A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (2) ◽  
pp. 351-359
Author(s):  
Natasha Ironside ◽  
Brandon Christophe ◽  
Samuel Bruce ◽  
Amanda M. Carpenter ◽  
Trae Robison ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Phase Ii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Study Drug ◽  
Double Blind ◽  
Clinical Trial Registration

OBJECTIVEDelayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.METHODSIn this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.RESULTSOf the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.CONCLUSIONSThe power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov)

Abstract T P352: Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage - A Randomized Placebo-Controlled Trial to Assess Safety, Tolerability and Feasibility

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Susanne Muehlschlegel ◽  
Raphael Carandang ◽  
Wiley Hall ◽  
Kini Nisha ◽  
Saef Izzy ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Liver Toxicity ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Delayed Cerebral Ischemia ◽  
Double Blind ◽  
Outcome Differences ◽  
Infusion Period

Introduction: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) in humans. We evaluated safety/tolerability and feasibility of intravenous dantrolene (IV-D) after aSAH. Methods: In this single-center, randomized, double-blind, placebo-controlled trial, 31 patients with acute aSAH were randomized to IV-D 1.25 mg IV every 6 hours x 7 days (n=16) or placebo (n=15). Primary endpoint was incidence of hyponatremia (sNa ≤ 134 mmol/L) and liver toxicity (% patients with ALT, AST and AlkPhos >5x upper limit of normal). Secondary safety endpoints included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored by clinical, transcranial Doppler (TCD) or angiographic cVSP occurrence, delayed cerebral ischemia (DCI) and 3-month modified-Rankin-Scale, Glasgow Outcome Scale and Barthel Index. Statistical analysis was performed using non-parametric tests, generalized estimating equations and mixed models. Results: Between IV-D vs. placebo, no differences were observed in the primary outcome (hyponatremia: 44% vs. 67% [p=0.29]; liver toxicity 6% vs. 0% [p=1.0]). Numerically more AEs and SAEs were seen in the IV-D group, but did not reach statistical significance (16 vs. 5 AEs, of which 5 vs. 2 were severe; RR 2.2; 95% CI 0.7-6.7; p=0.16). Three IV-D vs. two placebo patients reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain edema requiring osmotherapy. No differences in angiographic, TCD, clinical cVSP, DCI, or 3-month functional outcomes were seen. Quantitative angiogram analysis revealed a trend towards increased vessel diameters in the IV-D group after the 7-day infusion-period (p=0.05). Conclusion: In this small trial, IV-Dantrolene after aSAH was feasible, tolerable and safe, but was underpowered to show efficacy or outcome differences.

Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery

1991 ◽  
Vol 74 (1) ◽  
pp. 8-13 ◽  
Author(s):  
Juha Öhman ◽  
Antti Servo ◽  
Olli Heiskanen
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Ct Scanning ◽  
Long Term Effects ◽  
Cerebral Infarcts ◽  
Double Blind ◽  
Content Type

✓ A total of 213 patients with verified aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) were enrolled in a double-blind placebo-controlled trial to determine the effect of intravenous nimodipine on delayed ischemic deterioration and computerized tomography (CT)-visualized infarcts after SAH and surgery. The administration of the drug or matching placebo was started immediately after the radiological diagnosis of a ruptured aneurysm had been made. Of the 213 patients enrolled in the study, 58 were operated on early (within 72 hours after the bleed: Days 0 to 3), 69 were operated on subacutely (between Days 4 and 7), and 74 had late surgery (on Day 8 or later). Eleven patients died before surgery was undertaken and one was not operated on. A follow-up examination with CT scanning, performed 1 to 3 years after the SAH (mean 1.4 years), revealed no significant differences in the overall outcome between the groups. However, nimodipine treatment was associated with a significantly lower incidence of deaths caused by delayed cerebral ischemia (p = 0.01) and significantly lower occurrence of cerebral infarcts visualized by CT scanning in the whole population (p = 0.05), especially in patients without an associated intracerebral hemorrhage on admission CT scan (p = 0.03).

scholarly journals Procalcitonin in the context of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

2020 ◽  
pp. 1-9
Author(s):  
Michael Veldeman ◽  
Daniel Lepore ◽  
Anke Höllig ◽  
Hans Clusmann ◽  
Christian Stoppe ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Infarction ◽  
Time Course ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Outcome Analysis ◽  
Clinical Trial Registration ◽  
Additional Increase ◽  
Long Term Outcome

OBJECTIVEAneurysmal subarachnoid hemorrhage (aSAH) initiates a deleterious cascade activating multiple inflammatory processes, which can contribute to delayed cerebral ischemia (DCI). Procalcitonin (PCT) is an established marker for sepsis treatment monitoring, and its time course in the context of DCI after aSAH remains unclear. The aim of this trial was to assess the predictive and confirmative value of PCT levels in the context of DCI.METHODSAll patients admitted to the authors’ institution with aSAH between 2014 and 2018 were prospectively screened for eligibility. Daily PCT levels were recorded alongside relevant aSAH characteristics. The predictive and confirmative values of PCT levels were assessed using a receiver operating characteristic and area under the curve (AUC) analysis. The course of PCT levels around the DCI event was evaluated in an infection-free subgroup of patients.RESULTSA total of 132 patients with aSAH were included. Early PCT levels (first 3 days post-aSAH) had a low predictive value for the development of DCI (AUC 0.661, standard error [SE] 0.050; p = 0.003) and unfavorable long-term outcome (i.e., Glasgow Outcome Scale–Extended scores 1–4; AUC 0.674, SE 0.054; p = 0.003). In a subgroup analysis of infection-free patients (n = 72), PCT levels were higher in patients developing DCI (p = 0.001) and DCI-related cerebral infarction (p = 0.002). PCT concentrations increased gradually after DCI and decreased with successful intervention. In refractory cases progressing to cerebral infarction, PCT levels showed a secondary increase.CONCLUSIONSEarly higher PCT levels were associated with the later development of DCI and unfavorable outcome. Analysis of PCT beyond the first couple of days after hemorrhage is hampered by nosocomial infections. In infection-free patients, however, PCT levels rise during DCI and an additional increase develops in patients developing cerebral infarction.Clinical trial registration no.: NCT02142166 (clinicaltrials.gov)

scholarly journals Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial

2017 ◽  
Vol 38 (7) ◽  
pp. 1190-1198 ◽  
Author(s):  
Masato Naraoka ◽  
Naoya Matsuda ◽  
Norihito Shimamura ◽  
Kenichiro Asano ◽  
Kenichi Akasaka ◽  
...  
Keyword(s):  
Placebo Group ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Pleiotropic Effects ◽  
Neurological Deficits ◽  
Double Blind ◽  
Long Acting

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

scholarly journals Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis

2011 ◽  
Vol 31 (6) ◽  
pp. 1443-1451 ◽  
Author(s):  
Nima Etminan ◽  
Mervyn DI Vergouwen ◽  
Don Ilodigwe ◽  
R Loch Macdonald
Keyword(s):  
Systematic Review ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Clinical Outcome ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Meta Analysis ◽  
Delayed Cerebral Ischemia ◽  
Double Blind ◽  
Poor Outcome ◽  
Methodological Problems

As it is often assumed that delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is caused by vasospasm, clinical trials often focus on prevention of vasospasm with the aim to improve clinical outcome. However, the role of vasospasm in the pathogenesis of DCI and clinical outcome is possibly smaller than previously assumed. We performed a systematic review and meta-analysis on all randomized, double-blind, placebo-controlled trials that studied the effect of pharmaceutical preventive strategies on vasospasm, DCI, and clinical outcome in SAH patients to further investigate the relationship between vasospasm and clinical outcome. Effect sizes were expressed in pooled risk ratio (RR) estimates with corresponding 95% confidence intervals (CI). A total of 14 studies randomizing 4,235 patients were included. Despite a reduction of vasospasm (RR 0.80 (95% CI 0.70 to 0.92)), no statistically significant effect on poor outcome was observed (RR 0.93 (95% CI 0.85 to 1.03)). The variety of DCI definitions did not justify pooling the DCI data. We conclude that pharmaceutical treatments have significantly decreased the incidence of vasospasm, but not of poor clinical outcome. This dissociation between vasospasm and clinical outcome could result from methodological problems, sample size, insensitivity of clinical outcome measures, or from mechanisms other than vasospasm that also contribute to poor outcome.

Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial

2009 ◽  
Vol 111 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Ming-Yuan Tseng ◽  
Peter J. Hutchinson ◽  
Hugh K. Richards ◽  
Marek Czosnyka ◽  
John D. Pickard ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
National Institutes Of Health ◽  
Neuroprotective Effects ◽  
Double Blind ◽  
End Points ◽  
Age Range ◽  
To Receive

Object Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH. Methods Within 72 hours of aSAH, 80 patients (age range 24–82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months. Results Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p = 0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p = 0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p = 0.001), a shortened duration of impaired autoregulation (ipsilateral side, p < 0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p = 0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p = 0.008). Conclusions This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Phase 1/2a Trial of ISPASM

Stroke ◽  
2021 ◽  
Author(s):  
Mario Zanaty ◽  
Lauren Allan ◽  
Edgar A. Samaniego ◽  
Anthony Piscopo ◽  
Eleanor Ryan ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Intravenous Infusion ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Phase 1 ◽  
External Ventricular Drain ◽  
Delayed Cerebral Ischemia ◽  
Unique Identifier

Background and Purpose: Microthrombosis could play a role in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Tirofiban has shown promising results in reducing delayed cerebral ischemia in retrospective studies. However, the safety of using tirofiban in aneurysmal subarachnoid hemorrhage is not rigorously established. Methods: A phase 1/2a double-blinded randomized controlled trial (2:1 randomization) to assess the safety of a 7-day intravenous infusion of tirofiban compared with placebo, in patients with aneurysmal subarachnoid hemorrhage treated with ventriculostomy placed in the operative room and coiling was conducted. The primary end point was any intracranial hemorrhage during the hospital stay. The secondary end points were: incidence of radiographic and clinical vasospasm, incidence of delayed cerebral ischemia, and incidence of cerebral ischemic changes noted on magnetic resonance imaging or computed tomography. Results: Eighteen patients received intravenous tirofiban and 12 received placebo. There was no difference in baseline characteristics except for higher male proportions in the tirofiban group. There was no difference in death, in development of new or change in existing intracranial hemorrhages, in thrombocytopenia, and need for shunts in the two arms. However, the tirofiban arm had a lower incidence of delayed cerebral ischemia compared with placebo (6% [1/18] versus 33% [4/12]; P =0.04), and less radiographic vasospasm as detected by catheter angiogram or computed tomography angiography ( P =0.01) and computed tomography perfusion ( P =0.01). Conclusions: The above preliminary results support proceeding with further testing of the safety and efficacy of 7-day intravenous infusion of tirofiban in a pragmatic (placing external ventricular drain by the bedside), multicenter setting, and using a larger population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03691727.

scholarly journals Randomized, Placebo-controlled, Double-blind, Pilot Trial to Investigate Safety and Efficacy of Cerebrolysin in Patients with Aneurysmal Subarachnoid Hemorrhage

2019 ◽  
Author(s):  
Peter Yat-Ming Woo ◽  
Sandy Lam ◽  
Joanna WK Ho (Dr.) ◽  
Natalie MW Ko ◽  
Ronald PT Li ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Adverse Effects ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Small Sample ◽  
P Value ◽  
Study Group ◽  
Double Blind

Abstract Background There are limited treatment options for aneurysmal subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia, a major determinant of mortality and morbidity. Cerebrolysin, a brain-specific pleiotropic neuroprotective agent, has been suggested to improve functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of Cerebrolysin for conferring such benefits in SAH patients. Methods This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. 50 patients received either daily Cerebrolysin (30ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Score (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the occurrence of adverse effects, six-month mortality, the occurrence of cerebral vasospasm, delayed cerebral ischemia and infarction. Results No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 0.53; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for good six-month recovery indicated by a modified Rankin Scale of 0 to 2 (OR: 0.53; 95% CI 0.43-5.17) and a Barthel Index of 70 or more (OR: 0.52; 95% CI: 0.29-12.72) were also similar for both groups. There was a significantly lower risk of three- and six-month mortality for patients that received Cerebrolysin (OR: 0.46; 95% CI: 0.33-0.63). There were no deaths in the Cerebrolysin group, but the morality rate for the control group was 16% (4/25). The commonest cause of death was due to delayed cerebral ischemia. There were no differences in the overall incidence of delayed cerebral ischemia (p-value: 0.78), cerebral vasospasm (p-value: 0.16) and infarction (p-value: 0.77) between the two groups. Conclusions Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. Results suggest a benefit in reducing three- and six-month mortality. Due to the exploratory nature of this study and its small sample size, these findings should be confirmed in a larger-scale clinical trial.

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