A Study of the Effectiveness and Safety of Different Doses of Fluticasone Propionate Taken From a Dry Powder Inhaler (Puffer) in Adolescents and Adults Who Have Asthma That is Not Controlled by High Dose Inhaled Corticosteroid Asthma Medications
Condition: Asthma
MeSH terms: Asthma
Intervention: Fp MDPI; Placebo MDPI; Flovent Diskus; albuterol/salbutamol
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 50, 100, 200 or 400 mcg of Fp one inhalation twice a day for a total daily dose of 100, 200, 400 or 800 mcg. Study drug was administered in the morning and in the evening.; Placebo multidose dry powder inhaler (MDPI) in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI.; Flovent Diskus contains the active ingredient fluticasone propionate (Fp). Flovent Diskus 250 mcg was used twice a day, once in the morning and evening, for a total daily dose of 500 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).
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: 889.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Dose ranging; Fluticasone Propionate; Dry Powder Inhaler (DPI); High Dose ICS; Asthma

Summary:

      The primary objective of this study is to evaluate the dose response, efficacy and safety of
      4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as
      Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in
      subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high
      dose ICS therapy.
    

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. ATS/ERS 2005 criteria for acceptability, reproducibility, and end
             of test must be met for spirometry

          6. Reversibility of Disease: Demonstrated a ≥12% 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 ≥12% then the subject is not eligible
             for the study and will not be allowed to re-screen. Reversibility values of 11.50 -
             11.99 will be rounded to 12. Documented historical reversibility of ≥ 12 % within 3
             months of the Screening Visit will be accepted.

          7. Current Asthma Therapy: Subjects will be required to be on a short acting β2 agonist
             and inhaled corticosteroid for a minimum of 8 weeks before the Screening Visit and
             have been maintained on a stable dose of inhaled corticosteroids for four weeks prior
             to the Screening Visit at one of the following doses:

               -  Fluticasone propionate HFA MDI ≥ 880 mcg/day

               -  Fluticasone propionate DPI≥ 1000 mcg/day

               -  Beclomethasone dipropionate DPI ≥ 2000 mcg/day

               -  Beclomethasone dipropionate HFA (QVAR)≥ 640 mcg/day

               -  Beclomethasone dipropionate HFA (Clenil Modulite)≥ 2000 mcg/day

               -  Budesonide DPI ≥ 1600 mcg/day

               -  Budesonide MDI ≥ 1600 mcg/day

               -  Flunisolide ≥ 2000 mcg/day

               -  Triamcinolone acetonide ≥ 2000 mcg /day

               -  Mometasone furoate DPI ≥ 880 mcg/day

               -  Ciclesonide HFA MDI ≥ 640 mcg/day

             Exception 1: Based upon the investigator's judgment that there is no inherent harm in
             changing the subject's current ICS/LABA therapy and the subject provides consent,
             subjects on inhaled Fluticasone propionate/salmeterol DPI ≥ 1000 mcg/day, or
             Fluticasone propionate/salmeterol HFA ≥ 880 mcg/day, or Fluticasone
             propionate/Formoterol ≥ 1000 mcg/day,or Beclomethasone dipropionate/Formoterol ≥ 400
             mcg/day, or Budesonide/formoterol HFA ≥ 640 mcg/day, or Budesonide/formoterol DPI ≥
             800 mcg/day, or Mometasone furoate/formoterol MDI ≥ 800 mcg/day or subjects on a
             qualifying ICS dose plus a long-acting β2-agonists (LABA) administered via separate
             inhalers, may be switched to a qualifying dose of fluticasone propionate provided the
             subjects will not participate in the PK portion of the study.

             Exception 2: Subjects on a qualifying dose of fluticasone propionate who wish to
             participate in the PK portion of the study and who provide consent may have their
             fluticasone propionate switched to a different qualifying ICS (non-fluticasone
             propionate) at a pre-screening visit. The subject will be required to return to the
             clinic to complete the Screening Visit following a 1-week washout period.

          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
             it's 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 β2 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

               -  Non-childbearing potential, defined as:

                    -  Before menarche, 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

               -  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 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

                    -  Monogamous with a vasectomized male partner or is of

               -  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 of 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 1 month of the Screening
             Visit. A subject must not have had any hospitalization for asthma within 2 month 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
             inhaled 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 inhaled 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. Untreated oral candidiasis at the Screening Visit. Subjects with clinical visual
             evidence of oral candidiasis and who agree to receive treatment and comply with
             appropriate medical monitoring may enter the study

          9. History of any adverse reaction to 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 4 weeks prior to the Screening
             Visit

               -  Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological
                  disease is permitted

               -  Use of intranasal corticosteroids or ocular 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 for the treatment of allergy at a stable maintenance dose for at least
             90 days prior to the Screening Visit and which will remain at a stable dose without
             escalation throughout the study is permitted.

         14. Use of Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole,
             itraconazole) within 4 weeks prior to the Screening Visit. Strong and moderate CYP3A4
             inhibitors are prohibited and weak CYP3A4 are allowed.

         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.