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Safety and effectiveness of a novel neuroprotectant, KUS121, in patients with non-arteritic central retinal artery occlusion: An open-label, non-randomized, first-in-humans, phase 1/2 trial.
Ikeda, HO, Muraoka, Y, Hata, M, Sumi, E, Ikeda, T, Nakagawa, T, Abe, H, Tada, H, Morita, S, Kakizuka, A, et al
PloS one. 2020;(2):e0229068
Abstract
Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 μg (low-dose) in the first three patients and 50 μg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.
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Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.
Woo, PYM, Ho, JWK, Ko, NMW, Li, RPT, Jian, L, Chu, ACH, Kwan, MCL, Chan, Y, Wong, AKS, Wong, HT, et al
BMC neurology. 2020;(1):401
Abstract
ASBTRACT BACKGROUND There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). 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): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.
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A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study.
Gold, J, Marta, M, Meier, UC, Christensen, T, Miller, D, Altmann, D, Holden, D, Bianchi, L, Adiutori, R, MacManus, D, et al
Multiple sclerosis and related disorders. 2018;:123-128
Abstract
BACKGROUND Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. OBJECTIVES To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. METHODS This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. RESULTS All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. CONCLUSIONS Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.
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Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial.
Fehlings, MG, Nakashima, H, Nagoshi, N, Chow, DS, Grossman, RG, Kopjar, B
Spinal cord. 2016;(1):8-15
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Abstract
BACKGROUND Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). OBJECTIVES The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4-C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. SETTING Acute trauma centers worldwideMethods:A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025. RESULTS Currently enrolling in 11 centers. CONCLUSION This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI.
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Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.
Fauchère, JC, Koller, BM, Tschopp, A, Dame, C, Ruegger, C, Bucher, HU, ,
The Journal of pediatrics. 2015;(1):52-7.e1-3
Abstract
OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.
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Methodology of the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) phase 3 trial: Part 2 - prehospital study methods.
Saver, JL, Starkman, S, Eckstein, M, Stratton, S, Pratt, F, Hamilton, S, Conwit, R, Liebeskind, DS, Sung, G, Sanossian, N, et al
International journal of stroke : official journal of the International Stroke Society. 2014;(2):220-5
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RATIONALE In acute stroke, the volume of salvageable brain tissue is maximal at onset and declines rapidly with time. Prehospital start of clinical trial interventions would enable delivery of neuroprotective agents, such as magnesium sulfate, to stroke patients in the hyperacute period when they are potentially most effective. AIMS A broad aim of the FAST-MAG study is to develop and validate techniques to perform pivotal trials of neuroprotective therapies for acute stroke in the prehospital setting. In tandem with an accompanying general trial design article, this manuscript provides a detailed overview of several novel prehospital study methods employed in the NIH FAST-MAG Trial. DESIGN Multicenter, randomized, double-blinded, placebo-controlled, pivotal clinical trial. Special Prehospital Procedures Distinctive prehospital methods deployed in FAST-MAG include: identifying likely stroke patients using the Los Angeles Prehospital Stroke Screen; eliciting explicit informed consent from patients or on scene legally authorized representatives via cellphone discussion with off-scene physicians; paramedic rating of pretreatment stroke severity using the Los Angeles Motor Scale; assigning patients to a study arm using blinded, pre-encounter randomization; facilitating continuity of study infusion from the field to the ED by stocking ambulances with study kits including both field and hospital doses; and electronic fax consent signature documentation by geographically separated subjects and enrolling physicians. DISCUSSION The suite of prehospital trial methods developed for the FAST-MAG Trial enable enrollment of patients in very early time windows, including the hyperacute, 'golden hour' period immediately after stroke onset.
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[An impact of neuroprotective therapy on blood rheological and morphodensitometric parameters in patients with chronic cerebral ischemia].
Anisimova, AV, Kolesnikova, TI, Iutskova, EV, Galkin, SS, Zimin, IA
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2014;(10):72-80
Abstract
OBJECTIVE To explore the dynamics of aggregation of platelets and erythrocytes, their deformity and computed morphodensitometric parameters in patients with chronic cerebral ischemia, stages I and II, treated with cerebrolysin. MATERIAL AND METHODS We examined 300 patients, including 87 men and 213 women, aged from 30 to 55 years. Patients were randomized by disease stage and treatment (standard treatment with or without cerebrolysin). The dynamics of neurological and emotional status as well as cognitive functions and results of laboratory studies were assessed. RESULTS AND CONCLUSION Along with the total positive effect of cerebrolysin on the clinical picture, additional mechanisms of its action (antiaggregant, antihypoxic and membranotropic) improved the erythrocyte morphodensitometric parameters, hemostatic, hemorheological and blood gas transport characteristics, in particular on the microcirculatory level.
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Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial.
Dorhout Mees, SM, Algra, A, Vandertop, WP, van Kooten, F, Kuijsten, HA, Boiten, J, van Oostenbrugge, RJ, Al-Shahi Salman, R, Lavados, PM, Rinkel, GJ, et al
Lancet (London, England). 2012;(9836):44-9
Abstract
BACKGROUND Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. METHODS We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome-defined as a score of 4-5 on the modified Rankin Scale-3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). FINDINGS 1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85-1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86-1·08). INTERPRETATION Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. FUNDING Netherlands Heart Foundation, UK Medical Research Council.
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Ginsenoside-Rd improves outcome of acute ischaemic stroke - a randomized, double-blind, placebo-controlled, multicenter trial.
Liu, X, Wang, L, Wen, A, Yang, J, Yan, Y, Song, Y, Liu, X, Ren, H, Wu, Y, Li, Z, et al
European journal of neurology. 2012;(6):855-63
Abstract
BACKGROUND AND PURPOSE Ginsenoside-Rd is a receptor-operated calcium channel antagonist and has shown promise as a neuroprotectant in our phase II study. As an extended work, we sought to confirm its efficacy and safety of Ginsenoside-Rd in patients with acute ischaemic stroke. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 390 patients with acute ischaemic stroke in a 3:1 ratio to receive a 14-day intravenous infusion of Ginsenoside-Rd or placebo within 72 h after the onset of stroke. Our primary end-point was the distribution of disability scores on the modified Rankin scale (mRs) at 90 days. RESULTS The efficacy analysis was based on 386 patients (Ginsenoside-Rd group: 290; placebo group: 96). Ginsenoside-Rd significantly improved the overall distribution of scores on the mRs, as compared with the placebo (P = 0.02; odds ratios [OR], 1.74; 95% confidence interval [CI], 1.08-2.78). There were significant differences between the two groups when we categorized the scores into 0-1 vs. 2-5 (P = 0.01; OR, 2.32; 95% CI, 1.23-4.38; 66.8% vs. 53.1%). It also improved the National Institutes of Health Stroke Scale (NIHSS) at 15 days [P < 0.01; least squares mean (LSM), -0.77; 95% CI, -1.31 to -0.24]. Mortality and rates of adverse events were similar in the two groups. CONCLUSIONS Ginsenoside-Rd improved the primary outcome of acute ischaemic stroke and had an acceptable adverse-event profile.
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Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.
Fehlings, MG, Wilson, JR, Frankowski, RF, Toups, EG, Aarabi, B, Harrop, JS, Shaffrey, CI, Harkema, SJ, Guest, JD, Tator, CH, et al
Journal of neurosurgery. Spine. 2012;(1 Suppl):151-6
Abstract
In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.