Table 4.
Human Studies of Neuroinflammation after TBI: Selected Clinical Trials
| Clinical Trials | ||||||||
|---|---|---|---|---|---|---|---|---|
| Therapy | Effects on Inflammation | Study / Design | N | Dose | Primary Outcome | Secondary Outcomes | Comments | Refs |
| Anatibant | Block bradykinin signaling, prevent BBB disruption | “Brain Trial” Multicenter RCT | 228 adults with GCS ≤ 12 | Low (10mg load, 5mg/d), Mid (20mg load, 10mg/d), High (30mg load, 15mg/d) vs. placebo | No difference in incidence of serious adverse events | Trend towards harm in discharge GCS, DRS, and HIREOS | Recruitment paused due to DSMB concerns Terminated due to withdrawal of funding |
173 |
| Cyclosporin A | Reduces T-cell counts and activation | Single center RCT | 38 adults with GCS ≤ 8 | 5mg/kg over 24h vs. 10mg/kg over 48h vs. placebo | No difference in T-cell counts in blood | No difference in incidence of infection | Reduced lymphocyte count on admission associated with worse outcome and increased respiratory infections | 261 |
| Dexanabinol | Inhibitor of TNFα NMDA antagonism |
Multicenter RCT | 861 adults with ICP monitoring, GCS motor 2–5 | Single 150mg dose vs. placebo, within 6h of injury | No difference in GOS-E at 6mo | No difference in adverse events | 262 | |
| Erythropoietin | Decreases production of pro-inflammatory cytokines and chemokines IL-1 and TNF block EPO production |
“EPO-TBI” Multicenter RCT | 606 adults with moderate and severe groups - GCS 9–12 and GCS ≤ 8 | 40,000IU weekly x 3wk vs. placebo | No difference in GOS-E at 6mo | No difference in mortality or DVT | Mortality reduced in patients without mass lesions, no increase in good outcome Many patients did not receive full course |
16 |
| Multicenter RCT | 200 adults with TBI, unable to follow commands | 500IU/kg q24h x 3 doses or 500IU/kg x 1 dose then weekly x 2wk vs. placebo | No difference in GOS-E at 6mo | No difference in mortality, ARDS, or infection | Original dosing regimen (daily x 3 doses) stopped by FDA due to safety concern (higher mortality in stroke trial) | 15 | ||
| G-CSF | Stimulate stem cells to produce granulocytes | Multicenter RCT | 61 adults GCS ≤ 8 expected to require mechanical ventilation > 3d | 75μg/d vs. 300μg/d x 10d vs. placebo | Dose-dependent increase in neutrophil count | No difference in mortality, LOS, or nosocomial infection Significant decrease in bacteremia incidence |
Adverse events similar between groups Included patients with cerebral hemorrhage as well as TBI |
174 |
| Hypertonic saline | Improve T-cell function Reduced TNF-α and IL-10 |
Multicenter RCT | 1331 adults with severe TBI | 250mL bolus of 7.5% saline / 6% dextran 70 vs. 7.5% saline vs. 0.9% saline initiated pre-hospital | No difference in GOS-E at 6mo | No difference in survival at 28d | Terminated early for futility | 263 |
| Hypothermia | Humoral and cellular immune response is temperature dependent Decreased neutrophil accumulation in CNS Decreased IL-1β, possibly by reduction in temperature-dependent Caspase-1 activity |
“Cool Kids” Multicenter RCT | 77 children with GCS ≤ 8 | 32–33°C vs. 36.5–37.5°C for 48–72h | No difference in mortality at 3mo | No adverse events | Terminated early for futility | 264 |
| Multicenter RCT | 225 children with GCS ≤ 8 | 32.5°C vs. 37°C for 24h | No difference in 6mo PCPC score | No difference in mortality | Trend to increased mortality and significantly higher incidence of hypotension and vasoactive agent use during rewarming (+0.5°C q2h) | 11 | ||
| “NABIS: H II” Multicenter RCT | 97 adults with GCS 4–8 Enrolled within 2.5h of injury |
32–34°C vs. 35.5 – 37°C for 72h | No difference in 6mo outcome | No difference in mortality | Terminated early for futility Improved outcomes in patients with evacuated hematoma treated with hypothermia |
181 | ||
| Eurotherm3235 Multicenter RCT | 387 adults with severe TBI and ICP > 20mmHg despite stage 1 treatments | Cooled to 32–35°C followed by stage 2 if ICP remained high vs. stage 2 treatments alone | Lower GOS-E in hypothermia group | Stage 3 treatments (coma, craniectomy) were required in more patients of the control group | Terminated early for safety concerns | 180 | ||
| Anakinra | Block IL-1 signal transduction | Single Center RCT | 20 adults with GCS ≤ 8 | 100mg S.Q. q24h x 5 doses | Increased IL-1ra in CNS ECF within 6h | PCA of 42 cytokine multiplex demonstrated separation between treatment and placebo groups | Subsequent study showed patients receiving rIL-1ra had cytokines biasing to M1-like microglial phenotype Control patients were relatively biased to M2-like phenotype |
265,266 |
| Probiotics | Modify lymphocyte polarization prior to CNS infiltration | Single Center RCT | 52 adults with GCS 5–8 | 109 bacteria for 21d vs. placebo | No difference in 28d mortality | On day 21, treatment group had higher IFNγ and lower IL-10 and IL-4 | Trend to decrease late VAP Unclear what effects might be in CNS |
267 |
| Statins | Inhibit expression of vascular adhesion molecules and chemokines to reduce leukocyte infiltration of CNS Associated with reductions in pro-inflammatory cytokines |
Single Center RCT | 21 adults with GCS 9–13 | Rosuvastatin 20mg/d x 10d vs placebo | Modest decrease in amnesia and disorientation time | No difference in disability at 3mo | Subsequent study showed reduction in plasma TNFα at 72h | 268,269 |
| Steroids | Inhibit leukocyte activation and infiltration Modulate cytokine release Progesterone decreased upregulation of IL-1β, TNFα, and complement factors 3 and 5 Reduce M1-like microglial activation |
“CRASH” Multicenter RCT | 10,008 adults with GCS ≤ 14 |
Methylprednisolone Load: 2g over 1h Maintenance: 0.4g/h x 48h vs placebo |
Higher risk of mortality at 2wk in steroid group | Higher risk of mortality at 6mo in steroid group | Terminated early for safety concerns | 167 |
| Multicenter RCT | 161 adults with TBI and coma | Dexamethasone 100mg vs placebo | No difference in survival | No difference in 6mo outcome | 168 | |||
| Multicenter RCT | 163 adults with GCS 9–12 and 957 adults with GCS 4–8 |
Tirilazad 10mg/kg within 4h of injury and q6 x 5d vs placebo |
No difference in 6mo GOS | No difference in mortality | Significant differences in pretreatment hypotension and hypoxia related to inter-center variation | 170 | ||
| “Corti-TC” Multicenter RCT | 336 adults with GCS ≤ 8 |
Hydrocortisone (200mg/day, tapered) + Fludrocortisone (50μg/day) x 10d vs. placebo |
No difference in incidence of hospital acquired pneumonia | No change when analyzed according to presence or absence of adrenal insufficiency | Study may have been underpowered due to lower than expected incidence of hospital-acquired pneumonia | 171 | ||
| “ProTECT III” Multicenter RCT | 882 adults with GCS 4–12 |
Progesterone Infusion started within 4h of injury, duration 96h |
No difference in 6mo-GOS | No difference in mortality | Terminated for futility | 14 | ||
| “SyNAPSe” Multicenter RCT | 1195 adults with GCS ≤ 8 |
Progesterone 0.71mg/kg load then 0.5mg/kg/h infusion for 119h |
No difference in 6mo-GOS | No difference in mortality | 13 | |||
Abbreviations: TBI – traumatic brain injury; BBB – blood brain barrier; RCT – randomized controlled trial; GCS – Glasgow coma scale; DRS – Disability Rating Scale; HIREOS – head injury related early outcomes score; DSMB – data safety monitoring board; TNF – tumor necrosis factor; NMDA – N-methyl-D-aspartate; ICP – intracranial pressure; IL – interleukin; EPO – erythropoietin; DVT – deep venous thrombosis; ARDS – acute respiratory distress syndrome; LOS – length of stay; PCPC – pediatric cerebral performance category; CNS – central nervous system; ECF – extracellular fluid; PCA – principal components analysis; GABA – gamma-aminobutyric acid; IFN – interferon; VAP – ventilator associated pneumonia