A First Time in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Healthy Subjects and Stable Heart Failure Patients
Condition: Oedema, Pulmonary
MeSH terms: Pulmonary Edema; Heart Failure
Intervention: GSK2798745 solution; GSK2798745 suspension; GSK2798745 capsule; Placebo solution; Placebo suspension; Placebo capsule
Intervention description: Clear, colourless GSK2798745 (0.1 to 0.4mg) solution in aqueous citrate buffer with 4% captisol; Aqueous suspension of GSK2798745 (>=0.5 mg); White Opaque granule filled capsules of GSK2798745 (>=0.5 mg); Clear, colourless solution of aqueous citrate buffer with 4% captisol; Visually matching aqueous suspension of hypromellose acetate succinate powder; Matching white opaque placebo blend filled capsule
Intervention MeSH terms: Pharmaceutical Solutions
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 61.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: First Time in Human; TRPV4 inhibitor; Heart failure

Summary:

      This study is the first administration of GSK2798745 in humans. This will be a sponsor
      un-blinded, placebo-controlled study to investigate the safety, tolerability,
      pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2798745, given as single and repeat
      oral doses to healthy subjects and stable heart failure (HF) subjects. Approximately 28
      healthy subjects will be enrolled in the study cohorts (Cohort 1-3) involving single and
      repeat dose escalations of GSK2798745, while up to 24 stable heart failure subjects will be
      enrolled in Cohort 4 involving single and repeat dose administration of GSK2798745, with the
      dose selected based on data from healthy subject cohorts. This would be followed by
      enrollment of up to 8 subjects with heart failure in Cohort 5 involving repeat dose
      administration of GSK2798745. The study duration, including screening and follow-up, is not
      expected to exceed 17 weeks for subjects in the study (in any cohort).
    

Eligibility criteria:

        Inclusion Criteria:

        For Healthy Subject Cohorts (1-3):

          -  Male or female 18-75 years of age inclusive, at the time of signing the informed
             consent.

          -  Healthy as determined by a responsible and experienced physician, based on an
             evaluation including medical history, physical examination, laboratory tests and
             cardiac evaluation including ECG and echocardiogram. A subject with a clinical
             abnormality or laboratory parameter(s) which is/are not specifically listed in the
             inclusion or exclusion criteria, outside the reference range for the population being
             studied may be included only if the Investigator in consultation with the GSK Medical
             Monitor agree and document that the finding is unlikely to introduce additional risk
             factors and will not interfere with the study procedures.

          -  Body weight >=50 kilogram (kg) and Body Mass Index (BMI) within the range 18-32
             kilogram/ square meter (kg/m^2) (inclusive).

          -  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 (FSH) > 40
             milli-International Units per milliliter (mIU/mL) and estradiol <40
             picogram/millilitre (pg/mL) [<147 picomoles/liter (pmol/L)] is confirmatory.

          -  Male subjects with female partners of child-bearing potential must agree to use one of
             the contraception methods listed in the protocol. This criterion must be followed from
             the time of the first dose of study medication until 2 weeks post last dose.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  Alanine transaminase (ALT), alkaline phosphatase and bilirubin <= 1.5x Upper limit of
             normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated
             and direct bilirubin <35%).

          -  Based on averaged QTc values of triplicate ECGs obtained over a brief recording
             period: QTc <450 milliseconds (msec); or QTc <480 msec in subjects with Bundle Branch
             Block.

        For Heart Failure Subjects (Cohorts 4 and 5):

          -  Established diagnosis of mild or moderate heart failure of any aetiology with symptoms
             defined as corresponding to the New York Heart Association (NYHA) Class II or III on
             stable heart failure therapy for at least 1 month and was not hospitalized for HF for
             the last three months.

          -  Male or female 18 years or older, age inclusive, at the time of signing the informed
             consent.

          -  ALT, alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%).

          -  Based on averaged QTc values of triplicate ECGs obtained over a brief recording
             period: QTc <450msec; or QTc <480msec in subjects with Bundle Branch Block.

          -  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 (FSH) >40mIU/mL and
             estradiol <40pg/mL (<147pmol/L) is confirmatory.

          -  Male subjects with female partners of child-bearing potential must agree to use one of
             the contraception methods listed in the protocol. This criterion must be followed from
             the time of the first dose of study medication until 2 weeks post-last dose.

          -  Body weight >=50kg and BMI within the range 18-40kg/m^2 (inclusive).

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

        Exclusion Criteria:

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  History of acute coronary syndromes (including unstable angina), coronary angioplasty,
             or stenting within the past 6 months.

          -  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 240mL) of beer, 1
             glass (125mL) of wine or 1 (25mL) measure of spirits.

          -  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 and/or GSK
             Medical Monitor, contraindicates their participation.

          -  History of seizure disorder and or stroke within the last 5 years.

          -  Active ulcer disease or gastrointestinal (GI) bleeding.

          -  Current smokers (Cohorts 1-4 only).

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening.

          -  A positive pre-study drug/alcohol screen.

          -  A positive test for human immunodeficiency virus (HIV) antibody.

          -  A screening cardiac Troponin (cTn) level >ULN.

          -  Baseline presence of severe aortic stenosis.

          -  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.

          -  Left ventricular ejection fraction <50 percent - (Healthy subjects only).

          -  Subject who, in the Investigator/designee's judgement, poses a significant suicide
             risk. Evidence of serious suicide risk may include any history of suicidal behaviour
             and/or any evidence of suicidal ideation on any questionnaires e.g., Type 4 or 5 on
             the Columbia Suicide Severity Rating Scale (C-SSRS) in the last 5 years.

        For Heart Failure Subjects (Cohort 4):

          -  History of known primary pulmonary disease requiring current medication or other
             therapy.

          -  Orthopnoea of sufficient severity to preclude supine scanning as determined at
             screening.

          -  Uncontrolled hypertension (resting systolic blood pressure [BP] > 160 millimeters of
             mercury [mmHg] or resting diastolic BP > 100 mmHg).

          -  Resting hypoxia while breathing room air (Peripheral capillary oxygen saturation
             [SpO2] <88 percent).

          -  Estimated creatinine clearance (Cockcroft-Gault) <40 mL/minute.

          -  Contraindication to magnetic resonance imaging (MRI) contrast agents.

          -  Contraindication for MRI scanning (as assessed by local MRI safety questionnaire),
             which includes but is not limited to: a. Intracranial aneurysm clips (except Sugita^®;
             trademark owned by Mizuho Ikakogyo Co.Ltd. Tokyo) or other metallic objects; b. Intra-
             orbital metal fragments that have not been removed; c. Pacemakers or other implanted
             cardiac rhythm management/monitoring devices and non-MR conditional heart valves; d.
             Inner ear implants; and e. History of claustrophobia.

        For Heart Failure Subjects (Cohort 5):

          -  Uncontrolled hypertension (resting SBP >160 mmHg or reporting DBP >100 mmHg).

          -  Resting hypoxia while breathing room air (SpO2 <88 percent).