Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair
Condition: Surgical Procedures
MeSH terms: Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Thoracic
Intervention: GSK1278863; Placebo
Intervention description: White, round biconvex, film coated tablet with unit dose strength of 100 mg for oral administration; White, round biconvex, film coated GSK1278863 matching placebo tablet for oral administration
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GSK1278863; Thoracic Aortic Aneurysm Repair

Summary:

      This study will test the hypothesis that GSK1278863 will reduce neurologic, renal, and/or
      cardiac ischemia in patients undergoing elective descending thoracic aorta/thoracoabdominal
      aortic aneurysm (DTA/TAAA) repair, a population known to be at high risk for ischemic events
      from their underlying pathology and the surgical complexity required to address their
      disease. Approximately 160 subjects will be stratified according to intervention type
      (surgical or endovascular repair, with the latter limited to 50% of the total study
      population) and randomized in a 1:1 fashion to treatment with GSK1278863 (300 milligrams
      [loading dose] followed by 100 milligrams [mg]/day x 4 days) or placebo starting prior to
      planned repair, through postoperative day 3. The duration of participation in this study is
      expected to be approximately 4 to 8 weeks from screening to follow-up.
    

Eligibility criteria:

        Inclusion Criteria

          -  Adults >= 18 years of age who require the following types of descending thoracic aorta
             or thoracoabdominal aorta repair for atherosclerotic aneurysm or chronic dissection
             (de novo Type B or residual Type B [following Type A repair]) via open surgery or
             endovascular stenting (TEVAR) as per their treating surgeon

          -  Open surgery:

        Extent I TAAA (+/-distal arch) if it extends to or beyond renal ostia. Extent II TAAA
        (+/-distal arch). Extent III TAAA (defined as proximal extent or anastamosis superior to
        inferior pulmonary vein).

        Extent IV TAAA only with a prior TEVAR or if it is a redo procedure (in this setting a
        "redo" is a prior abdominal aortic aneurysm (AAA) open or endovascular aortic repair
        (EVAR), with either proximal suture line disruption or mesenteric segment aneurysm
        recurrence requiring redo Extent IV reconstruction).

        DTA repair with one of the following: Safi extent C coverage. Subclavian to diaphragm
        disease extent. >75% of total DTA length.

        -TEVAR with one of the following: Full DTA coverage with previous abdominal EVAR or open
        AAA. Full DTA coverage including Zone 2 to celiac (i.e., distal arch plus full coverage
        DTA).

        Full DTA coverage with celiac artery coverage with or without left subclavian artery
        coverage (Zone 2 or Zone 3 proximal landing), or full DTA (either Zone 2 or Zone 3) with
        extension distal to celiac with visceral debranching (e.g., the abdominal hybrid Extent 2
        TAAA).

        Note: Zone 2 is defined as between the left carotid through coverage of the left subclavian
        artery and Zone 3 is defined as the first 3cm distal to the left subclavian (e.g., between
        left subclavian and ligamentum [isthmus]).

          -  Completed any staging or bypass procedure that precedes the aortic repair at least 48
             hours prior to the repair.

          -  Expect placement of a lumbar CSF catheter during the procedure with plans to maintain
             it for at least 48 hours per the treating physician.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  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; or postmenopausal defined as 12 months of spontaneous amenorrhea
        [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)
        > 40 milli international unit /mililiter (mL) and estradiol < 40 picogram/mL (<147
        picomoles/Liter) 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 2-4 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 and agrees to use one of the contraception methods from screening
        until completion of the Follow-up Visit.

          -  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 Screening
             until the completion of the Follow-up Visit.

        Exclusion Criteria

          -  The subject has a traumatic aortic dissection.

          -  The subject has a baseline NIHSS > 1 or modified Rankin Scale > 1.

          -  The subject has a history of myocardial infarction, stroke, or spinal infarct within
             the past 3 months.

          -  The subject has active ulcer disease or recent gastrointestinal bleeding within the
             past 6 months.

          -  The subject has a history of deep venous thrombosis or pulmonary embolism in the past
             12 months.

          -  The subject has been treated for a malignancy (excluding non-melanomatous skin
             cancers) within the past 12 months and is not confirmed to be disease free.

          -  The subject has had treatment for retinal neovascularization (e.g., diabetic
             proliferative retinopathy or age related macular degeneration) within 3 months of
             randomization.

          -  The subject is currently receiving dialysis.

          -  The subject is currently receiving or expected to require treatment (within the study
             period) with erythropoiesis medication such as epoetin alfa (Procrit, Epogen), or
             darbepoetin alfa (Aranesp).

          -  The subject has any of the following at screening:

        Hemoglobin >15.5 gram (g)/decilitre (dL) (male subjects or post-menopausal females)
        Hemoglobin >14.5 g/dL (pre-menopausal female subjects) Single QTc >=480 millisecond (msec);
        or QTc >=500 msec in subjects with bundle branch block (these criteria do not apply to
        subjects with predominately paced rhythms) Aspartate aminotransferase and alanine
        aminotransferase >=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%) A positive pre-study drug/alcohol screen Lactation or pregnancy (as
        determined by positive serum or urine hCG test)

          -  The use of prohibited medications

          -  History of regular alcohol consumption within 6 months of the study defined as: an
             average weekly intake of >14 drinks for males or >7 drinks for females. One drink is
             equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine
             or 1.5 ounces (45 mL) of 80 proof distilled spirits.

          -  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).