Clinical trial NCT01920594: Study of GSK1278863 to Reduce Ischemic Events in Patients Undergoing Thoracic Aortic Aneurysm Repair
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Surgical Procedures
Keywords: GSK1278863
Thoracic Aortic Aneurysm Repair
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-08-12
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Primary outcomes:
measure: Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Follow-up (Day 45)
measure: Number of Participants With Vital Signs of Potential Clinical Importance (PCI)
timeFrame: Up to Follow-up (Day 45)
measure: Number of Participants With Abnormal Electrocardiography (ECG) Parameters
timeFrame: Up to Follow-up (Day 45)
measure: Number of Participants With Clinical Chemistry Parameters of PCI
timeFrame: Up to post-operative Day 7
measure: Number of Participants With Hematology Parameters of PCI
timeFrame: Up to post-operative Day 7
measure: Change From Baseline in Area Under Curve (AUC) for CSF S100 Beta to 48 Hours
timeFrame: Baseline(Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline in AUC for CSF GFAP to 48 Hours
timeFrame: Baseline(Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline to Peak in CSF Biomarker Erythropoietin Within 48 Hours Following DTA/TAAA Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline to Peak in CSF Biomarker Lactate Dehydrogenase Within 48 Hours Following DTA/TAAA Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline to Peak in CSF Biomarker Tau Protein Within 48 Hours Following DTA/TAAA Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
measure: Change From Baseline to Peak in CSF Biomarker Neuron-specific Enolase (NSE) Within 48 Hours Following DTA/TAAA Repair
timeFrame: Baseline (Day 0) to 48 hours following DTA/TAAA repair
measure: Number of Participants With Neurologic Outcomes Assessed by the National Institutes of Health Stroke Scale (NIHSS)
timeFrame: Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45)
measure: Number of Participants With Neurologic Outcomes Assessed by Modified Rankin Scale (mRS)
timeFrame: Post-operative Day 7 and follow-up (Day 45)
measure: Number of Participants With Neurologic Outcomes Assessed by the American Spinal Injury Association (ASIA) Lower Extremity Motor Outcome Scale
timeFrame: Surgical Day (Day 0), Post-operative Day 1, 2, 7 and follow-up (Day 45)
measure: Number of Participants With Clinical Composite of All Cause Mortality, Stroke, Spinal Infarction, MI, Need for Dialysis/Sustained Doubling of Serum Creatinine
timeFrame: Up to Follow-up (Day 45)
measure: Assessment in AUC for Markers of Ischemic Organ Injury Including Tropinin Within 48 Hours
timeFrame: Baseline (Day 0) and 8 to 48 hours following DTA/TAAA repair
measure: Number of Participants With Composite Index of All Cause Mortality and Disability (NIHSS>5/ASIA<40)
timeFrame: Up to Follow-up (Day 45)
measure: Pharmacokinetic (PK) Parameters in Blood: AUC(0-t) of GSK1278863
timeFrame: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3
measure: PK Parameters in CSF: AUC(0-t) of GSK1278863
timeFrame: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI
measure: PK Parameters in Blood: Maximum Observed Concentration (Cmax) of GSK1278863
timeFrame: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3
measure: PK Parameters in CSF: Cmax of GSK1278863
timeFrame: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI
measure: PK Parameters in Blood: Time of Occurrence of Cmax (Tmax) of GSK1278863
timeFrame: Pre-dose, 1 to 3 hours post-dose, every 5 hours for 24 hours, 1, 3, 8 and 24 hours post-dose on Day 1 and 3
measure: PK Parameters in CSF: Tmax of GSK1278863
timeFrame: Prior to potential neurological ischemia (PNI), 2, 24, 36 and 48 hours post PNI
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Charlottesville
country: United States
facility: GSK Investigational Site
state: Virginia
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Quebec City
country: Canada
facility: GSK Investigational Site
state: Quebec
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Aftab M, Coselli JS. Renal and visceral protection in thoracoabdominal aortic surgery. J Thorac Cardiovasc Surg. 2014 Dec;148(6):2963-6. doi: 10.1016/j.jtcvs.2014.06.072. Epub 2014 Jul 21.