A Study to Evaluate the Safety, Efficacy and Changes in Induced Sputum and Blood Biomarkers Following Daily Repeat Doses of Inhaled GSK2269557 in Chronic Obstructive Pulmonary Disease (COPD) Subjects With Acute Exacerbation
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: GSK2269557; Placebo; DISKUS; ELLIPTA
Intervention description: GSK2269557 500 mcg blended with lactose per blister and will be administered using a DISKUS dry powder inhaler device. Since GSK2269557 will no longer be manufactured for use with the DISKUS device, it will be replaced with ELLIPTA Device. Subjects will receive GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA.; Lactose will be administered using a DISKUS and ELLIPTA dry powder inhaler device; It is multi-dose dry powder inhaler containing one foil strip of drug with 60 blisters; It is multi-dose dry powder inhaler containing one foil strip of drug with 30 blisters
Intervention MeSH terms: Nemiralisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 44.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: double-blind; PI3Kdelta; GSK2269557; exacerbation; Chronic Obstructive Pulmonary Disease; randomised; placebo-controlled

Summary:

      The purpose of this study is to evaluate specific alterations in immune cell mechanisms
      related to neutrophil function as detected by PI3Kdelta-dependent changes in messenger
      ribonucleic acid (mRNA) extracted from induced sputum in patients experiencing an
      exacerbation of COPD, with or without treatment with GSK2269557. The efficacy of treatment
      with GSK2269557 will also be measured using functional respiratory imaging (FRI) and
      spirometry. This is a randomised, double-blind, placebo-controlled, parallel-group study. The
      study consisted of Screening Phase (up to 3 days prior to Day 1), Treatment Phase (Days 1 to
      84) and Follow phase (7 to 14 days after last dose). The total duration of the study is 13-14
      weeks including the screening visit. DISKUS TM and ELLIPTA TM are registered trademark of GSK
      group of companies.
    

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 is able to produce >100 milligram (mg) of sputum at screening for
             processing, (ie, total weight of sputum plugs).

          -  The subject has a post-bronchodilator FEV1/FVC <0.7 and FEV1 <=80 % of predicted.

          -  Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to
             include both 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; Change in sputum
             colour. Minor symptoms: Cough; Wheeze; 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 16 to 35
             kilogram per meter square (kg/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: (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. Females whose
             menopausal status is in doubt will be required to use, or have been using, one of the
             highly effective contraception methods as specified below from 30 days prior to the
             first dose of study medication and until completion of the follow-up visit.
             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. GSK
             Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP. 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. 1) Contraceptive
             subdermal implant that meets GSK standard criteria including a <1% rate of failure per
             year, as stated in the product label. 2) Intrauterine device or intrauterine system
             that meets GSK standard criteria including a <1% rate of failure per year, as stated
             in the product label. 3) Oral Contraceptive, either combined or progestogen alone. 4)
             Injectable progestogen. 5) Contraceptive vaginal ring. 6) Percutaneous contraceptive
             patches. 7) 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. 8) Male condom combined with a vaginal spermicide (foam, gel, film, cream, or
             suppository). 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. Specific inclusion criteria for Male subjects with female partners of
             reproductive potential is outlined below: 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. 1) Vasectomy with documentation of azoospermia. 2) Male condom plus partner use
             of one of the contraceptive options below: Contraceptive subdermal implant that meets
             GSK standard criteria including a <1% rate of failure per year, as stated in the
             product label. Intrauterine device or intrauterine system that meets GSK standard
             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. 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 this 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 [<48
             hour] Non-invasive ventilation [NIV] or continuous positive airway pressure [CPAP] is
             acceptable); Haemodynamic instability or clinically significant heart failure;
             Confusion; Clinically significant pneumonia, identified by chest X-ray at screening,
             and as judged by the Investigator.

          -  Subjects who have 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 noninsulin-dependent diabetes
             mellitus [NIDDM]) 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.

          -  ALT >2xupper 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 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 or long term antibiotics.

          -  Subject is being treated with long term oxygen therapy (LTOT) (>15 hours/day).

          -  The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-TNF),
             or any other immunosuppressive therapy (except corticosteroid) 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 (g) of alcohol: a half-pint (~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 immunodeficiency 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.