Discussion
In this phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial, Edaravone Dexborneol at different doses was compared with edaravone alone for efficacy and safety. Our result showed that, compared with edaravone alone, Edaravone Dexborneol was safe and well tolerated at all doses, although no significant improvement in functional outcomes was observed.
Neuroprotective drugs might extend the therapeutic time window after stroke for thrombolysis or thrombectomy therapy by delaying cell death and blocking reperfusion injury. Edaravone Dexborneol could provide as a new and effective treatment of stroke in the future.13 After onset of ischaemic stroke, several risk factors were associated with the damage process of neurons under ischaemia: energy failure, free radicals production, formation of neurotoxin, inflammatory responses and apoptosis.14 Although vascular recanalisation could effectively salvage reversible ischaemic tissue,15 the risk of reperfusion injury was high. Edaravone could limit vascular endothelial cell injury, brain oedema,16 17 tissue injury18 and delayed neuronal death, and consequently reduced neurological deficits.19 Additionally, as seen on sequential magnetic resonance spectroscopy, preservation of N-acetyl-aspartate, a neuron-specific amino acid, in the ischaemic brain of edaravone-treated patients has been reported.20 Edaravone Dexborneol is a novel neuroprotective agent indicated for AIS.10 It is a compound preparation comprising edaravone and (+)-borneol in a 4:1 ratio. The natural borneol consists of over 96% borneol that could inhibit the production or expression of inflammation-related proteins such as tumour necrosis factor-α (TNF-α), interleukin-1β, cyclo-oxygenase-2 and induced nitric oxide synthase (iNOS), and prevent brain injury or impairment.11 Borneol has been widely used to treat cerebrovascular disease, but is rarely used alone.21
In this trial, the major adverse reactions included pruritus, skin rash, acute liver injury and kidney injury. The adverse reactions of Edaravone Dexborneol seemed to show a dose-dependent relationship. It is worth noting that, among a total of 29 SAEs, 2 events (severe liver and kidney damage) were related to Edaravone Dexborneol, both of which happened in one patient in the high-dose group. The underlying pharmacological mechanisms remained unclear. In consideration of safety, high-dose Edaravone Dexborneol should not be recommended for further clinical investigation.
Although no significant difference was found among the four groups in the primary efficacy outcome, proportions of the patients with mRS score of ≤1 at 90 days in the group treated with medium-dose (69.39%) or high-dose (65.63%) Edaravone Dexborneol were higher than in the group treated with edaravone (60.64%), and we found the efficacy of the medium-dose Edaravone Dexborneol was likely to be even better than the high-dose one. In combination with efficacy and safety data, a phase III clinical trial with the medium-dose edaravone group, with a dose of 37.5 mg/time (edaravone 30 mg, (+)-borneol 7.5 mg) is suggested.
Edaravone Dexborneol can improve acute brain injury considerably in animal models of focal cerebral ischaemia (reperfused or permanent) and whole cerebral ischaemia reperfusion.22 No drug interaction in vivo between edaravone and (+)-borneol was observed from the preclinical pharmacokinetic study, including absorption, distribution, metabolism and excretion. Edaravone and (+)-borneol rapidly distributed in most tissues and excreted mainly from urine and bile in a conjunction form. Edaravone, (+)-borneol and Edaravone Dexborneol were not inhibitors or inducers of major CYP (Cytochrome P450 proteins) enzymes (online supplementary table 2). The risk of genetic and reproductive toxicity was not observed in the preclinical studies (online supplementary tables 3 and 4). The pathophysiological mechanism of cerebral ischaemic injury is complex, involving factors such as excitatory amino acids, calcium overload, free radicals, inflammatory response and apoptosis.18 Pharmacological intervention alone cannot affect this complex process effectively.9 Studies that engage multiple targets to improve ischaemic injury are ongoing.23–25 In theory, using two different agents to target different steps of ischaemic injury is likely superior to a single agent in preventing ischaemia.26
Edaravone Dexborneol enhanced inhibition of iNOS and TNF-α expression and lower level of ONOO− in the ischaemic brain. It could contribute to the synergetic effect of edaravone and borneol in combination. However, this study has several limitations. First, since the study is a phase II study and the sample is small, we cannot make further explorations on the effect of Edaravone Dexborneol on each TOAST (Trial of Org 10 172 in Acute Stroke Treatment) type with stratification analysis, which will be done in the phase III study. Second, for ethical reasons, only a positive control group (edaravone group) was set up in the study and there was no placebo control group. Third, since no blood samples were collected from the patients in the study, we cannot measure the changes in inflammatory factors before and after medication, and inflammatory factors will be used as secondary indicators to analyse the anti-inflammatory effect of Edaravone Dexborneol.