Minimal invasive surgery treatment for the patients with spontaneous supratentorial intracerebral hemorrhage ( MISTICH ) : protocol of a multi-center randomized controlled trial Running title : Minimally invasive surgery for intra cerebral hemorrhage

Rationale: Surgical treatment for patients with spontaneous intracerebral h emorrhage is still controversial. Some minimally invasive treatments incl ude stereotactic aspiration and neuroendoscope assisted surgery have been applied to he ma ma evacuation. However, study on minimally invasive surgery for patie nts with spontaneous intracerebral hemorrhage is insufficient. Aims: To determine if minimally invasive surgery improves the prognosis compared to craniotomy for patients with spontaneous intracerebral hemorrhage. Design: The MISTICH is a multi-center, prospective, randomized, assessorblinded, parallel group, controlled clinical trial. 2448 eligible patients wi ll be assigned to the neuroendoscopy group, stereotactic aspiration group and craniotomy group ra ndomly. Patients will receive the corresponding surgery based on the resul t of randomization. Operation will be conducted by well-trained surgeons and standard medica l treatment will be given in all patients. Patients will be followed up at 7 days, 30 days, and 6 months. Study outcomes: The primary outcome of this study is the unfavorable outcome at 6 months. The secondary outcomes include: mortality at 30 days, and 6 months after surgery; neurological functional status of 6 months after surgery measured b y GOS, Modified Rankin Scale (mRS), Barthe index (BI), and National Institutes of Hea lth Stroke Scale (NIHSS) separately; complications include rebleeding, ische mic stroke, intracranial infection; days of hospitalization. Introduction Spontaneous intracerebral hemorrhage (sICH) is the most devastate kind of all stokes. It was estimated that sICH affects over 1 million people worldw ide every year[1, 2]. The case fatality rate of sICH at 30 days is about 30%-55%, and only 12%-39% of the survivors could live independently after 6 months[3-5]. The treatment of sICH is still controversial among neurosurgeons and neurologists. The focus of debate is whether evacuation of hematoma will be abl e to improve the prognosis of patients. Previous studies showed that the removal of hemat oma might reduce nervous tissue damage, possibly by relieving local ischemia and removing noxious chemicals[6-8]. Several studies aiming to explore the effi cacy of surgery for patients with sICH have been carried out but showed different result s. In 1961, Mickissock and colleagues published the first prospective randomized c ontrolled trial. Their results showed that patients treated surgically had a worse outcome than the patients in the conservative group [9]. Another influential study is the STICH series trials, which concluded that there was no overall benefit of early surgery for patients with supratentorial sICH compared with conservative treatment[10, 11 ]. Some researchers attributed this to additional surgical traumatizati on. In order to reduce surgical traumatization, some minimal invasive techniques have be en used in hematoma evacuation. These minimal invasive techniques include stereota ctic aspiration and neuroendoscope assisted surgery. The stereotactic aspi ration guided by CT was successfully applied for hematoma evacuation by Backlund and collogues at 1978, and this minimal invasive surgery was further improved by some sc holars[12]. It was reported that the stereotactic aspiration combined with f ibrinolytic drugs could be more effective in hematoma evacuation than aspiration alone[13]. Anot her category of minimal invasive technique is neuroendoscope. Auer, et al. r ported that neuroendoscope could be applied to hematoma evacuation, but a subsequent randomized controlled trial showed that the outcome of surgical patient s with putaminal or thalamic hemorrhage was not better than medical trea tment [14, 15]. Recently, a lot of studies exploring the efficacy of minimally invasive surgery (MIS) compared with conservative craniotomy or medical treatment were c ar ied out, but none of them provided sufficient evidence regarding the choice of tr atment [16-20]. A further meta-analysis showed that patients with supratentorial intracerebral hemorrhage might benefit more from MIS than other treatment options [21]. Though MIS seems less invasive than the traditional craniotomy, it was reported that the incidence of some complications (e.g. rebleeding and infection) was hig her than craniotomy. In addition, with assistance of neuronavigation and operative mi croscope, hematoma evacuation by craniotomy could also be minimal invasive [22 , 23]. Until now, there is no randomized controlled trial comparing the efficacy of neuroendoscopy, stereotactic aspiration and craniotomy in patients wit h pontaneous intracerebral hemorrhage except a small-scale trial by Cho and colleges. Thus, a large-scale clinical trial is necessary to provide robust evidence for c linical practice by assessing the safety and efficacy of different surgical me thods including neuroendoscopy, CT-stereotactic aspiration and neuronavigation-assiste d craniotomy for sICH. Here we designed a randomized, assessor-blinded, parallelg oup, controlled, multi-center clinical study termed minimal invasive s urgery treatment for patients with spontaneous supratentorial intracerebral hemorrhage (MISTICH ). Design The MISTICH is a multi-center, prospective, randomized, assessor-blinded, par allel group, controlled clinical trial. The overall flow of MISTICH is showed in fig.1. A total of 20 centers from around China are included. The centers were eligible if t hey: have the ability to carry out all kinds of minimal invasive surgery of this trial ; demonstrate adequate trial experience; have previous adherence to trial gui delines with high follow-up rates. All participating hospital sites are to receive appr oval from the relevant ethics committee before initiation of the study. This study has be en registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-12002026) . All the patients or their legal surrogate will be fully informed and informed consent will be signed in this trial.