A Study to Investigate the Efficacy, Safety, and Tolerability of Repeat Doses of Inhaled GSK2269557 in Adults With Persistent, Uncontrolled Asthma
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: GSK2269557 DPI; Placebo DPI
Intervention description: GSK2269557 will be supplied as a lactose blend in a DISKUS DPI with a unit dose strength of 500 mcg. 2 inhalations will be taken every morning before breakfast.; Placebo will be lactose in a DISKUS DPI. 2 inhalations will be taken every morning before breakfast.
Intervention MeSH terms: Nemiralisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: GSK2269557; Asthma; Pharmacokinetics; Safety; Adults; DISKUS Dry Powder Inhaler; Efficacy

Summary:

      This study is a multi-centre, randomised, double-blind, placebo-controlled (with rescue
      medication), two period crossover study in subjects with persistent uncontrolled asthma,
      currently not treated with an inhaled corticosteroid (ICS) or long acting beta 2 agonist
      (LABA). This study is the first administration of GSK2269557 to asthmatic subjects, and the
      aims of the study are to investigate the efficacy, safety, tolerability, and pharmacokinetics
      of four weeks of treatment with orally inhaled GSK2269557 1000 microgram (mcg) in subjects
      with persistent uncontrolled asthma. In a sub-study, biological mediators will be measured
      from induced sputum and blood.

      Approximately 50 subjects will be randomised into the study (including approximately 16
      subjects in the sputum sub-study). Each subject will complete two treatment periods: subjects
      will be randomised to receive GSK2269557 1000 mcg in one treatment period, and matching
      placebo in the other treatment period. Each treatment will be administered once daily for 28
      days (+/- 2 days) via the DISKUS™ dry powder inhaler (DPI).

      The study will consist of a Screening Visit; a Run-in Period (approximately 2 weeks in
      duration); two 28-day Treatment Periods (each with 4 clinic visits); a 4-week Washout Period
      (between the Treatment Periods); and a Follow-up Visit. The total duration of the study for
      each subject will be approximately 16 weeks. DISKUS is a registered trademark of the
      GlaxoSmithKline group of companies.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 70 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 and currently being treated only with an intermittent short acting
             beta 2 agonist (SABA) or other non-corticosteroid controllers. Non corticosteroid
             controllers (e.g. leukotriene receptor antagonists [LTRAs]) must be discontinued from
             Screening until the end of Treatment Period 2.

          -  Able to replace current SABA treatment with salbutamol metered dose inhaler (MDI) at
             Screening for use as needed for the duration of the study. Judged capable of
             withholding salbutamol for at least 4 hours prior to FEV1 assessments.

          -  No use of an ICS or LABA for at least 12 weeks prior to first dose of study
             medication.

          -  A best pre-bronchodilator FEV1 >=60 percent (%) of the predicted normal value at
             screening.

          -  FEV1 increase by >=12% and >=200 milliliter (mL) over baseline value within 10-40
             minutes of inhalation of 400 mcg salbutamol MDI (a spacer device may be used if
             required).

          -  Positive skin prick test to common aero-allergen(s) at screening (not historical).

          -  Sputum sub-study only: Able to produce >100 milligram (mg) of sputum at screening or
             during the run-in period.

          -  Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 18-32
             kilogram per meter square (kg/m^2) (inclusive).

          -  Male subject: Male subjects with female partners of child bearing potential must
             comply with the following contraception requirements from the first dose of study
             medication until completion of the follow-up visit.

               1. Vasectomy with documentation of azoospermia.

               2. Male condom plus partner use of one of the contraceptive options below:

        Contraceptive subdermal implant with a <1% rate of failure per year, as stated in the
        product label; Intrauterine device or intrauterine system with a <1% rate of failure per
        year, as stated in the product label; Oral contraceptive, either combined or progestogen
        alone, injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive
        patches.

          -  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:

               1. 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
                  [refer to laboratory reference ranges for confirmatory levels]). 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.

               2. Reproductive potential and agrees to follow one of the options listed below in
                  the GlaxoSmithKline (GSK) modified list of highly effective methods for avoiding
                  pregnancy in females of reproductive potential (FRP) requirements from 30 days
                  prior to the first dose of study medication and until completion of the follow-up
                  visit.

        Contraceptive subdermal implant that meets the effectiveness criteria including a <1% rate
        of failure per year, as stated in the product label; Intrauterine device or intrauterine
        system that meets the effectiveness criteria including a <1% rate of failure per year, as
        stated in the product label; Oral contraceptive, either combined or progestogen alone;
        Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches;
        Male partner sterilization with documentation of azoospermia prior to the female subject's
        entry into the study, and this male is the sole partner for that subject; Male condom
        combined with a vaginal spermicide (foam, gel, film, cream, or suppository).

        This list does not apply to FRP with same sex partners, when this is their preferred and
        usual lifestyle or for subjects who are and will continue to be abstinent from
        penile-vaginal intercourse on a long term and persistent basis. These allowed methods of
        contraception are only effective when used consistently, correctly and in accordance with
        the product label. The investigator is responsible for ensuring that subjects understand
        how to properly use these methods of contraception.

          -  Capable of giving signed informed consent as described in the protocol which includes
             compliance with the requirements and restrictions listed in the consent form and the
             protocol. The informed consent must be signed prior to any study related procedure,
             including change in asthma medication.

        Exclusion Criteria:

          -  History of life-threatening asthma, defined as an asthma episode that required
             intubation and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic
             seizures.

          -  Any severe asthma exacerbation, defined as deterioration of asthma requiring the use
             of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of screening,
             or an inpatient hospitalisation or emergency department visit due to asthma that
             required systemic corticosteroids within 6 months of screening.

          -  Respiratory Infection: culture-documented or suspected bacterial or viral infection of
             the upper or lower respiratory tract, sinus or middle ear that has not resolved within
             4 weeks of screening 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.

          -  Concurrent Respiratory Disease: current evidence of pneumonia, pneumothorax,
             atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic
             bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other
             respiratory abnormalities other than asthma.

          -  Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) and bilirubin >1.5xULN
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  QTc >450 millisecond (msec) or QTc >480 msec in subjects with bundle branch block.

          -  Other laboratory abnormalities or concurrent diseases/clinical: clinically significant
             laboratory abnormality, uncontrolled condition or disease state that, in the opinion
             of the investigator (in consultation with the GSK Medical Monitor, if required), 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.

          -  Use of any of the prohibited medications listed in the protocol.

          -  Current smokers or subjects with a history of smoking within 6 months of screening, or
             with a total pack year history of >5 pack years.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1
             glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  History of sensitivity to any of the study medications, or components thereof
             (including lactose) or a history of drug or other allergy (including a milk protein
             allergy) that, in the opinion of the investigator or Medical Monitor, contraindicates
             their participation.

          -  Sputum sub-study only: History of sensitivity to the induced sputum procedure.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study medication.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 56 days.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dose of study medication
             in the current study: 30 days, 5 half-lives or twice the duration of the biological
             effect of the investigational product (whichever is longer).

          -  Exposure to more than 4 investigational medicinal products within 12 months prior to
             the first dose of study medication.

          -  Affiliation with investigator site: subject is an investigator; sub-investigator;
             study co-ordinator; employee of a participating investigator or study site; or, an
             immediate family member of the aforementioned, that is involved in this study.