EARLYDRAIN- outcome after early lumbar CSF-drainage in aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Aneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.</p> <p>In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage has not been evaluated prospectively in a randomized controlled trial yet.</p> <p>Methods/Design</p> <p>This is a protocol for a 2-arm randomized controlled trial to compare an intervention group receiving early continuous lumbar CSF-drainage and standard neurointensive care to a control group receiving standard neurointensive care only. Adults suffering from a first aneurysmal subarachnoid hemorrhage whose aneurysm has been secured by means of coiling or clipping are eligible for trial participation. The effect of early CSF drainage (starting < 72 h after securing the aneurysm) will be measured in the following ways: the primary endpoint will be disability after 6 months, assessed by a blinded investigator during a personal visit or standardized telephone interview using the modified Rankin Scale. Secondary endpoints include mortality after 6 months, angiographic vasospasm, transcranial Doppler sonography (TCD) mean flow velocity in both middle cerebral arteries and rate of shunt insertion at 6 months after hospital discharge.</p> <p>Discussion</p> <p>Here, we present the study design of a multicenter prospective randomized controlled trial to investigate whether early application of a lumbar drainage improves clinical outcome after aneurysmal subarachnoid hemorrhage.</p> <p>Trial registration</p> <p>www.clinicaltrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01258257">NCT01258257</a></p

Ebola: translational science considerations

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as “Ebola”, ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective

Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18–75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5mg/h, 15mg/h or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale (GOSE) at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively. Introduction Advances have been made in the management of patients with aneurysmal subarachnoid hemorrhage (aSAH). Mortality among those who reach hospital alive has decreased 0.9% per year since 1980 [1]. Nevertheless, case fatality is still 40% and half of all survivors suffer some form of physical, emotional or cognitive impairment [2–4]. The causes of morbidity and mortality are mainly initial effects of the aSAH and delayed ischemic neurological deficit (DIND), which is usually due to cerebral vasospasm [5]. Indeed, vasospasm is considered to be one of the main preventable causes of morbidity and mortality [6]. Angiographic vasospasm (vasospasm that is visible on an angiogram) occurs in up to 70% of patients after aSAH [6]; DIND has been estimated to account for 50% of deaths in people surviving the initial SAH [7]. Current management options for the prevention and treatment of vasospasm and DIND include hemodynamic therapy, nimodipine, fasudil (in Japan), intra-arterial vasodilators and angioplasty, but none are very effective [7–12]. Clazosentan is an endothelin receptor antagonist under investigation for the prevention of vasospasm and subsequent morbidity and mortality. A phase 2a proof-of-principle trial administered 0.2 mg/kg/h clazosentan (corresponding to 15 mg/h for an individual weighing 75 kg) beginning within 48 h of the aneurysm securing procedure and continuing until Day 14 after aSAH. Clazosentan reduced moderate/severe angiographic vasospasm by 55% relative to placebo (angiographic vasospasm was observed in 88% and 40% of placebo- and clazosentan-treated patients, respectively, P = 0.008) [13]. These results supported conduct of a dose-finding safety trial (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage CONSCIOUS-1; phase 2b]). The primary outcome was angiographic vasospasm. The sample size was estimated from the effect on angiographic vasospasm in the phase 2a trial and the doses selected based on the phase 2a trial and also phase 1 clinical trials administering clazosentan to healthy volunteers and observing clinical and cardiovascular effects [13,14]. CONSCIOUS-1 recruited 413 patients from 11 countries [15]. Patients were randomized to intravenous clazosentan (1, 5 or 15 mg/h) or placebo, beginning within 56 h of aSAH and continuing until Day 14 after aneurysm rupture. Clazosentan significantly and dose-dependently reduced moderate/severe angiographic vasospasm relative to placebo; the highest dose (15 mg/h) led to a 65% risk reduction (P < 0.0001) [15]. CONSCIOUS-1 was not powered to detect a change in morbidity, mortality or patient-centered clinical outcome, but has been repeatedly and incorrectly cited as evidence that angiographic vasospasm does not contribute to poor outcome after aSAH [16]. This idea was put forth at least 35 years ago, but the basis remains as speculative now as it was then [17]. Post hoc, central analysis of all-cause mortality and vasospasm-related morbidity in CONSCIOUS-1 found a trend towards improved outcomes with clazosentan [15]. Two large, multinational phase 3 studies, CONSCIOUS-2 and CONSCIOUS-3, have now been initiated, based on the results of the CONSCIOUS-1 trial, to further investigate the effect of clazosentan on outcome after aSAH. This manuscript describes the rationale for the design and methodology of these studies. Methods Study design CONSCIOUS-2 and CONSCIOUS-3 are prospective, multinational, double-blind, placebo-controlled studies. The primary objective is to determine if clazosentan decreases vasospasm-related morbidity and all-cause mortality in patients with aSAH. Patients are randomized within 56 h of aSAH to intravenous clazosentan (5 mg/h in CONSCIOUS-2; 5 or 15 mg/h in CONSCIOUS-3) or placebo administered until Day 14 after aSAH, with a post-aSAH follow-up period of up to 12 weeks (Figure 1). Randomization is by an independent contract research organization using an interactive web response system, which assigns a randomization number according to a predefined randomization scheme. Randomization is stratified by site. In both studies, patients are managed according to procedures for aSAH at the study center (i.e., study drug is added to usual care) although patient management guidelines have been implemented (see below) to standardize care between centers. Drugs or procedures that are not standard care are forbidden including intravenous magnesium or statins when prescribed for the prevention of cerebral vasospasm, thrombolytics and antifibrinolytics, hypertonic saline without hyponatremia or increased intracranial pressure, calcineurin inhibitors, and endothelin receptor antagonists other than the study drug. Oral nimodipine is permitted, but not intravenous nimodipine or intravenous nicardipine. The study protocols are approved by local institutional review boards. The trials are registered on clinicaltrials.gov: registration numbers: NCT00558311 (CONSCIOUS-2) and NCT00940095 (CONSCIOUS-3). CONSCIOUS-2 enrolled 1157 patients in 102 centers in 27 countries; CONSCIOUS-3 is expected to enroll more than 1400 patients in approximately 150 centers in more than 25 countries. The rationale for separate studies of clipped and coiled patients was based on CONSCIOUS-1 analyses, indicating differences in endpoint occurrence when patients were stratified by securing procedure. Specifically, in CONSCIOUS-1 patients secured by clipping, the incidence of the composite endpoint in the placebo group was 45% compared with 46%, 25% and 40% in 1 mg/h, 5 mg/h and 15 mg/h groups, respectively. In contrast, in patients secured by coiling, the incidence of the composite endpoint in the placebo group was lower at 34% compared with 31%, 32% and 20% in 1 mg/h, 5 mg/h and 15 mg/h groups, respectively. Furthermore, an exploratory, retrospective analysis of CONSCIOUS-1 data showed that, relative to coiled patients, clipped patients had significantly higher rates of angiographic vasospasm (36% vs. 55%, respectively) and DIND (15% and 23%, respectively) [18]. Together these observations supported the conduct of separate trials for clipped and coiled patients and suggested that while the 5 mg/h dose might be most appropriate for clipped patients a potentially higher dose was additionally worth investigating in coiled patients