Autologous Stem Cell Study for Adult TBI (Phase 2b)

Traumatic brain injuries are associated with 33% of all trauma related deaths. There are no effective therapies to treat secondary brain injury and the post-injury response of CNS apoptosis and neuroinflammation. Pre-clinical and Phase I clinical progenitor cell therapies have shown promise in TBI/stroke via (1) promotion of CNS structural preservation, and (2) reducing the neuroinflammatory response to injury. This is a multicenter, randomized, blinded, Bayesian CRM dose-escalation placebo-controlled study designed to treat severe, acute TBI in adult patients with an IV infusion of autologous bone marrow mononuclear cells. 55 adult TBI patients will be randomized to receive a single IV infusion of BMMNs (6 x 10\^6 or 9 x 10\^6) or placebo. Study subjects will be consecutive admissions of adults with severe TBI meeting inclusion/exclusion criteria. Adults, ages 18-55 years, hospitalized at Memorial Hermann Hospital (Houston, Texas) for severe TBI (GCS 3-8) will be screened for eligibility. Informed consent, the bone marrow/sham harvest, and stem cell/placebo infusion must take place within 48 hours of the initial injury. Following consent and baseline procedures, subjects will be randomized in a 3:2 ratio (using permuted blocks and stratified by GCS of 3-4 or 5-8) to autologous BMMNC infusion (n=33) and placebo (n = 22), respectively. Administration will begin with the lowest dose (i.e. 6 x 10\^6 cells/kg body weight) with each dose given to cohorts of 3 subjects treated with BMMNC (note: the cohort size refers only to subjects treated with autologous BMMNC). After each cohort of 3 subjects treated with autologous BMMNC infusion (accumulated on average after every 5.5 adults randomized), the dosage for the next cohort of 3 autologous BMMNC-treated subjects will be determined by the CRM based on the findings for all subjects previously treated and the prior probabilities of the likelihood of toxicity assigned by the investigators before starting the study. At all doses, the algorithm is designed to avoid administering doses that will have a p(toxicity) exceeding 0.15. Subjects will be monitored closely for infusion related toxicity and complications during the first 14 days post-infusion while also receiving the usual standard of care for traumatic brain injury . Safety and outcome assessments will be performed at 1, 6, and 12 months post-injury study visits.