Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01920594
First received: August 8, 2013
Last updated: August 28, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Surgical Procedures
Drug: GSK1278863
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase II, Randomized, Placebo-Controlled, Double-Blind (Sponsor Open) Study of GSK1278863, a HIF-Prolyl Hydroxylase Inhibitor, to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change from baseline to peak in cerebor spinal fluid (CSF) S100beta and Glial fibrillary acidic protein (GFAP) within 48 hours following DTA/TAAA repair [ Time Frame: Baseline, Day 0, Day 1, Day 2 ] [ Designated as safety issue: No ]
    To assess the effect of prophylactic GSK1278863 versus placebo on CSF markers (S100beta and GFAP) of central nervous system (CNS) injury. Samples of approximately 5mL of CSF will be obtained directly from the lumbar drain


Secondary Outcome Measures:
  • Number of subjects with adverse event (AEs). [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
    AEs will be collected from the start of Study Treatment and until the follow-up contact

  • Electrocardiogram (ECG) measurement as a measure of safety and tolerability. [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
    Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected for heart rate intervals.

  • Vital sign measurement as a measure of safety and tolerability [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
    Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.

  • Clinical observation by nurses/physician as a measure of safety and tolerability [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
  • Laboratory parameter assessment as a measure of safety and tolerability [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
    Laboratory parameters will include: hematology, clinical chemistry and additional parameters

  • Area-under-the-curve (AUC) for CSF GFAP and S100beta from baseline to 48 hours [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
    AUC for CSF GFAP and S100beta from baseline to 48 hours will be assessed to measure CNS injury

  • Change from baseline to peak in CSF biomarkers [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
    Biomarker will include lactate, erythropoietin, tau protein, and neuron-specific enolase

  • Neurologic outcomes assessed by three validated [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
    The NIHSS is a tool that provides a quantitative measure of stroke-related neurologic deficit.

  • Troponin assessment as a measure of ischemic organ injury [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
  • CPK assessment as a measure of ischemic organ injury [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
  • Creatinine assessment as a measure of ischemic organ injury. [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
  • Liver function test as a measure of ischemic organ injury [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
  • Clinical composite of all-cause mortality, stroke, spinal infarction, myocardial infarction, need for dialysis/sustained doubling of serum creatinine [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
  • Composite index of all-cause mortality and disability (NIHSS>5/ASIA<40) [ Time Frame: Up to 45 days ] [ Designated as safety issue: No ]
  • Composite of PK parameters in blood and CSF [ Time Frame: Up to Day 4 ] [ Designated as safety issue: No ]
    PK parameters include: maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration time


Estimated Enrollment: 150
Study Start Date: October 2013
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK1278863
Subject will receive GSK1278863 300mg on Day-1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 100mg once daily for 4 days starting from Day 0.
Drug: GSK1278863
White, round biconvex, film coated tablet with unit dose strength of 100 mg for oral administration
Placebo Comparator: Placebo
Subject will receive GSK1278863 matching placebo on Day-1 (12 +/- 4 hours prior to planned surgery) as a loading dose followed by GSK1278863 matching placebo once daily for 4 days starting from Day 0.
Drug: Placebo
White, round biconvex, film coated GSK1278863 matching placebo tablet for oral administration

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01920594

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Alabama
GSK Investigational Site Not yet recruiting
Birmingham, Alabama, United States, 35233
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, California
GSK Investigational Site Recruiting
Los Angeles, California, United States, 90048
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Colorado
GSK Investigational Site Recruiting
Aurora, Colorado, United States, 80045
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Georgia
GSK Investigational Site Recruiting
Atlanta, Georgia, United States, 30322
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Michigan
GSK Investigational Site Not yet recruiting
Ann Arbor, Michigan, United States, 48109-5864
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Minnesota
GSK Investigational Site Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, North Carolina
GSK Investigational Site Recruiting
Durham, North Carolina, United States, 27710
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Ohio
GSK Investigational Site Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Pennsylvania
GSK Investigational Site Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Pittsburgh, Pennsylvania, United States, 308902
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Texas
GSK Investigational Site Recruiting
Houston, Texas, United States, 77030
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Virginia
GSK Investigational Site Recruiting
Charlottesville, Virginia, United States, 22908
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Richmond, Virginia, United States, 23298
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Canada, Alberta
GSK Investigational Site Recruiting
Calgary, Alberta, Canada, T2N 2T9
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Canada, Quebec
GSK Investigational Site Recruiting
Quebec City, Quebec, Canada, G1V 4G5
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01920594     History of Changes
Other Study ID Numbers: 116097
Study First Received: August 8, 2013
Last Updated: August 28, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
GSK1278863
Thoracic Aortic Aneurysm Repair

Additional relevant MeSH terms:
Aneurysm
Aortic Aneurysm
Aortic Aneurysm, Thoracic
Vascular Diseases
Cardiovascular Diseases
Aortic Diseases
Prolyl-Hydroxylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 19, 2014