A Study of the Effectiveness and Safety of Different Doses of Fluticasone Propionate Taken From a Dry Powder Inhaler in Adolescents and Adults Who Have Asthma That is Not Controlled by Asthma Medications Not Containing Steroids
Condition: Asthma
MeSH terms: Asthma
Intervention: Fp MDPI; Flovent Diskus; albuterol/salbutamol; Placebo MDPI
Intervention description: Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened.
During the treatment period, participants were randomized to 12.5, 25, 50 or 100 mcg of Fp one inhalation twice a day for a total daily dose of 25, 50, 100 or 200 mcg. Study drug was administered in the morning and in the evening; Flovent Diskus contains the active ingredient fluticasone propionate (Fp). Flovent Diskus 100 mcg was used twice a day, once in the morning and evening, for a total daily dose of 200 mcg of Fp. This therapy was not blinded as the inhaler device was different than the MDPI used in the other treatment arms.; A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Placebo multidose dry powder inhaler in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI.
Intervention MeSH terms: Fluticasone; Xhance; Albuterol; Adrenergic Agonists
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 909.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Dose Ranging; Fluticasone Propionate; Dry Powder Inhaler (DPI); Non-steroidal; Asthma

Summary:

      This is a randomized, double-blind, placebo- and open-label active controlled,
      parallel-group, multicenter, dose ranging study in male or female subjects ages 12 years and
      older with persistent asthma who are uncontrolled on non-steroidal therapy. The primary
      objective of this study is to evaluate the dose response, efficacy and safety of 4 different
      doses of fluticasone propionate delivered as Fluticasone Propionate DPI (Dry Powder Inhaler)
      when administered twice daily.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent/assent signed and dated by the subject and/or parent /legal
             guardian before conducting any study related procedure.

          2. Male or female 12 years and older, as of the Screening Visit. Male or female 18 years
             and older, as of the Screening Visit, in countries where local regulations or the
             regulatory status of study medication permit enrollment of adults only.

          3. General good health, and free of any concomitant conditions or treatment that could
             interfere with study conduct, influence the interpretation of study
             observations/results, or put the subject at increased risk during the study.

          4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health (NIH).

          5. Severity of Disease: A best forced expiratory volume in one second (FEV1) of 40%-85%
             of the predicted normal value during the Screening Visit. NHANES III predicted values
             will be used for subjects aged ≥12 years and adjustments to predicted values will be
             made for African American subjects.

          6. Reversibility of Disease: Demonstrated a ≥15% reversibility of FEV1 within 30 minutes
             following 2 inhalations of albuterol/salbutamol inhalation aerosol (if required,
             spacers are permitted for reversibility testing only) at the Screening Visit. If a
             subject fails to demonstrate an increase in FEV1 ≥15%, then the subject is not
             eligible for the study and will not be allowed to re-screen.

          7. Current Asthma Therapy: Subjects must be on a short-acting β2-agonist alone or a
             non-corticosteroid maintenance medication (with or without a short-acting β2-agonist)
             for ≥ 3 months preceding the Screening Visit. Subjects must not have used an inhaled
             corticosteroid for at least 6 weeks preceding the Screening Visit.

             Exception: Based upon the investigator's judgment that there is no inherent harm in
             changing the subject's current ICS therapy and the subject provides consent, subjects
             on low dose ICS (100mcg Fp BID or equivalent) may be switched to a short-acting β2
             agonist alone at a Pre-screening Visit. The subject will be required to return to the
             clinic to complete the Screening Visit once the 2-week washout period has been
             completed.

          8. Short-Acting β2-Agonists: All subjects must be able to replace their current
             short-acting β2-agonists with albuterol/salbutamol inhalation aerosol at the Screening
             Visit for use as needed for the duration of the study. The use of spacer devices with
             the metered dose inhaler (MDI) will not be allowed during the study with exception of
             its use during reversibility testing at the Screening Visit. Nebulized
             albuterol/salbutamol will not be allowed at any time during the study. Subjects must
             be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for
             at least 6 hours prior to all study visits.

          9. If female, is currently not pregnant, breast feeding, or attempting to become
             pregnant, has a negative serum pregnancy test, and is of

               1. Non-childbearing potential, defined as:

                    -  Before menarche or > or =1 year post-menopausal or

                    -  Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy)
                       or

                    -  Congenital sterility or

                    -  Diagnosed as infertile and not undergoing treatment to reverse infertility
                       or is of

               2. Child-bearing potential, willing to commit to using a consistent and acceptable
                  method of birth control as defined below for the duration of the study:

                    -  Systemic contraception used for > or = 1 month prior to screening, including
                       birth control pills, transdermal patch (Ortho Evra®), vaginal ring
                       (NuvaRing®), levonorgesterel (Norplant®), or injectable progesterone
                       (Depo-Provera®) or

                    -  Double barrier methods (condoms, cervical cap, diaphragm, and vaginal
                       contraceptive film with spermicide) or

                    -  Intrauterine device (IUD) or is of

               3. Child-bearing potential and not sexually active, willing to commit to using a
                  consistent and acceptable method of birth control as defined above for the
                  duration of the study, in the event the subject becomes sexually active.

         10. Capable of understanding the requirements, risks, and benefits of study participation,
             and, as judged by the investigator, capable of giving informed consent/assent and
             being compliant with all study requirements (visits, record-keeping, etc).

        Exclusion Criteria:

          1. History of life-threatening asthma that is defined for this protocol as an asthma
             episode that required intubation and/or was associated with hypercapnea, respiratory
             arrest or hypoxic seizures.

          2. Culture-documented or suspected bacterial or viral infection of the upper or lower
             respiratory tract, sinus, or middle ear that is not resolved within 2 weeks prior to
             the Screening Visit. In addition, the subject must be excluded if such infection
             occurs between the Screening Visit and the Randomization Visit.

          3. Any asthma exacerbation requiring oral corticosteroids within 3 months of the
             Screening Visit. A subject must not have had any hospitalization for asthma within 6
             months prior to the Screening Visit.

             Note: An exacerbation of asthma is defined as any worsening of asthma requiring any
             treatment other than rescue albuterol/salbutamol HFA MDI and/or the subject's regular
             non-corticosteroid maintenance treatment. This includes requiring the use of systemic
             corticosteroids and/or emergency room visit or hospitalization, a change in the
             subject's regular non-corticosteroid maintenance treatment, or the addition of other
             asthma medications.

          4. Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal
             cell carcinoma.

          5. Historical or current evidence of a clinically significant disease including, but not
             limited to: cardiovascular (e.g., congestive heart failure, known aortic aneurysm,
             clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal,
             hematological, neuropsychological, endocrine (e.g., uncontrolled diabetes mellitus,
             uncontrolled thyroid disorder, Addison's disease, Cushing's syndrome),
             gastrointestinal (e.g., poorly-controlled peptic ulcer, GERD), or pulmonary (e.g.,
             chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic
             fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease).
             Significant is defined as any disease that, in the opinion of the investigator, would
             put the safety of the subject at risk through participation, or which could affect the
             efficacy or safety analysis if the disease/condition exacerbated during the study.

          6. Have any of the following conditions that, in the judgment of the investigator, might
             cause participation in this study to be detrimental to the subject, including, but not
             limited to:

               -  Current malignancy excluding basal cell carcinoma; History of malignancy is
                  acceptable only if the subject has been in remission for one year prior to the
                  Screening Visit. (Remission is defined as no current evidence of malignancy and
                  no treatment for the malignancy in the 12 months prior to the Screening Visit)

               -  Current or untreated tuberculosis; History of tuberculosis is acceptable only if
                  a subject has received an approved prophylactic treatment regimen or an approved
                  active treatment regimen and has had no evidence of active disease for a minimum
                  of 2 years • Uncontrolled hypertension (systolic BP ≥160 or diastolic BP >100)

               -  Stroke within 3 months prior to the Screening Visit

               -  Immunologic compromise

          7. History of a positive test for HIV, hepatitis B or hepatitis C infection.

          8. Clinical visual evidence of oral candidiasis at the Screening Visit.

          9. History of any adverse reaction, including immediate or delayed hypersensitivity to
             any β2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic
             corticosteroid therapy. Known or suspected sensitivity to the constituents of the dry
             powder inhalers (Spiromax or Diskus) used in the study (i.e., lactose).

         10. History of severe allergy to milk protein.

         11. Use of systemic, oral or depot corticosteroids within 12 weeks prior to the Screening
             Visit

               -  Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological
                  disease is permitted

               -  Use of intranasal corticosteroids at a stable dose for at least 4 weeks prior to
                  the Screening Visit and throughout the study is permitted

         12. Use of immunosuppressive medications within 4 weeks prior to the Screening Visit and
             during the study.

         13. Immunotherapy at a stable dose for at least 90 days prior to the Screening Visit and
             throughout the study for the treatment of allergies is permitted.

         14. Use of potent Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole,
             itraconazole) within 4 weeks prior to the Screening Visit.

         15. History of alcohol or drug abuse within two years preceding the Screening Visit.

         16. Current smoker or a smoking history of 10 pack years or more (a pack year is defined
             as smoking 1 pack of cigarettes/day for 1 year). A subject may not have used tobacco
             products within the past one year (e.g., cigarettes, cigars, chewing tobacco, or pipe
             tobacco).

         17. Study participation by clinical investigator site employees and/or their immediate
             relatives.

         18. Study participation by more than one subject from the same household at the same time.
             However, after the study completion or discontinuation by one subject another subject
             from the same household may be screened.

         19. Participation in any investigational drug study within the 30 days (starting at the
             final follow-up visit) preceding the Screening Visit or planned participation in
             another investigational drug study at any time during this study.

         20. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for
             in vitro fertilization during the study period or for 30 days following the subject's
             last study related visit (for eligible subjects only - if applicable). Eligible female
             subjects unwilling to employ appropriate contraceptive measures to ensure that
             pregnancy will not occur during the study will be excluded.