A Multicenter Phase II Randomized Trial of a HIF-Prolyl Hydroxylase Inhibitor for Neuroprotection in High Risk Thoracic Aortic Repair (S7.008)
Bibliographic record
Abstract
Introduction: Thoracic aortic repair has risk of brain and spinal cord ischemia. We hypothesized that GSK1278863, an oral prolyl hydroxylase inhibitor (PHI) will reduce cerebrospinal fluid (CSF) markers of injury, clinical strokes, and spinal infarcts via upregulation of hypoxia inducible factor and erythropoietin (EPO). Methods: Double blind randomized trial at 15 sites in North America (funded by GSK) comparing GSK1278863 to placebo in patients undergoing thoracic aortic repair with lumbar drain, stratified by open surgery or stenting. Subjects received 300mg study medication the evening before surgery and then 100mg daily for 4 days. The primary outcome was change in CSF S100β and Glial Fibrillary Acidic Protein (GFAP) from baseline to peak within 48 hours. Results: The study planned to enroll 160 patients but halted early due to more serious adverse events (SAEs) in patients on GSK1278863. Fifty-five patients were enrolled, 39 (71[percnt]) open surgery and 16 (29[percnt]) stenting, mean age 61.5 (±14.5), 19 (35[percnt]) female, 12 (22[percnt]) non-white. Treatment arms were balanced at baseline except for higher risk surgical anatomy in patients receiving GSK1278863. There were trends toward greater changes in CSF S100β (2772 vs 543 ng/L, p=0.08) and GFAP (1070 vs 292 ug/L, p=0.2) on GSK1278863. Change in CSF EPO level from baseline to peak was greater in patients given GSK1278863 (18 vs -16 U/L, p<0.001). Stroke occurred in 7 patients (4 GSK1278863 and 3 placebo, p=0.70) and spinal ischemia in 12 (9 GSK1278863 and 3 placebo, p=0.06). Patients given GSK1278863 had more SAEs, 20 (74[percnt]) vs 14 (50[percnt]), p=0.10, and deaths, 6 (22[percnt]) vs 2 (7[percnt]), p=0.14. Conclusions: Perioperative GSK1278863 was associated with more clinical events and SAEs but this is potentially confounded by imbalanced surgical risk in this small study. Overall, neurologic complications were common in this high risk population and additional studies of neuroprotection are needed.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".