Vanessa Mazandi, MD
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania
Disclosure information not submitted.
David Jang, MD, MSc
Assistant Professor
University of Pennsylvania, United States
Disclosure information not submitted.
Samuel Shin, MD, PhD
Neurocritical Care Fellow
Perelman School of Medicine, University of Pennsylvania, United States
Disclosure information not submitted.
Abhay Ranganathan, BA, MS
Program Coordinator
Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
Nile Delso, MS
Research Assistant
Childrens Hospital of Phialdelphia, United States
Disclosure information not submitted.
William Landis, BS
Research Assistant
Childrens Hospital of Philadelphia, United States
Disclosure information not submitted.
Sanjeev Chawla, PhD
Research Assistant Professor of Radiology
Perelman School of Medicine, University of Pennsylvania, United States
Disclosure information not submitted.
Kevin Browne, BA
Research Specialist/Lab Manager
University of Pennsylvania, United States
Disclosure information not submitted.
Jonathan Starr, BS
Lab Operations Coordinator
Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
Kacy Cullen, PhD
Associate Professor of Neurosurgery
Perelman School of Medicine, University of Pennsylvania, United States
Disclosure information not submitted.
Todd Kilbaugh, MD
Associate Professor of Anesthesia, Critical Care, & Pediatrics
Childrens Hospital of Philadelphia, United States
Disclosure information not submitted.
Title: Randomized, blinded placebo-controlled, pre-clinical trial in a large animal TBI model
Introduction: Traumatic brain injury [TBI] is a significant source of morbidity and mortality in the United States, affecting 2.8 million people per year. Lifetime costs following TBI have been estimated as high as $76.5 billion dollars. Despite high costs to society, there are no approved therapeutics. One significant hurdle is the lack of translational large animal platforms in TBI. We compared neuroimaging following intervention with a novel alpha-lipoic acid [ALA] analogue, CMX-2043, in a randomized, placebo control trial with neuroimaging as the primary outcome metric.
Methods: Yorkshire piglets, n=21, 4-weeks old, were randomized into sham [5], placebo [8] and treatment [8] groups. All groups were blinded to treatment and to downstream teams performing neuroimaging. Sham animals mimicked surgical incision and anesthesia. Placebo and treatment pigs underwent a moderate-severe controlled cortical impact [CCI] injury. Treatment animals received CMX-2043 (18mg/kg) intravenous boluses at one-, 13-, 24-, 48-, 72- and 96-hours following injury. Five days after injury, animals underwent diffusion tensor imaging magnetic resonance imaging [DTI MRI] prior to sacrifice. Fractional anisotropy [FA] and mean diffusivity [MD] were compared among all groups. Higher FA indicates greater structural integrity in myelinated brain tissue. High MD is an indicator of tissue edema. Mean values of DTI metrics were computed from peri-contusion tissues and normalized to contralateral normal brain parenchyma.
Results: Swine in the treatment group demonstrated significantly higher FA values compared to placebo (0.1216+/-0.0086 versus 0.0901+/-0.0058, p< 0.05). There was no significant difference between FA values of swine in the treatment and sham groups (0.1216+/-0.0086 versus 0.1377+/-0.0199). Swine in the treatment group did not have a statistically significant difference in MD (0.00107+/-0.00004) compared to placebo (0.001092+/-0.00011) five days after injury.
Conclusions: Following five days of treatment with CMX-2043, treatment animals had significantly higher FA values compared to placebo, demonstrating preservation in structural integrity of the white matter following injury. There was no difference in cerebral edema at five days post-TBI as measured by DTI MRI MD.