A phase 1 trial of riluzole in spinal muscular atrophy. Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial.
Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease.
                To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy.
                Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms.
                Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities.
                Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA. Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8.
                A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.
                Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs. We performed a randomized double-blind placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of cisplatin (CDDP)-induced neurotoxicity.
                Fifty patients with advanced gastric cancer treated with a weekly CDDP-based regimen were included in this study. In patients randomized to receive GSH, GSH was given at a dose of 1.5 g/m2 in 100 mL of normal saline solution over a 15-minute period immediately before CDDP administration, and at a dose of 600 mg by intramuscular injection on days 2 to 5. Normal saline solution was administered to placebo-randomized patients. Clinical neurologic evaluation and electrophysiologic investigations have been performed at baseline and after 9 (CDDP dose, 360 mg/m2) and 15 (CDDP dose, 600 mg/m2) weeks of treatment.
                At the 9th week, no patients showed clinically evident neuropathy in the GSH arm, whereas 16 patients in the placebo arm did. After the 15th week, four of 24 assessable patients in the GSH arm suffered from neurotoxicity versus 16 of 18 in the placebo arm (P = .0001). In confirmation of this neuroprotective effect, the neurophisiologic investigations, based on the evaluation of the median, ulnar, and sural sensory nerve conduction, showed a statistically significant reduction of these values in the placebo arm but not in the GSH arm, above all considering potential amplitude. In this trial, GSH also reduced hemotransfusion requirements (32 v 62 hemotransfusions) and treatment delay (55 v 94 weeks). The response rate was 76% (20% complete response) in the GSH group and 52% (12% complete response) in the placebo arm, confirming preliminary reports about the lack of reduction in activity of cytotoxic drugs induced by GSH.
                This study provides evidence that GSH is a promising and effective new drug for the prevention of CDDP-induced neuropathy, and that it does not reduce the clinical activity of chemotherapeutic drugs. ALS is a progressive motor neuron disease with no effective treatment. The anti-excitotoxic drug riluzole (100 mg/day) has been shown to decrease mortality and muscular deterioration in ALS patients. To confirm and extend the therapeutic effect of riluzole, we performed a double-blind, placebo-controlled, multicenter, international, dose-ranging (50, 100, 200 mg/day), stratified study in 959 ALS outpatients treated for up to 18 months. Primary efficacy criterion was survival and the effect of treatment was analyzed before (Wilcoxon and log rank tests) and after adjustment on prognostic factors (Cox model). Secondary efficacy criterion was disease progression assessed through change in functional measures. Tracheostomy-free survival rates were: 50.4% (placebo), 55.3% (50 mg riluzole) (p = 0.23, Wilcoxon test; p = 0.25, log-rank test), 56.8% (100 mg riluzole) (p = 0.05, Wilcoxon test; p = 0.076, log-rank test), and 57.8% (200 mg riluzole) (p = 0.061, Wilcoxon test; p = 0.075, log-rank test). At the end of the 18-month study, there was a significant dose-related decrease in risk of death or tracheostomy (p = 0.04). Adjustment for baseline prognostic factors showed a 35% decreased risk of death with the 100-mg dose compared with placebo (p = 0.002). No significant treatment effects were detected for the functional assessments. The most frequent dose-related adverse events included nausea, asthenia, and elevated liver enzyme levels. This study confirms the therapeutic effect of riluzole in a large representative ALS sample, over an 18-month period. Riluzole is well tolerated and decreases the risk of death or tracheostomy in ALS patients. Elucidation of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.
                To examine the efficacy of gavestinel (GV150526), an antagonist of the glycine site of the N-methyl-D-aspartate receptor, as a neuroprotective therapy for acute ischemic stroke when administered within 6 hours of symptom onset.
                The Glycine Antagonist in Neuroprotection (GAIN) Americas trial, a randomized, double-blind placebo-controlled trial with enrollment from April 1998 to October 1999.
                One hundred thirty-two hospital centers across the United States and Canada.
                The primary efficacy population consisted of 1367 ischemic stroke patients with a predefined level of limb weakness and functional independence prior to stroke, stratified at randomization by age (</=75 vs >75 years) and initial stroke severity (National Institutes of Health [NIH] Stroke Scale scores of 2-5, 6-13, or >/=14).
                Patients were randomly assigned to receive an intravenous loading dose (800 mg) plus 5 maintenance doses (200 mg every 12 hours) of gavestinel (n = 701) or placebo (n = 666) for 3 days.
                Functional capability at 3 months, measured by the Barthel Index (BI), with scores trichotomized as dead/0-55, 60-90, and 95-100, compared between the gavestinel and placebo groups.
                Treatment groups were well matched for baseline characteristics. For each group, median NIH Stroke Scale was 12, median age was 72 years, and median time to treatment was 5.2 hours. No statistically significant improvement on the 3-month BI trichotomy was demonstrated for gavestinel (P =.79). The proportion who were functionally independent (BI score = 95-100) was 39% in the gavestinel group and 37% in the placebo group. No statistically significant difference in 3-month survival was observed using Kaplan-Meier curves (P =.11). No other secondary end point suggested an advantage for gavestinel. Among the 333 patients (24%) who received recombinant tissue-type plasminogen activator, there was also no benefit for gavestinel (P =.53). There were no serious safety issues.
                In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months. CP-101,606 is a postsynaptic antagonist of the glutamate-mediated NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When administered intravenously (i.v.) at the time of injury, CP-101,606 is neuroprotective in animal models of traumatic brain injury (TBI) and ischemia. Minimal adverse effects have been observed in normal human volunteers given i.v. doses of up to 3 mg/kg/hr for 72 hours. The objective of the present clinical trial was to assess the safety, pharmacokinetics, and tolerability of CP-101,606 infused for various times in patients who had suffered either an acute moderate or mild TBI (Glasgow Coma Score 9-14) or hemorrhagic stroke. Patients began receiving treatment within 12 hours of brain injury. A total of 53 subjects (45 with TBI and 8 with stroke) were randomized in a double-blind fashion to receive CP-101,606 or placebo (4 drug: 1 placebo). Drug/placebo was administered by i.v. infusion (0.75 mg/kg/hr) for 2 hours and then stopped (n = 25) or continued for 22 hours (n = 4) or 70 hours (n = 24) at a rate of 0.37 mg/kg/hr. Mean plasma drug concentrations were well above the predicted therapeutic concentration of 200 ng/ml within two hours of initiating treatment and were sustained as long as drug was infused. All the patients tolerated their drug/placebo treatment, and there were no clinically significant cardiovascular or hematological abnormalities in either group. A Neurobehavioral Rating Scale, used to detect personality changes and behavioral disturbances, indicated that all subjects showed an improvement from their postinjury, predosing baseline but did not significantly differ from each other with respect to type of head injury and/or treatment with drug or placebo. Modified Kurtzke Scoring also showed a similar pattern of improvement irrespective of type of head injury or drug/placebo treatment. This study suggests that CP-101,606, infused for up to 72 hours has no psychotropic effects and is well-tolerated in patients who have sustained a mild or moderate TBI or hemorrhagic stroke. Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole.
                160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion.
                Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance.
                Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population. GV150526 is a novel glycine site antagonist at the N-methyl-D-aspartate receptor complex. It is a potent neuroprotective agent in animal models of stroke, including permanent middle cerebral artery occlusion in the rat. Unlike antagonists at the glutamate ligand binding site, GV150526 appears to be free of hemodynamic and central nervous system adverse effects. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of loading and maintenance infusions of GV150526 in patients with acute stroke.
                This was a randomized, placebo-controlled, parallel-group, ascending-dose study conducted in 2 phases. In part A of the study, loading doses of 50, 100, 200, 400, or 800 mg were administered. In part B, the maximum loading dose from part A was followed by maintenance infusions (5 infusions at 12-hour intervals), aiming to maintain neuroprotective levels. Safety data were collected throughout. The study was not designed to test efficacy, but outcome data (Barthel Index and National Institutes of Health Stroke Scale) were collected.
                Sixty-six patients were recruited to the study over 11 months; 18 patients received placebo. GV150526 was well tolerated by the 48 patients who received it. There was no excess of central nervous system or hemodynamic adverse events compared with placebo. Minor abnormalities in liver function tests were observed in association with the higher maintenance doses tested. Four of 7 patients receiving the 800-mg loading dose followed by 400 mg BID and 1 of 6 patients who received the 200-mg BID maintenance dose showed a small rise in bilirubin, and 3 patients had increases in transaminases; the mean values at 72 hours remained under twice the upper limit of normal. These changes were asymptomatic and resolved within 10 days.
                GV150526 is an emerging neuroprotective agent, with no apparent significant central nervous system or hemodynamic effects. Dose-limiting effects appear to be restricted to mild transient and asymptomatic rises in bilirubin and/or transaminases, primarily observed at high maintenance doses, and there were no findings that should preclude further clinical development. Seventy-five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic encephalopathy. The control group received 4 g of enteral neomycin daily along with 25% dextrose by a central venous catheter. The experimental group received a placebo resembling neomycin and isocaloric dextrose plus a modified amino acid mixture enriched with branched-chain amino acids to 36% and deficient in aromatic amino acids and methionine. Thirty patients in the F080 group and 29 in the control group completed the trial. The group receiving the modified amino acid mixture demonstrated a statistically significant improvement in encephalopathy as compared to the neomycin group, while maintaining nitrogen equilibrium. Survival and discharge from the hospital were statistically greater in the group treated with the modified amino acid solution and hypertonic dextrose. Treatment of hepatic encephalopathy in the presence of hepatic decompensation with an amino acid solution formulated for its treatment seems to produce faster, more complete recovery with improved capacity for nutritional support.
There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reduction of death or dependence by 8% or more has been excluded for gavestinel and lubeluzole, which contribute most of the data for this review. However, mechanistic understanding of neuroprotection is too poor to extrapolate from these two failed development plans to all glutamate modulators. Further clinical trials of neuroprotective agents remain justified, since confidence limits around estimates of effect remain wide for most agents, and cannot reliably exclude benefit. Although numbers of patients are too small to confirm or refute a trend towards increased mortality with some NMDA antagonists, further commercial development of these agents is exceedingly unlikely.