12 research outputs found
The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage
BackgroundFor patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.MethodsREACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.DiscussionIn the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39)
Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage
Background and Purpose- Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH), although no effect on long-term functional outcome has been demonstrated. Thick clot on initial computed tomography is associated with an increased risk of vasospasm and delayed cerebral ischemia. In this post hoc analysis, we hypothesized that use of clazosentan in this subpopulation would provide stronger benefit. Methods- We analyzed SAH patients enrolled in the CONSCIOUS-2 and CONSCIOUS-3 studies (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) and compared the effects of clazosentan 5 mg/h, 15 mg/h, and placebo starting the day after aneurysm repair. The analysis was performed separately based on the presence or absence of thick (≥4 mm) and diffuse (≥3 cisterns) SAH on admission computed tomography. The primary composite end point was all-cause mortality and vasospasm-related morbidity at 6 weeks, and the main secondary end point was the extended Glasgow Outcome Scale at 3 months, adjusted for admission clinical grade. Results- Of 1718 randomized patients, 919 (53%) had thick and diffuse SAH. The primary composite end point in this group occurred in 36% of placebo-treated patients (n=294), 30% patients treated with clazosentan 5 mg/h (n=514; relative risk, 0.82; 95% CI, 0.67-0.99), and 19% patients treated with clazosentan 15 mg/h (n=111; relative risk, 0.54; 95% CI, 0.36-0.80). Despite this, death or poor functional outcome (Glasgow Outcome Scale ≤4) occurred in 33% of placebo-treated patients, 34% of patients treated with clazosentan 5 mg/h (relative risk 1.02; 95% CI, 0.84-1.23), and 35% of patients treated with clazosentan 15 mg/h (relative risk 1.14; 95% CI, 0.88-1.48). Conclusions- In an enriched population with thick and diffuse SAH, clazosentan at a dose of 5 and 15 mg/h was able to significantly reduce vasospasm-related morbidity in a dose-dependent manner. The absence of an effect on long-term functional status likely reflects the complexity and multiplicity of factors that contribute to poor outcome after SAH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00558311; NCT00940095
Thick and diffuse cisternal clot independently predicts vasospasm-related morbidity and poor outcome after aneurysmal subarachnoid hemorrhage
OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade.
METHODS: In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)-2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale-Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models.
RESULTS: Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III-V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%-41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%-19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%-38.3%) and 16.2% (95% CI 12.1%-21.1%) of patients with and without thick, diffuse SAH, respectively.
CONCLUSIONS: In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm
Reversal of Vasospasm with Clazosentan After Aneurysmal Subarachnoid Hemorrhage: A Pilot Study
BACKGROUND: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm.
METHODS: The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis.
RESULTS: The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0-61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively.
CONCLUSIONS: Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial
Cancer adolescent pathway in France between 1988 and 1997.
International audienceWe report an adolescent cancer pathway from referral, through diagnosis and treatment, to follow-up in France. All cases of cancer among 15-19 years, diagnosed from 1988 to 1997, recorded by nine French population-based cancer registries (10% of French population) were included. The management of adolescent cancer by paediatricians was rare. An adolescents' pathway through cancer care can be summarized as first visit to general practitioner, referral to adult oncologist for haematological malignancy and medical or surgical specialists for solid tumours, treatment in adult unit, and follow-up by adult oncologist, adult medical or surgical specialist, or general practitioner. Only 9% of the 15-19 years are entered into a clinical trial (respectively 6% and 3% into adult and paediatric clinical trial). The inclusion rate changes according to the diagnosis, higher for acute lymphoblastic leukaemia (39%), non-Hodgkin's lymphomas (NHL) (27%), and acute non-lymphoblastic leukaemia (20%). Only 4% of adolescent cancers were managed on shared adult/paediatric departments, especially for soft-tissue sarcomas (14.9%), malignant bone tumours (13.4), central nervous system tumours (6.2%), and NHL (4.4%). Whatever the reasons for lack of participation in clinical trials, an ideal model requiring communication and cooperation between all adult and paediatric specialists involved in adolescent cancer treatment should reduce the large gap in access to cooperative groups
Cancer survival among adolescents in France.
International audienceCancer is the third most significant cause of mortality in French adolescents. The aim of this study was to investigate survival of adolescents with cancer. Overall (OS), disease-specific (DSS) and event-free survival (EFS) were used for the outcome analysis of adolescents (15-19 years) with cancer, recorded by nine French population-based registries during the 1988-1997 period. Five-year OS, DSS and EFS were, respectively, 74.0% (70.7-77.4), 74.5% (71.2-77.9), and 69.0% (65.4-72.5). Five-year DSS was 94% for carcinomas, 89% for germ-cell tumours, 85% for lymphomas, 67% for soft-tissue sarcomas, 64% for CNS tumours, 55% for malignant bone tumours, and 41% for leukaemia. Compared with paediatric series, poor results in acute lymphoblastic leukaemia, malignant bone tumours, and soft-tissue sarcomas have to be highlighted, and deserve further studies concerning the type of regimens used for these patients. Multidisciplinary management of adolescent cancer in paediatric, adult, or specialized units will improve cure rates and treatment outcomes for these patients
Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2)
We report here results of a randomized, double-blind, placebo-controlled study ( http://www.ClinicalTrials.gov , NCT00558311) that investigated the effect of clazosentan (5 mg/h, n = 768) or placebo (n = 389) administered for up to 14 days in patients with aneurysmal subarachnoid hemorrhage (SAH) repaired by surgical clipping. The primary endpoint was a composite of all-cause mortality, new cerebral infarction or delayed ischemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was the Glasgow Outcome Scale Extended (GOSE), which was dichotomized. Twenty-one percent of clazosentan- compared to 25% of placebo-treated patients met the primary endpoint (relative risk reduction [RRR] [95% CI]: 17% [-4% to 33%]; p = 0.10). Poor outcome (GOSE score ≤ 4) occurred in 29% of clazosentan- and 25% of placebo-treated patients (RRR: -18% [-45% to 4%]; p = 0.10). In prespecified subgroups, mortality/vasospasm-related morbidity was reduced in clazosentan-treated patients by 33% (8-51%) in poor WFNS (World Federation of Neurological Surgeons) grade (≥III) and 25% (5-41%) in patients with diffuse, thick SAH. Lung complications, anemia and hypotension occurred more frequently with clazosentan. Mortality (week 12) was 6% in both groups. The results showed that clazosentan nonsignificantly decreased mortality/vasospasm-related morbidity and nonsignificantly increased poor functional outcome in patients with aneurysmal SAH undergoing surgical clipping
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
Clazosentan for patients with subarachnoid haemorrhage: lessons learned – Authors' reply
Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)
BACKGROUND:
Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality.
METHODS:
In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311.
FINDINGS:
In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups.
INTERPRETATION:
Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH.
FUNDING:
Actelion Pharmaceuticals.
Copyright © 2011 Elsevier Ltd. All rights reserved