Early surgery versus initial conservative treatment in patients with traumatic intracerebral haemorrhage [STITCH(Trauma)] : the first randomized trial

Acknowledgements This project was funded by the NIHR Health Technology Assessment programme (project number 07/37/16). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II):Statistical analysis plan

<p>Abstract</p> <p>Background</p> <p>Previous studies had suggested that the outcome for patients with spontaneous lobar intracerebral haemorrhage (ICH) and no intraventricular haemorrhage (IVH) might be improved with early evacuation of the haematoma. The Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) set out to establish whether a policy of earlier surgical evacuation of the haematoma in selected patients with spontaneous lobar ICH would improve outcome compared to a policy of initial conservative treatment. It is an international, multi-centre, prospective randomised parallel group trial of early surgery in patients with spontaneous lobar ICH. Outcome is measured at six months via a postal questionnaire.</p> <p>Results</p> <p>Recruitment to the study began on 27 November 2006 and closed on 15 August 2012 by which time 601 patients had been recruited. The protocol was published in <it>Trials</it> (<url>http://www.trialsjournal.com/content/12/1/124/</url>). This update presents the analysis plan for the study without reference to the unblinded data. The trial data will not be unblinded until after follow-up is completed in early 2013. The main trial results will be presented in spring 2013 with the aim to publish in a peer-reviewed journal at the same time.</p> <p>Conclusion</p> <p>The data from the trial will provide evidence on the benefits and risks of early surgery in patients with lobar ICH.</p> <p>Trial registration</p> <p>ISRCTN: ISRCTN22153967</p

Surgical trial in traumatic intracerebral hemorrhage (STITCH(Trauma)) : study protocol for a randomized controlled trial

Peer reviewedPublisher PD

Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II):a randomised trial

SummaryBackgroundThe balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10–100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients.MethodsIn this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967.Findings307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3·7% [95% CI −4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367).InterpretationThe STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage.FundingUK Medical Research Council

Individual Patient Data Subgroup Meta-Analysis of Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage

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Early Endarterectomy Carries a Lower Procedural Risk Than Early Stenting in Patients With Symptomatic Stenosis of the Internal Carotid Artery: Results From 4 Randomized Controlled Trials.

BACKGROUND AND PURPOSE: Patients undergoing carotid endarterectomy (CEA) for symptomatic stenosis of the internal carotid artery benefit from early intervention. Heterogeneous data are available on the influence of timing of carotid artery stenting (CAS) on procedural risk. METHODS: We investigated the association between timing of treatment (0-7 days and >7 days after the qualifying neurological event) and the 30-day risk of stroke or death after CAS or CEA in a pooled analysis of individual patient data from 4 randomized trials by the Carotid Stenosis Trialists' Collaboration. Analyses were done per protocol. To obtain combined estimates, logistic mixed models were applied. RESULTS: Among a total of 4138 patients, a minority received their allocated treatment within 7 days after symptom onset (14% CAS versus 11% CEA). Among patients treated within 1 week of symptoms, those treated by CAS had a higher risk of stroke or death compared with those treated with CEA: 8.3% versus 1.3%, risk ratio, 6.7; 95% confidence interval, 2.1 to 21.9 (adjusted for age at treatment, sex, and type of qualifying event). For interventions after 1 week, CAS was also more hazardous than CEA: 7.1% versus 3.6%, adjusted risk ratio, 2.0; 95% confidence interval, 1.5 to 2.7 (P value for interaction with time interval 0.06). CONCLUSIONS: In randomized trials comparing stenting with CEA for symptomatic carotid artery stenosis, CAS was associated with a substantially higher periprocedural risk during the first 7 days after the onset of symptoms. Early surgery is safer than stenting for preventing future stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00190398; URL: http://www.controlled-trials.com. Unique identifier: ISRCTN57874028; Unique identifier: ISRCTN25337470; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) Protocol

<p>Abstract</p> <p>Background</p> <p>Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment.</p> <p>Methods/Design</p> <p>an international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (≤1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power.</p> <p>Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN22153967">ISRCTN22153967</a></p

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Opening up the participation laboratory: the co-creation of publics and futures in upstream participation.

How to embed reflexivity in public participation in techno-science and to open it up to the agency of publics are key concerns in current debates. There is a risk that engagements become limited to “laboratory experiments,” highly controlled and foreclosed by participation experts, particularly in upstream techno-sciences. In this paper, we propose a way to open up the “participation laboratory” by engaging localized, self-assembling publics in ways that respect and mobilize their ecologies of participation. Our innovative reflexive methodology introduced participatory methods to public engagement with upstream techno-science, with the public contributing to both the content and format of the project. Reflecting on the project, we draw attention to the largely overlooked issue of temporalities of participation, and the co-production of futures and publics in participation methodologies. We argue that many public participation methodologies are underpinned by the open futures model, which imagines the future as a space of unrestrained creativity. We contrast that model with the lived futures model typical of localized publics, which respects latency of materials and processes but imposes limits on creativity. We argue that to continue being societally relevant and scientifically important, public participation methods should reconcile the open future of research with the lived futures of localized publics