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

NCT01920594 | Completed Phase 2 Results DMC

• 1 other identifier: 116097
• Study Type: interventional
• Target: 57
• Locations: 2 countries
• Sites: 15

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.

Conditions

Surgical Procedures

Keywords

GSK1278863; Thoracic Aortic Aneurysm Repair

Outcome Measures

Primary Outcomes (2)

• Change From Baseline to Peak in Cerebrospinal Fluid (CSF) S100 Beta Within 48 Hours Following Descending Thoracic Aorta/Thoracoabdominal Aortic Aneurysm (DTA/TAAA) Repair

  S100 beta is a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. CSF samples were collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF S100 beta. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

  Baseline (Day 0) to 48 hours following DTA/TAAA repair

• Change From Baseline to Peak in CSF Glial Fibrillary Acidic Protein (GFAP) Within 48 Hours Following DTA/TAAA Repair

  GFAP is a CSF biomarker that rise significantly in participants with neurologic injury following DTA/TAAA surgery. CSF samples for the analysis of GFAP was collected at Baseline and within 48 hours following DTA/TAAA repair to assess peak change from Baseline in CSF GFAP. Baseline was defined at Day 0. Change from Baseline was calculated as post-Baseline value minus Baseline value.

  Baseline (Day 0) to 48 hours following DTA/TAAA repair

Secondary Outcomes (23)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to Follow-up (Day 45)

• Number of Participants With Vital Signs of Potential Clinical Importance (PCI)

  Up to Follow-up (Day 45)

• Number of Participants With Abnormal Electrocardiography (ECG) Parameters

  Up to Follow-up (Day 45)

• Number of Participants With Clinical Chemistry Parameters of PCI

  Up to post-operative Day 7

• Number of Participants With Hematology Parameters of PCI

  Up to post-operative Day 7

Study Arms (2)

GSK1278863

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

GSK1278863 DRUG

White, round biconvex, film coated tablet with unit dose strength of 100 mg for oral administration

GSK1278863

Placebo DRUG

White, round biconvex, film coated GSK1278863 matching placebo tablet for oral administration

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (15)

GSK Investigational Site

Birmingham, Alabama, 35233, United States

Location

GSK Investigational Site

Los Angeles, California, 90048, United States

Location

GSK Investigational Site

Aurora, Colorado, 80045, United States

Location

GSK Investigational Site

Atlanta, Georgia, 30322, United States

Location

GSK Investigational Site

Ann Arbor, Michigan, 48109-5864, United States

Location

GSK Investigational Site

Rochester, Minnesota, 55905, United States

Location

GSK Investigational Site

Durham, North Carolina, 27710, United States

Location

GSK Investigational Site

Cleveland, Ohio, 44195, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 308902, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Charlottesville, Virginia, 22908, United States

Location

GSK Investigational Site

Richmond, Virginia, 23298, United States

Location

GSK Investigational Site

Calgary, Alberta, T2N 2T9, Canada

Location

GSK Investigational Site

Québec, Quebec, G1V 4G5, Canada

Location

Related Publications (1)

• 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.

  PMID: 25135232 DERIVED

MeSH Terms

Interventions

GSK1278863

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2013
• First Posted: August 12, 2013
• Study Start: October 31, 2013
• Primary Completion: October 8, 2014
• Study Completion: October 8, 2014
• Last Updated: December 7, 2017
• Results First Posted: December 7, 2017

Record last verified: 2017-11

Locations

US (13); CA (2)