An Efficacy Study of GSK2269557 Added to Standard Care in Subjects With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: GSK2269557; Placebo
Intervention description: Dry powder for inhalation via DISKUS 'device' with unit dose strength of 500 micrograms (mcg) per actuation with total dose of 1000 mcg daily; Dry powder for inhalation via DISKUS 'device'
Intervention MeSH terms: Nemiralisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 126.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: functional respiratory capacity; High-resolution computed tomography; GSK2269557; acute exacerbation of COPD; lung capacity

Summary:

      The purpose of this study is to evaluate the efficacy of GSK2269557 administered in addition
      to standard of care in adult subjects diagnosed with an acute exacerbation of Chronic
      Obstructive Pulmonary Disease (COPD). Additionally study will also assess safety,
      tolerability and pharmacokinetic data. The total duration of the study will be 13-14 weeks
      including screening, treatment period and a follow up visit. Subjects will receive once daily
      study treatment administration starting on Day 1. Study is planned to recruit approximately
      120 subjects such that approximately 100 subjects complete the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 40 and 80 years of age inclusive, at the time of signing the informed consent

          -  The subject has a confirmed and established diagnosis of COPD, as defined by the
             global initiative for chronic Obstructive Lung Disease (GOLD) guidelines for at least
             6 months prior to entry.

          -  The subject has a post-bronchodilator FEV1/Forced Vital Capacity (FVC) < 0.7 and FEV1
             <= 80 % of predicted (Predictions should be according to the European Community of
             Coal and Steel [ECCS] equations), documented in the last 5 years.

          -  Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to
             include corticosteroid and antibiotics. Acute exacerbation to be confirmed by an
             experienced physician and represent a recent change in at least two major and one
             minor symptoms, one major and two minor symptoms, or all 3 major symptoms. Major
             symptoms: subjective increase in dyspnea, increase in sputum volume, and change in
             sputum colour. Minor symptoms: cough, wheeze and sore throat.

          -  The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack
             years (pack years = [cigarettes per day smoked/20 x number of years smoked])

          -  Body weight >= 45 kilogram (kg) and body mass index (BMI) within the range 18 - 32
             kg/metered squared (m^2) (inclusive).

          -  Male

          -  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:

        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 and 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.

        Reproductive potential and agrees to follow one of the options listed below in the 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.

        GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in
        Females of Reproductive Potential (FRP):

        Contraceptive subdermal implant that meets the standard operating procedure (SOP)
        effectiveness criteria including a <1% rate of failure per year, as stated in the product
        label.

        Intrauterine device or intrauterine system that meets the SOP 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).

          -  Male subjects with female partners of child bearing potential must comply with the
             following contraception requirements from the time of first dose of study medication
             until after the completion of the follow up visit.

        Vasectomy with documentation of azoospermia. Male condom plus partner use of one of the
        contraceptive options below: Contraceptive subdermal implant that meets the SOP
        effectiveness criteria including a <1% rate of failure per year, as stated in the product
        label. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria
        including a <1% rate of failure per year, as stated in the product label. Oral
        Contraceptive, either combined or progestogen alone or injectable progestogen.
        Contraceptive vaginal ring. Percutaneous contraceptive patches.

        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 which includes compliance with the
             requirements and restrictions listed in the consent form and in the study protocol.

        Exclusion Criteria:

          -  To avoid recruitment of subjects with a severe COPD exacerbation, the presence of any
             one of the following severity criteria will render the subject ineligible for
             inclusion in the study:

        Need for invasive mechanical ventilation (short term (< 48hour) Non-invasive Ventilation
        (NIV) or Continuous Positive Airway Pressure [CPAP] is acceptable).

        Haemodynamic instability or clinically significant heart failure. Confusion.

          -  Subjects who have a history or current medical conditions or diseases that are not
             well controlled and, which as judged by the Investigator, may affect subject safety or
             influence the outcome of the study. (Note: Patients with adequately treated and well
             controlled concurrent medical conditions [e.g. hypertension or non-insulin dependent
             diabetes mellitus] are permitted to be entered into the study).

          -  Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt
             bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that
             might, in the opinion of the investigator, compromise the safety of the subject or
             affect the interpretation of the results.

          -  Alanine aminotransferase >2x upper limit of normal (ULN) and bilirubin >1.5xULN
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%).

          -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the exclusion criteria, outside of the reference range for the
             population being studied may be included if the Investigator [in consultation with the
             GSK Medical Monitor if required] documents that the finding is unlikely to introduce
             additional risk factors and will not interfere with the study procedures.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or demonstrating
             a clinically significant arrhythmia requiring treatment.

          -  QTcF > 450 millisecond (msec) or QTcF > 480 msec in subjects with Bundle Branch Block,
             based on single QTcF value.

          -  Subjects who have undergone lung volume reduction surgery.

          -  Subject is currently on chronic treatment with macrolides; long term oxygen therapy (>
             15 hours/day).

          -  The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-TNF),
             anti-Interleukin-1 (anti-IL1), or any other immunosuppressive therapy within 60 days
             prior to dosing.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >28 units for males or >21 units for females. One unit is
             equivalent to 8 gram of alcohol: a half-pint ( equivalent to 240 milliliter [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 (such as
             lactose) or a history of drug or other allergy that, in the opinion of the
             investigator or Medical Monitor, contraindicates their participation.

          -  A known (historical) positive test for human immune virus (HIV) antibody.

          -  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 treatment. NOTE:
             Because of the short window for screening, treatment with GSK2269557 may start before
             receiving the result of the hepatitis tests. If subsequently the test is found to be
             positive, the subject may be withdrawn, as judged by the Principal Investigator in
             consultation with the Medical Monitor.

          -  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 dosing day 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 dosing day.