A Multicenter Trial of Autologous Bone Marrow Mononuclear Cells for the Treatment of Adult Severe Traumatic Brain Injury
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Brain Injuries, Traumatic
- Sponsor
- The University of Texas Health Science Center, Houston
- Enrollment
- 37
- Locations
- 1
- Primary Endpoint
- Macro and micro structural properties of grey matter (GM) and white matter (WM) regions will measured using high-resolution anatomical MRI and diffusion tensorm imaging and comparisons made between groups.
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Charles Cox
Professor, Department of Pediatric Surgery
The University of Texas Health Science Center, Houston
Eligibility Criteria
Inclusion Criteria
- •Adults 18 to 55 years of age on the day of injury,
- •Non-penetrating closed head trauma.
- •Glasgow Coma Score between (GCS) between 3 and 8, (best un-medicated post-resuscitation score during screening).
- •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.
- •Ability to speak English or Spanish.
Exclusion Criteria
- •Known history of:
- •previous brain injury,
- •intellectual deficiency or psychiatric condition likely to invalidate our ability to assess post-injury changes in cognition or behavior,
- •neurologic impairment and/or deficit,
- •seizure disorder requiring anti-convulsant therapy,
- •recently treated significant infection,
- •renal disease/altered renal function (post-resuscitation serum creatinine \> 1.5 mg/dL),
- •chronic hepatic disease or altered liver function (post-resuscitation SGPT \> 150 U/L, and/or T. Bilirubin \>1.3 mg/dL),
- •Chemical or ETOH dependency,
- •immunosuppression (admission WBC \< 3X103),
Outcomes
Primary Outcomes
Macro and micro structural properties of grey matter (GM) and white matter (WM) regions will measured using high-resolution anatomical MRI and diffusion tensorm imaging and comparisons made between groups.
Time Frame: up to 6 months. Post Head Injury
Subjects will undergo three 3T-MRI evaluations. The first will occur 7 to 10 days after hospitalization, when clinically stable. The following five pulse sequences constitute a complete imaging session: 1) conventional localizer/scout 2) 3D isotropic T1-weighted MPRAGE 3) 3D isotropic T2-weighted TSE 4) 32-direction single-shot spin-echo diffusion sensitized echo-planar (DTI-32dir) 5) 3D-FLAIR. The 3T-MRI will be repeated at 1 and 6 months post-injury. Composite scores will be calculated for comparison.
Secondary Outcomes
- Compare neuro-inflammatory biomarkers between groups..(Changes From Baseline to 6 mo. Post Head Injury)
- Quantify the extent and location of microglial activation by brain PET imaging and how activity correlates with performance of neurocognitive outcomes measures.(1 yr. Post Head Injury)
- Brain imaging measures of GM and WM structural integrity will be compared to functional and neurocognitive scores and comparisons made between groups.(Changes From Baseline to 6 mo. Post Head Injury)
- Measure spleen ultrasound size over time and corresponding changes in inflammatory cytokines.(up to 6 mo. Post Head Injury)
- Determine the extent to which an IV infusion of autologous BMMNC post-injury impacts microglial activation by brain PET imaging.(1 yr. Post Head Injury)
- Measure the number of participants with infusion related adverse events.(up to 6 mo. Post Head Injury)
- Determine if microglial activation is associated with TBI and can be accurately measured with brain PET and DT-MRI imaging when compared to PET imaging data from healthy volunteers (enrolled under a different protocol).(1 yr. Post Head Injury)