GSK2339345 Hypertussive Challenge Study
Condition: Cough
MeSH terms: Cough
Intervention: GSK2339345; Placebo
Intervention description: Clear colorless solution in clear glass vial for oral inhalation via aqueous droplet inhaler with unit dose strength of 1000 microgram (mcg) inhaled in two actuations.; Clear colorless solution of 0.9% sodium chloride for oral inhalation via aqueous droplet inhaler inhaled in two actuations.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: efficacy; hypertussive challenge; voltage gated sodium channels (VGSC); anaesthesia; Safety and tolerability; capsaicin challenge; cough; citric acid challenge; pharmacokinetics

Summary:

      This study is designed to evaluate the effect of GSK2339345 relative to placebo on the number
      of coughs in patients with Chronic Idiopathic Cough (CIC) administered by an Aqueous Droplet
      Inhaler (ADI). The primary aim is to investigate the efficacy of GSK2339345 on reducing
      objective cough frequency in CIC patients. The secondary aim of this study is to investigate
      the efficacy of GSK2339345 in inhibiting a hypertussive cough response elicited by capsaicin
      and citric acid in CIC patients which have a hyperresponsive cough reflex.

      Following the screening visit, all eligible subjects will attend the unit for dosing at
      Visits 1-7. At Visits 1, 2 and 3 (Part A of the study), subjects will receive two doses of
      either GSK2339345 or placebo, 4 hours apart and will undergo 8 hours of cough monitoring. At
      Visits 4 and 5 (Part B of the study) and Visits 6 and 7 (Part C of the study), subjects will
      be administered a single dose of either GSK2339345 or placebo. Subjects will then undergo
      capsaicin (Part B) or citric acid (Part C) tussive challenge and will undergo cough
      monitoring for 1 hour post dose.

      The maximum study duration will be approximately 11 weeks, including 3 weeks screening and 2
      weeks follow-up. Approximately 30 patients will be randomised into the study, such that
      approximately 24 patients complete dosing and critical assessments.
    

Eligibility criteria:

        Inclusion Criteria

          -  Chronic Idiopathic Cough patients according to the criteria listed below, determined
             by a responsible and experienced physician, based on a medical evaluation: Idiopathic
             cough defined as chronic cough resistant to treatment targeted at potential triggers.
             Chronic cough defined as cough lasting for more than 8 weeks.

          -  A patient with a clinical abnormality or laboratory parameters outside the reference
             range for the population being studied may be included only if the Investigator and
             the GSK Medical Monitor agree that the finding is unlikely to introduce additional
             risk factors and will not interfere with the study procedures.

          -  Male/females aged >=18 years old, at the time of signing the informed consent.

          -  Non-smoker for at least 6 months with a cumulative history of <= 10 pack years. Pack
             years = (No. of cigarettes smoked/day/20) x (No. of years smoked).

          -  Body weight >= 50 kilograms.

          -  A female subject is eligible to participate if she is of; Non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy
             [for this definition, "documented" refers to the outcome of the
             investigator's/designee's review of the subject's medical history for study
             eligibility, as obtained via a verbal interview with the subject or from the subject's
             medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in
             questionable cases a blood sample with simultaneous follicle stimulating hormone > 40
             milli international unit/milliliter (mL) and estradiol < 40 picogram/ml (<147
             picomoles/Liter [L]) is confirmatory]. Females on hormone replacement therapy (HRT)
             and whose menopausal status is in doubt will be required to use one of the
             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 enrollment. For most forms of HRT, at least 2 to4 weeks will elapse between the
             cessation of therapy and the blood draw; this interval depends on the type and dosage
             of HRT. Following confirmation of their post-menopausal status, they can resume use of
             HRT during the study without use of a contraceptive method.

        Child-bearing potential with negative pregnancy test as determined by serum human chorionic
        gonadotropin test at screening or prior to dosing and Agrees to use one of the
        contraception methods for an appropriate period of time (as determined by the product label
        or investigator) prior to the start of dosing to sufficiently minimize the risk of
        pregnancy at that point. Female subjects must agree to use contraception until the follow
        up visit or has only same-sex partners, when this is her preferred and usual lifestyle.

          -  Male subjects with female partners of child-bearing potential must agree to use one of
             the contraception methods. This criterion must be followed from the time of the first
             dose of study medication until the follow up visit.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  Aspartate amino transferase and alanine amino transferase < 2xupper limit of normal
             (ULN); alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%).

          -  Based on averaged QT interval corrected (QTc) values of triplicate electrocardiograms
             (ECGs) obtained over a brief recording period: QTc using Fridericia's formula (QTcF) <
             450 millisecond.

          -  A 24 hour Holter ECG at screening that demonstrates no clinically significant
             abnormalities or finding that could interfere with interpretation of the study
             results, when assessed by an appropriately trained and experienced reviewer.

        Exclusion Criteria Based Upon Medical Histories

          -  Subjects who have evidence of current asthma, as confirmed by the Investigator or
             designee.

          -  Subjects with any clinically significant respiratory condition or lung pathology that
             could cause cough (apart from chronic idiopathic cough).

          -  Known lung cancer or other active malignancy, or history of.

          -  Subjects with current or a chronic history of cardiovascular disease (including
             uncontrolled hypertension, ischemic heart disease, angina, myocardial infarct,
             congestive heart failure, and stroke).

          -  Subjects with current central nervous system / peripheral nervous system conditions
             e.g. epilepsy and myasthenia gravis.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Any subject with a respiratory tract infection within 4 weeks of screening.

          -  Radiological imaging prior to the study, including chest X-rays, that have shown any
             evidence of clinically significant lung disease, as judged by the Investigator or
             designee.

          -  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 grams of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass
             (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  Any subject who has a history of an allergic reaction to a local anesthetic. History
             of sensitivity to any of the study medications, or components thereof or a history of
             drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline
             (GSK) Medical Monitor, contraindicates their participation.

          -  Any subject who has a known hypersensitivity to capsaicin or citric acid. Exclusion
             Criteria Based Upon Diagnostic Assessment

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening.

          -  Any subject who, upon oropharyngeal examination, is deemed by the Investigator to be
             unsuitable for oropharyngeal sensation assessments. This includes any injuries to the
             mucosa of the mouth or pharynx that could potentially increase systemic absorption
             e.g. oropharyngeal candidiasis.

          -  FEV1 less than 80% of the predicted normal value prior to first dosing of the study

          -  Any subject who does not reach C5 following an oral inhalation of capsaicin at a dose
             level of 250 micromolar at screening.

          -  Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or
             nicotine-containing products within 6 months prior to screening.

          -  A positive pre-study drug/alcohol screen. Other Exclusion Criteria

          -  Subjects who are unable to use the inhaler satisfactorily.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  Lactating females.

          -  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 four new chemical entities within 12 months prior to the first
             dosing day.