3 Month PHI PAD PoM Study
Condition: Vascular Disease, Peripheral
MeSH terms: Vascular Diseases; Peripheral Vascular Diseases; Peripheral Arterial Disease
Intervention: GSK1278863; Placebo
Intervention description: GSK1278863; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 46.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      This is a multi-center, randomized, blinded, placebo controlled study to evaluate the safety
      of GSK1278863 and its acute and short-term (e.g. 14d) effects on calf muscle endurance and
      walking ability in subjects with PAD and symptomatic claudication.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects ≥ 40 years of age.

          -  Male subjects must use one of the contraceptive methods listed in Section 8.1 for 90
             days post-last dose.

          -  Females must be postmenopausal, surgically sterilized, or practicing a suitable method
             of birth control so that in the opinion of the investigator they will not become
             pregnant during the course of the study.

        A female subject is eligible to participate if she is of child-bearing potential and agrees
        to use one of the contraception methods listed in Section 8.1 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 30 days post-last dose.

          -  Peripheral artery disease defined as an ankle-brachial index (ABI) at rest ≤ 0.90 in
             at least one leg in which the patient experiences claudication. For all subsequent
             evaluations, the Index Leg refers to the symptomatic leg with the lowest ABI.

          -  Claudication symptoms with stable severity for at least 3 months prior to screening.

          -  The patient is able to provide written informed consent to participate in this study.

          -  AST and ALT < 2xULN; alkaline phosphatase and bilirubin greater than or equal too
             1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
             direct bilirubin <35%).

          -  Confirmed QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with bundle branch
             block.

          -  Subjects must be able to perform performance/exercise testing

        Exclusion Criteria:

          -  Coronary artery bypass graft (CABG), open peripheral vascular procedures, or major
             surgical procedures within 6 months prior to screening or patients likely to require
             revascularization during the course of the trial. Endovascular procedures within 3
             months prior to screening.

          -  Any unstable vascular syndromes (such as TIA, CVA, unstable angina or acute MI),
             including major changes to related medications, within 6 months prior to
             randomization.

          -  Critical leg ischemia classified as Fontaine Stage III-IV (rest pain, tissue necrosis
             or gangrene).

          -  Pregnant or nursing women (women capable of childbearing must have a negative
             pregnancy test).

          -  A hemoglobin value at screening is:

        Male subjects or post-menopausal females: > 15.5 g/dL Female subjects: > 14.5 g/dL

          -  Active malignancy or diagnosis of malignancy within 5 years prior to screening
             (excluding successfully treated basal or squamous cell carcinoma).

          -  Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic,
             neurological, psychiatric, immunological, gastrointestinal, hematological, or
             metabolic disease that is, in the opinion of the Investigator or the Medical Monitor,
             not stabilized or may otherwise confound the results of the study.

          -  Patients with a baseline medical history of proliferative diabetic retinopathy,
             preproliferative diabetic retinopathy, or wet age-related macular degeneration (AMD)

          -  Previously enrolled in a gene therapy clinical study unless patient was randomized to
             placebo.

          -  Plans to initiate a formal exercise training program during the course of the study,
             or initiation of a formal exercise training program within 3 months prior to
             screening.

          -  Poorly controlled hypertension (defined as seated resting BP >160 mmHg systolic or >
             95 mmHg diastolic, or both).

          -  Hypotension (defined as seated resting BP < 95 mmHg systolic or < 55 mmHg diastolic,
             or both, or symptomatic hypotension [seated, supine, or orthostatic]).

          -  Exercise tolerance, including bilateral heel raise and Six-Minute Walk Test
             performance, that is limited by co-morbid conditions or diseases other than
             claudication.

          -  Poorly controlled diabetes defined as Hemoglobin A1c (HbA1c) > 10%.

          -  Creatinine > 2.5 mg/dL or undergoing hemodialysis.

          -  Thrombocytopenia defined as platelet count < 100,000/mm3 at screening.

          -  Hematocrit ≤ 30% or ≥ 55%.

          -  International Normalized Ratio (INR) > 1.5.

          -  A positive Hepatitis B surface antigen or positive Hepatitis C antibody result if
             performed within 3 months of screening (testing not required at Screening).

          -  History of alcohol or drug abuse, or a significant medical or psychiatric disorder
             that may impair compliance with the requirements of the protocol.

          -  The patient has received an investigational drug within 30 days prior to this study.

          -  The patient is enrolled or plans to enroll in another clinical trial during this study

          -  History of venous thrombosis, defined as deep vein thrombosis, pulmonary embolism or
             other venous thrombotic condition, within 1 year prior to Screening.

          -  Acute peptic ulcer disease or history of chronic rectal bleeding.

          -  Patients with a pre-existing condition interfering with normal gastrointestinal
             anatomy or motility, and/or hepatic function that could interfere with the absorption,
             metabolism, and/or excretion of the study drugs. Examples of conditions that could
             interfere with normal gastrointestinal anatomy or motility include gastrointestinal
             bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy,
             malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue.

          -  Use of prescription drugs within 7 days prior to first dose of study drug (Day 1)
             until after completion of all study drug doses and Day 35 assessments:

        which are known to be inhibitors of CYP 2C8 OR which are known to be both CYP 2C8 and
        OATP1B1 substrates OR which rely mainly on OATP1B1/1B3 for hepatic clearance as described
        in Section 9 of the protocol.

          -  Use of prescription drugs within 14 days prior to first dose of study drug (Day 1)
             until completion of all study drug doses and Day 35 assessments, which are known to be
             inducers of CYP 2C8, as described in Section 9 of the protocol.

          -  Use of non-prescription drugs, including vitamins, herbal and dietary supplements
             (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme
             inducer) or 5 half-lives (whichever is longer) prior to the first dose of study drug
             (Day 1) through the Follow-up Visit (Day 65), unless, in the opinion of the
             Investigator, medication will not interfere with the study procedures or compromise
             subject safety and GSK Medical Monitor concurs.

          -  History of sensitivity to any of the study drugs, or components thereof, or a history
             of drug or other allergy that, in the opinion of the investigator or GSK Medical
             Monitor, contraindicates their participation.

          -  Patient is mentally or legally incapacitated.