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

The purpose of this study is to determine the effect of intravenous infusion of autologous bone marrow mononuclear cells (BMMNC) on brain structure and neurocognitive/functional outcomes after severe traumatic brain (TBI) injury in adults. The primary objective is to determine if the intravenous infusion of autologous BMMNC after severe TBI results in structural preservation of global gray matter (GM) volume and white matter (WM) volume and integrity; as well as select regions of interest in the corpus callosum. THe secondary objectives are to determine if autologous BMMNC infusion improves functional and neurocognitive deficits in adults after TBI; reduces the neuroinflammatory response to TBI; evaluate spleen size and splenic blood flow over time using ultrasound and corresponding changes in inflammatory cytokines; and infusion related toxicity and long-term follow-up safety evaluations.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Adults 18 to 55 years of age on the day of injury,
2. Non-penetrating closed head trauma.
3. Glasgow Coma Score between (GCS) between 3 and 8, (best un-medicated post-resuscitation score during screening).
4. Ability to obtain legally authorized representative consent for participation and complete the BMMNC/Sham harvest and cell/placebo infusion within 48 hours of the initial injury.
5. Ability to speak English or Spanish.

Exclusion Criteria:

1. Known history of:

   1. previous brain injury,
   2. intellectual deficiency or psychiatric condition likely to invalidate our ability to assess post-injury changes in cognition or behavior,
   3. neurologic impairment and/or deficit,
   4. seizure disorder requiring anti-convulsant therapy,
   5. recently treated significant infection,
   6. renal disease/altered renal function (post-resuscitation serum creatinine \> 1.5 mg/dL),
   7. chronic hepatic disease or altered liver function (post-resuscitation SGPT \> 150 U/L, and/or T. Bilirubin \>1.3 mg/dL),
   8. cancer,
   9. Chemical or ETOH dependency,
   10. immunosuppression (admission WBC \< 3X103),
   11. HIV positive status;
2. Obliteration of perimesencephalic cistern on initial head CT/MRI suggesting prolonged hypoxic ischemic insult;
3. Initial hospital ICP \> 40 mm Hg;
4. Hemodynamic instability at the time of screening defined as SBP \< 90mmHg, ongoing fluid resuscitation and/or requirement for inotropic support to maintain MAP at or above normals for age - does not include CPP based inotropic support;
5. Uncorrectable coagulopathy at the time of screening;
6. Unstable pelvic fractures that in the P.I.'s opinion would preclude the bone marrow / sham harvest;
7. Pulmonary contusions defined as a chest x-ray with non-anatomic opacification and PaO2:FiO2 ratio \< 250 associated with the mechanism of injury;
8. Greater than AAST Grade III solid or hollow visceral injury of the abdomen and/or pelvis diagnosed by CT or other imaging;
9. Spinal cord injury diagnosed by CT or MR imaging or by clinical findings;
10. Persistent hypoxia defined as SaO2 \< 94% for \> 30 minutes occurring at any time from hospital admission to time of consent;
11. Positive pregnancy test (if applicable);
12. Concurrent participation in an interventional drug/device research study;
13. Unwillingness to return for follow-up visits;
14. Contraindications to MRI.