clinical examination, they
             will be able to benefit from both an increase in ICS dose and the addition of LABA
             therapy arising from and ICS/LABA combination.

          -  Ability to withhold LABA therapy: Other than what is provided during the study, LABA
             therapy is not permitted on the day of Visit 1 (Screening and Run-in Visit) and
             throughout the entire study. The last dose of LABA and LABA/ICS combinations are to be
             taken on the day before Visit 1. Sites should contact the medical monitor to discuss
             subject eligibility, for doses of commonly prescribed ICS and ICS/LABA combination
             medication; as mentioned in the study protocol.

          -  SABA: All subjects must be able to replace their current SABA treatment with rescue
             salbutamol/albuterol at Visit 1 (Screening and Run-in Visit) for use as needed for the
             duration of the study. Subjects must be able to withhold salbutamol/albuterol for at
             least 6 hours before each study visit.

          -  Liver safety criteria: Alanine aminotransferase (ALT) <=2 the upper limit of normal
             (ULN), Alkaline phosphatase and bilirubin <=1.5 ULN (isolated bilirubin >1.5 ULN is
             acceptable if bilirubin is fractionated and direct bilirubin is <35%) at Visit 1
             (Screening and Run-in Visit).

          -  Electrocardiogram (ECG) safety criteria: The subject must have no ECG abnormalities
             that would, in the opinion of investigator, compromise subject safety, or
             significantly affect subject's ability to complete the trial. As such, the
             investigator will determine the clinical significance of any ECG abnormality and
             determine if a subject is precluded from entering the study. At Visit 1 (Screening and
             Run-in Visit), ECG safety criteria must be: QT interval corrected for heart rate (QTc)
             or QT interval corrected for heart rate according to Fridericia formula (QTcF) <450
             msec or QTc <480 msec for subjects with bundle branch block; Investigators will be
             responsible for ensuring appropriate clinical interpretation of ECGs.

          -  The subject and/or the subject's legal guardian (if applicable) must be capable of
             giving informed consent/assent, which includes compliance with the study requirements
             and restrictions listed in the consent/assent form.

        Exclusion Criteria:

          -  History of life-threatening asthma: Defined for this protocol as an asthma episode
             that required intubation and/or was associated with hypercapnia, respiratory arrest or
             hypoxic seizures within the last 10 years

          -  Respiratory infection: Culture-documented or suspected 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 (Screening and Run-in Visit) 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 ability to participate in the study

          -  Asthma exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12
             weeks of Visit 1 (Screening and Run-in Visit) or that resulted in overnight
             hospitalisation requiring additional treatment for asthma within 6 months before Visit
             1 (Screening and Run-in Visit)

          -  Concurrent respiratory disease: 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

          -  Other concurrent diseases/abnormalities: A subject must not have any clinically
             significant, uncontrolled condition or disease state that, in the opinion of the
             investigator, would put the safety of the subject at risk through study participation
             or would confound the interpretation of the efficacy results if the condition/disease
             exacerbated during the study. Additional excluded conditions/diseases are included in
             the study protocol

          -  Evidence of a severe exacerbation, defined as deterioration of asthma requiring the
             use of systemic corticosteroids (tablets, suspension, or injection) for at least 3
             days or an in-patient hospitalisation or emergency department visit due to asthma that
             required systemic corticosteroids between Visit 1 (Screening and Run-in Visit) and
             Visit 2 (randomisation and Treatment Period 1 Baseline Visit)

          -  Oropharyngeal examination: A subject will not be eligible for the Run-in if he/she has
             clinical visual evidence of candidiasis at Visit 1 (Screening and Run-in Visit)

          -  Investigational medications: A subject must not have administered any investigational
             drug within 30 days before Visit 1(Screening and Run-in Visit) or within five
             half-lives of the prior investigational drug (whichever is the longer of the two). The
             prior investigational drug half-life may be confirmed with the prior investigational
             study sponsor or by consulting relevant study documentation

          -  Allergies: Drug allergy; Any adverse reaction including immediate or delayed
             hypersensitivity to any beta2 agonist, sympathomimetic drug, or any intranasal,
             inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the
             constituents of the FSC multi-dose inhaler and capsule-based inhaler (i.e., lactose),
             Milk protein allergy; History of severe milk protein allergy

          -  Concomitant medications: Administration of prescription or over the counter medication
             that would significantly affect the course of asthma, or interact with study
             treatment, such as: anticonvulsants (barbiturates, hydantoins, carbamazepine);
             polycyclic antidepressants; beta-adrenergic blocking agents; phenothiazines; and
             monoamine oxidase (MAO) inhibitors

          -  Immunosuppressive medications: A subject must not be using or require use of
             immunosuppressive medications during the study

          -  Cytochrome P450 3A4 (CYP3A4) inhibitors: Subjects who have received a potent CYP3A4
             inhibitor within 4 weeks of Visit 1(Screening and Run-in Visit) (e.g., ritonavir,
             ketoconazole, itraconazole)

          -  Subject is unable to refrain from the use of prescription or non-prescription drugs,
             including vitamins, herbal and dietary supplements (including St John's wort) within 7
             days (or 14 days if the drug is a potential enzyme inducer) or five half-lives
             (whichever is longer) before the first dose of study treatment, unless in the opinion
             of the investigator and medical monitor the medication will not interfere with the
             study procedures or compromise subject safety

          -  Any subjects that have previously received or are currently receiving omalizumab

          -  Use of the excluded medications are included in the study protocol

          -  Compliance: A subject will not be eligible if he/she or his/her parent or legal
             guardian has any infirmity, disability, disease, or geographical location that seems
             likely (in the opinion of the investigator) to impair compliance with any aspect of
             this study protocol, including visit schedule and completion of the daily diaries

          -  Tobacco use: Current smoker or a smoking history of ≥10 pack-years (e.g., 20
             cigarettes/day for 10 years). A subject must not have used inhaled tobacco products
             within the past 3 months (e.g., cigarettes, cigars or pipe tobacco). One pack year is
             defined as 20 manufactured cigarettes (1 pack) smoked per day for 1 year

          -  Pregnant females as determined by urine test at Visit 1 (Screening and Run-in Visit)
             or predosing. A confirmatory serum pregnancy test is required if the urine test is
             questionable or positive

          -  Lactating females

          -  A positive hepatitis B surface antigen or positive hepatitis C test result

          -  Subject is mentally or legally incapacitated

          -  Child in Care (CiC): A 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).

          -  Unwillingness or inability to follow the procedures outlined in the protocol.