Traumatic Brain Injury (TBI) is a complex disease process that occurs in two phases. The primary phase is the injury itself, typically a blow or acceleration force to the head from a fall or impact. The secondary phase describes the cellular changes that occur following the injury. This secondary injury phase is a critical determinant of patient outcomes—minimizing the damage that occurs during the secondary phase can significantly reduce the long-term consequences of TBI. Accordingly, much of the research conducted on TBI treatment specifically targets the secondary injury phase.
Earlier this year, an article was published about a study that tested a drug called ciclosporin as a treatment for moderate to severe TBI. Ciclosporin targets the secondary phase of TBI by preserving the function of the mitochondria, a critically important component of human cells that converts sugars and oxygen into usable energy. The mitochondria are typically compromised following TBI, preventing the brain from generating the energy needed to recover from injury.
Previous trials of ciclosporin used a different formulation of the drug, which was administered in low doses to avoid potentially adverse side effects. However, these low doses proved to have little impact, so researchers at the Copenhagen Head Injury Ciclosporin (CHIC) Study tested a new formulation called NeuroStat, which was more effective and had fewer adverse effects.
The study included 16 patients with severe TBI. The participants all received an initial dose of the drug at a concentration of 2.5 mg/kg. Then, over the course of the next 5 days, 10 of the patients received a continuous infusion of NeuroStat at a concentration of 5 mg/kg per day, and the remaining 6 patients received a higher dose of 10 mg/kg per day.
The researchers had two goals. They first wanted to determine whether NeuroStat could safely be administered to TBI patients and whether it was able to cross the blood-brain barrier (a layer of cells that act as a gate-keeper to the brain to permit the passage of molecules that are important for neural function while keeping potentially harmful molecules away from the brain). Their second goal was to determine whether NeuroStat improved TBI-related outcomes.
To explore the safety of the drug, the researchers looked at the whether the drug caused damage to the kidneys (assessed by measuring markers of kidney function in the blood), heart (assessed with electrocardiograms), or brain (assessed by measuring intracranial pressure), and whether the drug seemed to correlate with increased risk of infection. To determine whether the drug was crossing the blood-brain barrier to reach the brain, the researchers looked at whether they could detect NeuroStat in the patients’ cerebral spinal fluid. Finally, to determine the impact of NeuroStat on TBI-related outcomes, the researchers looked for the presence of TBI indicators in the cerebral spinal fluid following infusion of the drug.
The researchers found that, while there were no deaths attributed to NeuroStat, some adverse outcomes did occur. The majority of the outcomes were minor or moderate (for instance, constipation) and some (for instance, pneumonia) were more severe. NeuroStat did seem to have some effect on kidney function, but did not affect intracranial pressure. The researchers also found that NeuroStat was able to cross the blood-brain-barrier, and importantly, that it reduced the levels of all the TBI indicators that were tested, indicating that NeuroStat was effective in treating TBI.
Despite the occurrence of adverse outcomes, the researchers concluded that NeuroStat is a promising treatment for TBI. In fact, the results of the study were so significant that the Food and Drug Administration (FDA) placed clinical trials on a “Fast Track” in order to expedite the next phase of research and get closer to being able to market NeuroStat. It is important to note that, over the course of drug development, governing agencies like the FDA carefully weigh the risks and benefits of new treatments. Often, side effects occur in the short term and can be monitored by a health care team. No new drug is without the risk of side effects, but when side effects are minimal compared to the adverse effects of not using the treatment, the drug is typically considered to be safe and beneficial.
Kelsen, J., Karlsson, M., Hansson, M. J., Yang, Z., Fischer, W., Hugerth, M., ... & Wang, K. K. (2019). Copenhagen Head Injury Ciclosporin (CHIC) study: A phase IIa safety, pharmacokinetics and biomarker study of ciclosporin in severe head injury patients. Journal of neurotrauma, (ja).