TPCT1: ECONOMIC ANALYSIS OF TIRILAZAD MESYLATE FOR ANEURYSMAL SUBARACHNOID HEMORRHAGE: ECONOMIC EVALUATION COMBINING FOUR PHASE III CLINICAL TRIALS

AbstractThis study used data from a multinational phase III randomized, double-blind, vehicle-controlled trial to evaluate the cost-effectiveness of tirilazad mesylate (Freedox®) in the treatment of aneurysmal subarachnoid hemorrhage. In men, therapy with 6 mg/kg per day of tirilazad mesylate was associated with significantly increased survival, increased cost of care, and ratios of cost per death averted that compare favorably with the ratios of other life and death interventions. In women, it appeared to have no effects on costs or survival. Further clinical studies may provide additional information about the cost-effectiveness of this intervention.

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Protective effects of tirilazad mesylate and metabolite U-89678 against blood-brain barrier damage after subarachnoid hemorrhage and lipid peroxidative neuronal injury

Journal of Neurosurgery ◽

10.3171/jns.1996.84.2.0229 ◽

1996 ◽

Vol 84 (2) ◽

pp. 229-233 ◽

Cited By ~ 54

Author(s):

Sarah L. Smith ◽

Heidi M. Scherch ◽

Edward D. Hall

Keyword(s):

Subarachnoid Hemorrhage ◽

Blood Brain Barrier ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Brain Barrier ◽

Phase Iii ◽

Blue Dye ◽

Ferrous Ammonium Sulfate ◽

Protective Effects ◽

Blood Brain ◽

Tirilazad Mesylate

✓ The 21-aminosteroid lipid-peroxidation inhibitor, tirilazad mesylate (U-74006F), recently was shown in a large multinational Phase III clinical trial to decrease mortality and improve neurological recovery in patients 3 months after onset of aneurysmal subarachnoid hemorrhage (SAH). A major tirilazad metabolite in animals and man, U-89678 is formed when the 4–5 double bond in the A-ring is reduced and has been postulated to contribute significantly to tirilazad's neuroprotective effects. In the first experiment of the present study, the authors compared the effects of tirilazad and U-89678 on acute blood-brain barrier (BBB) damage in rats subjected to SAH via injection of 300 µl of autologous nonheparinized blood under the dura of the left cortex. The rats were treated by intravenous administration of either 0.3 or 1.0 mg/kg of tirilazad or U-89678 10 minutes before and 2 hours after SAH, and BBB damage was quantified according to the extravasation of the protein-bound Evans' blue dye into the injured cortex 3 hours post-SAH. The results revealed that 0.3 and 1.0 mg/kg tirilazad significantly reduced SAH-induced BBB damage 35.2% (p < 0.05) and 60.6% (p < 0.0001), respectively, in comparison to treatment with vehicle. The 0.3- and 1.0-mg/kg doses of U-89678 also decreased injury by 39.1% (p < 0.05) and 21.3% (not significant), respectively. In the second experiment, the investigators assessed the relative abilities of tirilazad and U-89678 to protect cultured neurons from iron-induced lipid peroxidative injury. Fetal mouse spinal cord cells were pretreated with 3, 10, or 30 µM tirilazad or U-89678 for 1 hour and then exposed to 200 µM ferrous ammonium sulfate (FAS) for 40 minutes. Cell viability was measured in terms of the uptake of [3H]α-(methyl)-aminoisobutyric acid 45 minutes after the FAS treatment. Both compounds enhanced neuronal survival in a concentration-dependent fashion. Although the two were equally efficacious, U-89678 was slightly more potent than its parent. On the basis of these findings, the authors conclude that the tirilazad metabolite, U-89678, possesses vaso- and neuroprotective properties that are essentially equivalent to the parent 21-aminosteroid. Hence, U-89678 probably contributes to the protective effects of tirilazad in SAH and other insults to the central nervous system.

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Results of the Economic Evaluation of the FIRST Study: A Multinational Prospective Economic Evaluation

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462300010989 ◽

1996 ◽

Vol 12 (4) ◽

pp. 698-713 ◽

Cited By ~ 35

Author(s):

Kevin A. Schulman ◽

Martin Buxton ◽

Henry Glick ◽

Mark Sculpher ◽

Gladys Guzman ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Clinical Trials ◽

Economic Evaluation ◽

Clinical Results ◽

Severe Congestive Heart Failure ◽

Multicenter Trial ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

International Multicenter

AbstractWe present the prospective economic evaluation that served as a secondary endpoint for the FIRST study, a randomized international multicenter trial of patients with severe congestive heart failure. Although the clinical results of this study were disappointing, we demonstrated the feasibility of incorporating prospective economic evaluation in phase III clinical trials.

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Abstract TMP21: Cilostazol for Prevention of Cerebral Vasospasm and Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Clinical Trials

Stroke ◽

10.1161/str.51.suppl_1.tmp21 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Iryna Lobanova ◽

Kathryn Qualls ◽

Renee L Martin ◽

Niraj Arora ◽

Premkumar Nattanmai ◽

...

Keyword(s):

Clinical Trials ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Meta Analysis ◽

Phase Iii ◽

Controlled Clinical Trials ◽

Randomized Controlled Clinical Trials ◽

Randomized Controlled ◽

Symptomatic Vasospasm

Introduction: Cilostazol, a selective inhibitor of phosphodiesterase 3, may reduce symptomatic vasospasm and associated cerebral ischemia and improve outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH) due to its anti-platelet, anti-proliferative, and vasodilatory effects. Due to recent publication of randomized controlled clinical trials, a meta-analysis was performed to identify the common treatment effect. Methods: We performed a meta-analysis of four randomized controlled clinical trials. The primary endpoint of interest was cerebral ischemia related to vasospasm. Secondary endpoints were angiographic vasospasm, new cerebral infarct, mortality, and death or disability at the 90 days following randomization. Using random-effects models with study as a random effect, relative risks (RR) and 95% confidence intervals (CI) were generated Results: A total of 405 subjects (200 randomized to oral cilostazol 100 mg twice per day) were included in the meta-analysis. The proportion of subjects with cerebral ischemia related to vasospasm was significantly lower in those who were assigned to cilostazol treatment (RR 0.46; 95% CI 0.21-1.00; p< 0.050) without any heterogeneity between the trials (Cochran’s Q statistic 1.52, df 2; P = .468, I 2 =0.0%). The proportion of subjects who had new cerebral infarction was significantly lower in subjects who were assigned to cilostazol treatment (RR 0.40, 95% CI 0.32-0.49, p=0.0009). There was a lower rate of death or disability at 90 days in subjects who were assigned to cilostazol treatment (RR 0.44, 95% 0.28-0.70, p=0.011) without any heterogeneity between the trials (Cochran’s Q statistics 1.49, df 3; P = .685, I 2 =0.0%). The proportion of subjects who had any adverse events was not significantly different in subjects who were assigned to cilostazol treatment (RR 1.24, 95% 0.68-2.25, p=0.26). Conclusion: The reduction in rates of cerebral ischemia related to vasospasm and death or disability at follow-up support further evaluation of oral cilostazol in patients with aSAH in a phase III large randomized clinical trial.

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Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

Gastroenterology ◽

10.1016/s0016-5085(01)81411-6 ◽

2001 ◽

Vol 120 (5) ◽

pp. A284-A284

Author(s):

B NAULT ◽

S SUE ◽

J HEGGLAND ◽

S GOHARI ◽

G LIGOZIO ◽

...

Keyword(s):

Clinical Trials ◽

Irritable Bowel Syndrome ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Irritable Bowel ◽

Rome I

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Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials

Seminars in Oncology ◽

10.1053/sonc.2001.28598 ◽

2001 ◽

Vol 28 (6) ◽

pp. 620-625 ◽

Cited By ~ 4

Author(s):

Pierre Falardeau ◽

Pierre Champagne ◽

Patrick Poyet ◽

Claude Hariton ◽

[Eacute]ric Dupont

Keyword(s):

Clinical Trials ◽

Phase Iii ◽

Phase Iii Clinical Trials ◽

Naturally Occurring ◽

Antiangiogenic Drug

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Faculty Opinions recommendation of Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3358963.3047062 ◽

2010 ◽

Author(s):

Elfyn Thomas

Keyword(s):

Subarachnoid Hemorrhage ◽

Magnesium Sulphate ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Phase Iii ◽

Phase Iii Trial ◽

Multicenter Phase ◽

Intravenous Magnesium ◽

Double Blinded

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Animal and Human Vaccines against West Nile Virus

Pathogens ◽

10.3390/pathogens9121073 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1073

Author(s):

Juan-Carlos Saiz

Keyword(s):

Clinical Trials ◽

West Nile Virus ◽

Vaccine Development ◽

Phase Iii ◽

West Nile ◽

Specific Therapy ◽

Phase Iii Clinical Trials ◽

Neuroinvasive Disease ◽

The Us ◽

The Status

West Nile virus (WNV) is a widely distributed enveloped flavivirus transmitted by mosquitoes, which main hosts are birds. The virus sporadically infects equids and humans with serious economic and health consequences, as infected individuals can develop a severe neuroinvasive disease that can even lead to death. Nowadays, no WNV-specific therapy is available and vaccines are only licensed for use in horses but not for humans. While several methodologies for WNV vaccine development have been successfully applied and have contributed to significantly reducing its incidence in horses in the US, none have progressed to phase III clinical trials in humans. This review addresses the status of WNV vaccines for horses, birds, and humans, summarizing and discussing the challenges they face for their clinical advance and their introduction to the market.

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Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2009.10.jns09954 ◽

2010 ◽

Vol 112 (6) ◽

pp. 1235-1239 ◽

Cited By ~ 14

Author(s):

Ming-Yuan Tseng ◽

Peter J. Hutchinson ◽

Peter J. Kirkpatrick

Keyword(s):

Subarachnoid Hemorrhage ◽

Statin Therapy ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Controlled Trial ◽

Potential Interaction ◽

Repeated Measurements ◽

Unfavorable Outcome ◽

Phase Iii ◽

Neurovascular Protection ◽

Phase Iii Trials

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

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The role of future treatments in the management of neovascular age-related macular degeneration in Europe

European Journal of Ophthalmology ◽

10.1177/11206721211018348 ◽

2021 ◽

pp. 112067212110183

Author(s):

Laurent Kodjikian ◽

Carl Joe Mehanna ◽

Salomon-Yves Cohen ◽

François Devin ◽

Sam Razavi ◽

...

Keyword(s):

Clinical Trials ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Phase Iii ◽

Vascular Endothelial ◽

Real World Data ◽

Phase Iii Clinical Trials ◽

Age Related ◽

Injection Frequency ◽

Endothelial Growth Factor

Anti-vascular endothelial growth factor (VEGF) agents have transformed the management of patients with neovascular age-related macular degeneration (nAMD) over the past two decades. However, as more long-term real-world data become available, it is clear that treatment outcomes are inferior to those reported in large, controlled clinical trials. This is largely driven by undertreatment, that is, not maintaining a consistent injection frequency to achieve sustained VEGF suppression, whether due to patient non-compliance, an important injection burden, or non/incomplete anatomical response. Newer therapeutic advances under evaluation hold promise in achieving more, for less. We review the latest drugs currently in or having successfully finished phase III clinical trials, and determine their potential place in the management of patients with nAMD in Europe.

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