Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects
Condition: Asthma
MeSH terms: Asthma
Intervention: Fluticasone furoate (FF) Dry Powder Inhaler; Fluticasone propionate (FP) Dry Powder Inhaler; Budesonide (BUD) Turbuhaler; Placebo (ELLIPTA or DISKUS)
Intervention description: Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods; Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods; Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.; Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.
Intervention MeSH terms: Fluticasone; Xhance; Budesonide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Dose-response; AMP challenge; cortisol suppression; dose escalation; therapeutic index

Summary:

      This is a randomized, placebo-controlled, 2-period crossover, escalating repeat dose study,
      aiming to investigate whether higher potency of different inhaled corticosteroid confers an
      improvement in the topical efficacy to systemic activity ratio in asthmatic subjects. It will
      compare the dose response for topical efficacy via airway responsiveness (to
      adenosine-5'-monophosphate [AMP] challenge), and the dose response for systemic activity via
      24 hour plasma cortisol suppression, and thereby compare the relative therapeutic index, for
      the following inhaled corticosteroids: fluticasone furoate (FF), fluticasone propionate (FP)
      and budesonide (BUD). There will be a screening visit 4 - 42 days before the first dose of
      study treatment, and AMP challenge Provocative concentration 20 (PC20) of <=80 milligrams per
      milliliter (mg/mL) at screening visit 2 i.e. at 4 - 14 days before the first dose of study
      treatment. Subjects will be randomized to one of 5 or 12 treatment sequences, and will have
      one or two treatment periods, each comprising 5 consecutive 7-day phases of escalating doses
      of either FF, FP, BUD or placebo. There will be a 25- to 42-day washout period between
      treatment periods. The study duration for each subject will be approximately 13 or 24 weeks
      including the follow-up period.
    

Eligibility criteria:

        Inclusion Criteria - Subjects must be 18 to 65 years of age inclusive, at the time of
        signing the informed Consent. - Documented history of bronchial asthma, first diagnosed at
        least 6 months prior to the screening visit - Pre-bronchodilator FEV1 >=65% of predicted at
        screening; the pre-dose baseline FEV1 should not have changed significantly in the opinion
        of the investigator from the screening baseline value and should be >=65% predicted for the
        subject to continue - Documented sensitivity to AMP with a provocative concentration of AMP
        resulting in a fall of >=20% FEV1 with a PC20 AMP <=80 mg/mL at the screening visit -
        Current therapy could include short-acting Beta2-agonists (SABA) prescribed SABA for at
        least 12 weeks prior to screening, if needed; subjects receiving low-dose ICS may take part
        after a 4-week ICS washout prior to AMP challenge. The subject's asthma symptoms must
        remain stable during this 4-week period as assessed at screening visit 2. Stable asthma is
        defined as no more than 2 consecutive days where >=12 inhalations/day of salbutamol were
        used; or no severe asthma exacerbations requiring use of systemic corticosteroids (tablets,
        suspension, or injection) or an in-patient hospitalization or emergency department visit
        due to asthma that required systemic corticosteroids; or no clinical asthma worsening which
        in the opinion of the investigator requires additional asthma treatment other than study
        medication or salbutamol; subjects taking Long-acting beta2-agonist (LABA), long-acting
        muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy within three
        months prior to the start of the study are not eligible; subjects taking biological
        therapies within 6 months prior to start of the study are not eligible. - Bodyweight >=50
        Kilogram (kg) and BMI within the range 18.0-35.0 kg/meter (m)^2 (inclusive) - Male and
        female. Females: A female subject is eligible to participate if she is not pregnant (as
        confirmed by a negative urine human chorionic gonadotrophin [HCG] test), not lactating, and
        at least one of the following conditions applies prior to randomization: • Non-reproductive
        potential defined as pre-menopausal females with one of the following: Documented tubal
        ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
        bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy; Postmenopausal
        defined as 12 months of spontaneous amenorrhea, in questionable cases a blood sample with
        simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with
        menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in
        doubt will be required to use one of the highly effective contraception methods if they
        wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow
        confirmation of post-menopausal status prior to study enrolment. • Reproductive potential
        and agrees to follow one of the highly effective methods for avoiding pregnancy in females
        of reproductive potential from 30 days prior to the first dose of study medication and
        until at least five terminal half-lives after the last dose of study medication. The
        investigator is responsible for ensuring that subjects understand how to properly use these
        methods of contraception. - Aspartate aminotransferase and Alanine transaminase <2x upper
        limit of normal (ULN); alkaline phosphatase and bilirubin ≤1.5 x ULN (isolated bilirubin
        >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) - Light
        smokers, who smoke <=20 cigarettes per week or equivalent unit dose of other tobacco
        products or e-cigarettes, are eligible for the study. Smokers who intend to stop, reduce or
        increase their smoking habit during the study period are not eligible. - Having provided
        written informed consent, which includes compliance with the requirements and restrictions
        listed in the consent form.

        Exclusion Criteria: - A history of life-threatening asthma, defined as an asthma episode
        that required intubation and/or was associated with hypercapnia, respiratory arrest or
        hypoxic seizures within the last 5 years. - Other significant pulmonary diseases to include
        (but not limited to) severe pneumonia within 6 months of the screening visit, pneumothorax,
        atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis,
        emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory
        abnormalities other than asthma. - Culture-documented or suspected bacterial or viral
        infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of
        screening 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. - A subject will not be
        eligible if he/she has clinical visual evidence of oral candidiasis at screening. - Any
        asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that
        resulted in overnight hospitalization requiring additional treatment for asthma within 6
        months prior to randomization. - Use of prohibited medications including, anti-depressant
        drugs, and anti-asthma drugs (other than short acting inhaled beta-agonists supplied as
        rescue medication, oral contraceptives, non-steroidal anti-inflammatory drugs, stable doses
        of antihistamines, and paracetamol) for 1 week prior to screening and throughout the course
        of the study. Anti-histamines should be withheld 4 days prior to AMP challenge; subjects
        must also be able to abstain from short acting inhaled beta-agonists, for 8 hours prior to
        spirometry. - Subjects undergoing de-sensitization therapy - Current smokers who smoke > 20
        cigarettes per week or the equivalent unit dose of other tobacco products or e-cigarettes,
        or smokers with a smoking history of >=10 pack years. - History of regular alcohol
        consumption exceeding 21 units per week for men and 14 units per week for females (1 unit
        =5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of spirits)
        within 6 months of screening. - All subjects who are currently or in the last month have
        worked night-shifts are excluded from the study - Exposure to more than four new chemical
        entities within 12 months prior to the first dosing day or received an investigational
        product within 30 days of study start, or 5 half-lives of study drug if that is longer. - A
        subject has 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 study results if the
        condition/disease exacerbated during the study. (e.g. stroke or myocardial infarction
        within 3 months, uncontrolled hypertension, congestive heart failure, uncontrolled diabetes
        mellitus.) - Evidence of cancer or history of cancer in the past 5 years other than
        adequately treated basal or squamous cell carcinoma of the skin or adequately treated in
        situ carcinoma of the cervix. - Pregnant females as determined by positive urine HCG test
        at screening or by positive urine HCG test prior to dosing and lactating females. -
        Subjects with active or chronic infections including hepatitis B or C, human
        immunodeficiency virus. A positive serology at screening. - Allergies: History of severe
        milk protein allergy Drug Allergy defined as any adverse reaction including immediate or
        delayed hypersensitivity to intranasal, inhaled, or systemic corticosteroid therapy. Known
        or suspected sensitivity to the constituents of FF, FP or BUD (i.e., lactose or magnesium
        stearate etc.) Historical Allergy defined as history of drug or other allergy that, in the
        opinion of the investigator or GSK Medical Monitor, contraindicates their participation. -
        Significant abnormality in the 12-lead electrocardiogram (ECG) performed at screening. The
        mean of the three individual ECGs will be taken. Mean QT interval corrected for heart rate
        (QTc) >450 millisecond (msec) for males or QTc>470 msec for female subjects and >480 in
        subjects with bundle branch block. The QTc is the QT interval corrected for heart rate
        according to Fridericia's formula (QTcF).