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R. Loch Macdonald - One of the best experts on this subject based on the ideXlab platform.

  • Lessons from the CONSCIOUS-1 Study.
    Journal of Clinical Medicine, 2020
    Co-Authors: Alexander J. Schupper, Matthew E. Eagles, Sean N. Neifert, J Mocco, R. Loch Macdonald
    Abstract:

    After years of research on treatment of aneurysmal subarachnoid hemorrhage (aSAH), including randomized clinical trials, few treatments have been shown to be efficacious. Nevertheless, reductions in morbidity and mortality have occurred over the last decades. Reasons for the improved outcomes remain unclear. One randomized clinical trial that has been examined in detail with these questions in mind is Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1). This was a phase-2 trial testing the effect of Clazosentan on angiographic vasospasm (aVSP) in patients with aSAH. Clazosentan decreased moderate to severe aVSP. There was no statistically significant effect on the extended Glasgow outcome score (GOS), although the study was not powered for this endpoint. Data from the approximately 400 patients in the study were detailed, rigorously collected and documented and were generously made available to one investigator. Post-hoc analyses were conducted which have expanded our knowledge of the management of aSAH. We review those analyses here.

  • Acute kidney injury after aneurysmal subarachnoid hemorrhage and its effect on patient outcome: an exploratory analysis
    Journal of Neurosurgery, 2020
    Co-Authors: Matthew E. Eagles, Maria Powell, Oliver G.s. Ayling, Michael K. Tso, R. Loch Macdonald
    Abstract:

    OBJECTIVE Acute kidney injury (AKI) is associated with death in critically ill patients, but this complication has not been well characterized after aneurysmal subarachnoid hemorrhage (aSAH). The purpose of this study was to determine the incidence of AKI after aSAH and to identify risk factors for renal dysfunction. Secondary objectives were to examine what effect AKI has on patient mortality and functional outcome at 12 weeks post-aSAH. METHODS The authors performed a post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial data set (clinical trial registration no.: NCT00111085, https://clinicaltrials.gov). The primary outcome of interest was the development of AKI, which was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes of interest were death and a modified Rankin Scale score greater than 2 at 12 weeks post-aSAH. Propensity score matching was used to assess for a significant treatment effect related to Clazosentan administration and AKI. Univariate analysis, locally weighted scatterplot smoothing (LOWESS) curves, and stepwise logistic regression models were used to evaluate for associations between baseline or disease-related characteristics and study outcomes. RESULTS One hundred fifty-six (38%) of the 413 patients enrolled in the CONSCIOUS-1 trial developed AKI during their ICU stay. A history of hypertension (p < 0.001) and the number of nephrotoxic medications administered (p = 0.029) were independent predictors of AKI on multivariate analysis. AKI was an independent predictor of death (p = 0.028) but not a poor functional outcome (p = 0.21) on multivariate testing. Unresolved renal dysfunction was the strongest independent predictor of death in this cohort (p < 0.001). CONCLUSIONS AKI is a common complication following aSAH. Patients with premorbid hypertension and those treated with nephrotoxic medications may be at greater risk for renal dysfunction. AKI appears to confer an increased probability of death after aSAH.

  • Cognitive Impairment, Functional Outcome, and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.
    World Neurosurgery, 2019
    Co-Authors: Matthew E. Eagles, Michael K. Tso, R. Loch Macdonald
    Abstract:

    Background Measures such as modified Rankin Scale (mRS) may not reflect cognitive outcome following aneurysmal subarachnoid hemorrhage. The aim of this study was to assess the relationship between functional outcome, measured by mRS, and cognition, measured by mini-mental state examination (MMSE), after aSAH. A secondary analysis evaluated the impact of delayed cerebral ischemia (DCI) on the proportion of patients who had cognitive impairment. Methods We performed a post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial data. MMSE and mRS scores were compared using Kruskal-Wallis equality-of-populations rank test with pairwise comparison post hoc analysis. Cognitive impairment was defined as MMSE score Results CONSCIOUS-1 comprised 413 patients. Of these, 337 took an MMSE at their 12-week follow-up. Mean MMSE score was 27 with a median of 29 (range, 0–30; SD 5.4). There were no significant differences between MMSE scores of patients who had 12-week mRS scores of 0–2. On multivariate analysis, DCI was independently associated with cognitive impairment after aSAH. Conclusions Patients considered to have a good outcome on mRS had varying degrees of cognitive function on MMSE, whereas development of DCI was an independent predictor of cognitive impairment after aSAH. MMSE may not be sensitive enough to discern subtle defects in cognition, as the median score was 29 out of 30.

  • Thick and Diffuse Subarachnoid Blood as a Treatment Effect Modifier of Clazosentan After Subarachnoid Hemorrhage
    Stroke, 2019
    Co-Authors: Stephan A Mayer, R. Loch Macdonald, Nicolas Bruder, Abdel Hmissi, Angelina Marr, Sébastien Roux, E. Francois Aldrich, Tanuwong Viarasilpa, Randall T Higashida
    Abstract:

    Background and Purpose— Clazosentan, an endothelin receptor antagonist, has been shown to reduce angiographic vasospasm and vasospasm-related morbidity after aneurysmal subarachnoid hemorrhage (SAH...

  • A Propensity Score-Matched Study of the Use of Non-steroidal Anti-inflammatory Agents Following Aneurysmal Subarachnoid Hemorrhage
    Neurocritical Care, 2016
    Co-Authors: Farshad Nassiri, Christopher D. Witiw, George M. Ibrahim, Jetan H. Badhiwala, Alireza Mansouri, Naif M. Alotaibi, R. Loch Macdonald
    Abstract:

    Background Inflammation may contribute to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Here, we compared outcomes among propensity score-matched cohorts who did and did not receive non-steroidal anti-inflammatory drug (NSAID) use after aSAH. Methods Propensity score-matched analysis of 413 subjects enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUring after Subarachnoid hemorrhage (CONSCIOUS-1) study. Propensity score matching was performed on the basis of age, sex, baseline National Institutes of Health Stroke Scale score, World Federation of Neurological Societies grade on admission, procedure used for securing aneurysm, and SAH clot burden. Results 178 patients were matched (89 received NSAIDs, 89 did not). Propensity score matching was considered acceptable. Patients who had received NSAIDs during their hospital stay had significantly lower mortality rate, and reduced duration of intensive care unit stay and total length of hospital stay ( P  = 0.035, P  = 0.009, and P  = 0.053, respectively). At 6 weeks, 80.9 % of patients treated with NSAIDs had good functional outcome compared to 68.5 % of matched controls ( P  = 0.083). There was no significant difference in the proportions of patients who developed delayed ischemic neurological deficits, angiographic vasospasm, or required rescue therapy. Conclusions Inflammation may play a crucial role in the poor outcomes after SAH, and that NSAIDs may be a useful therapeutic option, once validated by larger prospective studies.

Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.

  • Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan.
    The AAPS Journal, 2020
    Co-Authors: Pierre-eric Juif, Christine Voors‐pette, Jasper Dingemanse, Mike Ufer
    Abstract:

    This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist Clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3-period, crossover study was conducted in 36 healthy subjects receiving Clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For Clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of Clazosentan (i.e., upper bound of 90% CI ∆∆QTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, Clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.

  • Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.
    Pharmaceutical Research, 2019
    Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten Lehr
    Abstract:

    Bosentan, Clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for Clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, Clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

  • Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists
    Pharmaceutical Research, 2019
    Co-Authors: Anke-katrin Volz, Jasper Dingemanse, Andreas Krause, Thorsten Lehr
    Abstract:

    Purpose Bosentan, Clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for Clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. Methods PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, Clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. Results Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. Conclusion The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

  • influence of rifampin mediated organic anion transporting polypeptide 1b1 1b3 inhibition on the pharmacokinetics of Clazosentan
    Clinical and Translational Science, 2019
    Co-Authors: Pierre-eric Juif, Mike Ufer, Peter Dogterom, Christine Voorspette, Jasper Dingemanse
    Abstract:

    Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of Clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when Clazosentan was given with rifampin than with placebo.

  • Influence of Rifampin‐Mediated Organic Anion‐Transporting Polypeptide 1B1/1B3 Inhibition on the Pharmacokinetics of Clazosentan
    Clinical and Translational Science, 2019
    Co-Authors: Pierre-eric Juif, Christine Voors‐pette, Mike Ufer, Peter Dogterom, Jasper Dingemanse
    Abstract:

    : Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of Clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when Clazosentan was given with rifampin than with placebo.

Peter Vajkoczy - One of the best experts on this subject based on the ideXlab platform.

  • Randomised Trial of Clazosentan, an Endothelin Receptor Antagonist, in Patients with Aneurysmal Subarachnoid Hemorrhage Undergoing Surgical Clipping (CONSCIOUS-2)
    Cerebral Vasospasm: Neurovascular Events After Subarachnoid Hemorrhage, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    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.

  • Abstract 43: Effect of Clazosentan on Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling: Results of the CONSCIOUS-3 Study
    Stroke, 2012
    Co-Authors: R. L. Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Isabel Wanke, Doris Bach, Andrew J. Molyneux, Aline Frey
    Abstract:

    Introduction: In CONSCIOUS-1, Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm (VSP) after aneurysmal subarachnoid hemorrhage (aSAH)...

  • Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling
    Stroke, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Background and Purpose—Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether Clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods—This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤14 days intravenous Clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results—CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; Clazosentan 5 mg/h, n=194; Clazosentan 15 mg/h, n=188). The primary end point oc...

  • 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
    Lancet Neurology, 2011
    Co-Authors: Loch R Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Summary 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.

  • Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials
    Neurocritical Care, 2010
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Aline Frey, Angelina Marr
    Abstract:

    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 (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to Clazosentan 5, 15 mg/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 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.

Aline Frey - One of the best experts on this subject based on the ideXlab platform.

  • Randomised Trial of Clazosentan, an Endothelin Receptor Antagonist, in Patients with Aneurysmal Subarachnoid Hemorrhage Undergoing Surgical Clipping (CONSCIOUS-2)
    Cerebral Vasospasm: Neurovascular Events After Subarachnoid Hemorrhage, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    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.

  • Abstract 43: Effect of Clazosentan on Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling: Results of the CONSCIOUS-3 Study
    Stroke, 2012
    Co-Authors: R. L. Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Isabel Wanke, Doris Bach, Andrew J. Molyneux, Aline Frey
    Abstract:

    Introduction: In CONSCIOUS-1, Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm (VSP) after aneurysmal subarachnoid hemorrhage (aSAH)...

  • Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling
    Stroke, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Background and Purpose—Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether Clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods—This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤14 days intravenous Clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results—CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; Clazosentan 5 mg/h, n=194; Clazosentan 15 mg/h, n=188). The primary end point oc...

  • 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
    Lancet Neurology, 2011
    Co-Authors: Loch R Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Summary 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.

  • Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials
    Neurocritical Care, 2010
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Aline Frey, Angelina Marr
    Abstract:

    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 (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to Clazosentan 5, 15 mg/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 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.

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  • Randomised Trial of Clazosentan, an Endothelin Receptor Antagonist, in Patients with Aneurysmal Subarachnoid Hemorrhage Undergoing Surgical Clipping (CONSCIOUS-2)
    Cerebral Vasospasm: Neurovascular Events After Subarachnoid Hemorrhage, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    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.

  • Abstract 43: Effect of Clazosentan on Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling: Results of the CONSCIOUS-3 Study
    Stroke, 2012
    Co-Authors: R. L. Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Isabel Wanke, Doris Bach, Andrew J. Molyneux, Aline Frey
    Abstract:

    Introduction: In CONSCIOUS-1, Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm (VSP) after aneurysmal subarachnoid hemorrhage (aSAH)...

  • Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling
    Stroke, 2012
    Co-Authors: R. Loch Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Background and Purpose—Clazosentan, an endothelin receptor antagonist, has been shown to reduce vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). CONSCIOUS-3 assessed whether Clazosentan reduced vasospasm-related morbidity and all-cause mortality postaSAH secured by endovascular coiling. Methods—This double-blind, placebo-controlled, phase III trial randomized patients with aSAH secured by endovascular coiling to ≤14 days intravenous Clazosentan (5 or 15 mg/h) or placebo. The primary composite end point (all-cause mortality; vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits; rescue therapy for vasospasm) was evaluated 6 weeks postaSAH. The main secondary end point was dichotomized extended Glasgow Outcome Scale (week 12). Results—CONSCIOUS-3 was halted prematurely following completion of CONSCIOUS-2; 577/1500 of planned patients (38%) were enrolled and 571 were treated (placebo, n=189; Clazosentan 5 mg/h, n=194; Clazosentan 15 mg/h, n=188). The primary end point oc...

  • Attributing Hypodensities on CT to Angiographic Vasospasm Is Not Sensitive and Unreliable
    Stroke, 2012
    Co-Authors: George M. Ibrahim, S. Weidauer, Andreas Raabe, Hartmut Vatter, R. Loch Macdonald
    Abstract:

    Background and Purpose—The presence of low-density areas on CT is used in clinical decision-making regarding treatment of angiographic vasospasm as well as in research as a surrogate marker for severity of angiographic vasospasm. We assess the interobserver variability in attributing hypodensities on CT to angiographic vasospasm-related delayed ischemic neurological deficit. Methods—Three experienced reviewers, 2 neurosurgeons, and a neuroradiologist independently reviewed CT scans of 413 patients enrolled in the Clazosentan to Overcome Neurological iSChemia and Infarction OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) trial, who universally underwent catheter angiography to determine severity of angiographic vasospasm. Interobserver variability was calculated using the κ statistic and the χ2 test was used to determine associations between dichotomized outcomes. Results—There was considerable interobserver variability in attributing CT hypodensities to vasospasm-related delayed ischemic neurologica...

  • 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
    Lancet Neurology, 2011
    Co-Authors: Loch R Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline Frey
    Abstract:

    Summary 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.