Clinical trials in spinal cord injury: lessons learned on the path to translation. The 2011 International Spinal Cord Society Sir Ludwig Guttmann Lecture.

After three decades of clinical research on interventions to improve neurological outcomes in persons with spinal cord injury (SCI), the promise of preclinical discovery has yet to be translated into a consensus standard of care treatment. Nonetheless, SCI researchers remain hopeful that advances in preclinical discovery coupled with improved clinical trial performance will yield effective restorative treatment. This historical review of key studies in SCI over the past 30 years illustrates the progress that has been achieved in establishing a high standard in the conduct of clinical research while providing important lessons for improving trial design, conduct and reporting. Through application of these lessons, the performance of SCI trials can be improved, thereby shortening the pathway to successful translation and the development of effective therapies.

A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson's disease patients.

The present single center, double-blind, delayed start study was conducted to examine possible symptomatic and disease-modifying effects of GM1 ganglioside in Parkinson's disease (PD). Seventy-seven subjects with PD were randomly assigned to receive GM1 for 120 weeks (early-start group) or placebo for 24 weeks followed by GM1 for 96 weeks (delayed-start group). Washout evaluations occurred at 1 and 2 years after the end of treatment. Seventeen additional subjects who received standard-of-care were followed for comparative information about disease progression. Primary outcome was change from baseline Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. At week 24, the early-start group had significant improvement in UPDRS motor scores vs. a significant worsening of scores in the delayed-start group. The early-start group also showed a sustained benefit vs. the delayed-start group at week 72 and at week 120. Both groups had significant symptom worsening during washout. This study provides evidence that GM1 use for 24 weeks was superior to placebo for improving motor symptoms and that extended GM1 use (up to 120 weeks) resulted in a lower than expected rate of symptom progression. The data from this small study suggest that GM1 may have symptomatic and potentially disease modifying effects on PD.

Liposomes functionalized with acidic lipids rescue Aß-induced toxicity in murine neuroblastoma cells.

The loss of synapses and neurons in Alzheimer's disease (AD) is thought to be at least partly induced by toxic species formed by the amyloid beta (Aß) peptide; therefore, therapeutics aimed at reducing Aß toxicity could be of clinical use for treatment of AD. Liposomes are suitable vehicles for therapeutic agents and imaging probes, and a promising way of targeting the various Aß forms. We tested liposomes functionalized with phosphatidic acid, cardiolipin, or GM1 ganglioside, previously shown to have high Aß-binding capacity. Mimicking Aß-induced toxicity in mouse neuroblastoma cell lines, combined with administration of cell viability-modulating agents, we observed that functionalized liposomes rescued cell viability to different extents. We also detected rescue of the imbalance of GSK-3ß and PP2A activity, and reduction in tau phosphorylation. Thus, these liposomes appear particularly suitable for implementing further therapeutic strategies for AD.

GM1 ganglioside in Parkinson's disease: Results of a five year open study.

Previous work demonstrated that short-term (i.e., 16 weeks) use of GM1 ganglioside resulted in significant symptom reduction in Parkinson's disease (PD) patients. As GM1 use may have long-term benefit for PD patients, the present study was conducted to evaluate the long-term safety and efficacy of GM1 in PD patients. Twenty-six patients who concluded a previous randomized double blind placebo controlled trial of GM1 volunteered for this open-extension study. At the end of 5 years of GM1 use, patients generally had lower Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (assessed during a practically defined "off" period) than at baseline prior to randomization into the original study. A similar result was found for UPDRS Activities of Daily Living scores. Performance of timed motor tests also remained mostly stable over the 5 year observation period. No consistent clinically significant changes in blood chemistry, hematologic indices or urine chemistry were noted over the course of this study. These results suggest that long-term GM1 use by PD patients is safe and may provide some clinical benefit for PD patients. Additional study is required to more completely assess the degree to which GM1 treatment may be a symptomatic and/or disease-modifying agent for treatment of PD.

Ganglioside GM1 (porcine) ameliorates paclitaxel-induced neuropathy in rats.

BACKGROUND: Paclitaxel, an anti-neoplastic agent effective against several solid tumors, has several side effects including peripheral neuropathy. So far, there are no effective treatments for this complication. Monosialic acid ganglioside (GM1) has been shown to protect neurons against injuries and degeneration. However, its efficacy in the treatment of paclitaxel-induced neuropathy has not been verified. OBJECTIVE: To evaluate the effect of porcine GM1 on neurophysiological abnormalities in rats receiving paclitaxel. MATERIAL AND METHOD: Fifty-four Wistar rats were divided into control, vehicle for paclitaxel (Cremophor EL), paclitaxel, and paclitaxel + GM1 groups. Paclitaxel 16 mg/kg/week for five consecutive weeks was given intraperitoneally. Treatment with 30 mg/kg 5 days per week of GM1 was started 3 days prior to the first dose and continued until 3 days after the last dose of paclitaxel. Tail and hind paw thermal thresholds including tail motor nerve conduction velocity (MNCV) were measured prior to and after the start of treatments. Histopathology of the sciatic nerve was also examined. RESULTS: Paclitaxel alone induced thermal hypoalgesia and reduced tail MNCV Less severe abnormalities were also found with the vehicle. GM1 appeared to prevent the development of hypoalgesia and ameliorated the decreased MNCV without any evidence of Guillain-Barre Syndrome. Mild endoneurial edema and axonal degeneration in the sciatic nerve sections were seen in paclitaxel treated rats. Microtubule accumulation and activated Schwann cell were also presented in the paclitaxel treated groups. CONCLUSION: These data suggest that porcine GM1 may be useful in the prevention and treatment of paclitaxel-induced neuropathy. However the adverse effect of Cremophor EL should be of concern.

Ganglioside mimicry as a cause of Guillain-Barré syndrome.

PURPOSE OF REVIEW: Campylobacter jejuni is the most frequent agent of antecedent infection in an axonal variant of Guillain-Barré syndrome, acute motor axonal neuropathy, and anti-GM1 or anti-GD1a IgG antibody is also associated with acute motor axonal neuropathy. Molecular mimicry has been found between human GM1 ganglioside and the lipo-oligosaccharide of C. jejuni isolated from an acute motor axonal neuropathy patient. Progress has been made in Guillain-Barré syndrome research, especially on acute motor axonal neuropathy subsequent to C. jejuni enteritis. RECENT FINDINGS: Sensitization of rabbits with C. jejuni lipo-oligosaccharide, as well as GM1, induced the production of anti-GM1 IgG antibody, and the subsequent development of acute flaccid paralysis. Pathological changes in rabbit peripheral nerves were identical to those seen in human acute motor axonal neuropathy. These findings provide conclusive evidence that molecular mimicry is a cause of human autoimmune disease. Ganglioside-like lipo-oligosaccharide is synthesized by sialyltransferase Cst-II, N-acetylgalactosaminyl-transferase CgtA, and galactosyltransferase CgtB. There is a strong association between the simultaneous presence of these genes and Guillain-Barré syndrome-associated C. jejuni strains. Knockout mutants of C. jejuni genes involved in lipo-oligosaccharide sialylation had reduced reactivity with anti-GM1 sera from Guillain-Barré syndrome patients, and did not induce an anti-GD1a IgG antibody response in mice. Lipo-oligosaccharide biosynthesis genes appear to be essential for the induction of anti-GM1 or anti-GD1a IgG antibody and the subsequent development of acute motor axonal neuropathy. SUMMARY: The concept that carbohydrate mimicry causes autoimmune disease provides a clue to the resolution of the pathogenesis of other immune-mediated diseases.

Pharmacological therapy after acute cervical spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment with methylprednisolone for either 24 or 48 hours is recommended as an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit. GM-1 GANGLIOSIDE: STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment of patients with acute spinal cord injuries with GM-1 ganglioside is recommended as an option without demonstrated clinical benefit.

Promising pharmacological agents in the management of acute spinal cord injury.

The search for a pharmacologic treatment of acute spinal cord injury (SCI) dates back to the 1960s. It was not until 1990 that the pharmacologic agent methylprednisolone demonstrated improved outcomes in humans. Methylprednisolone has shown superiority to placebo in humans in two large, multicenter trials, and is the standard of care thus far. Other potentially useful agents include tirilazad, ganglioside (GM-1), and naloxone. Additional studies are needed for these agents to determine the optimal dose and timing of administration.

GM1 ganglioside in the treatment of Parkinson's disease.

Since the early 1980s, numerous studies have been reported by laboratories around the world documenting the beneficial effects of GM1 ganglioside treatment on the damaged dopamine system in various animal and in vitro models. Based on the strength of these data, the first clinical studies designed to assess the efficacy and safety of chronic GM1 use in the treatment of Parkinson's disease were performed. In a double-blind placebo-controlled study, significant improvements in GM1-treated patients were demonstrated in clinical motor ratings, timed tests of motor function, activities of daily living, and some aspects of neuropsychological functioning. Patients who have elected to continue using GM1 in an open extension trial have either continued to improve over time or have shown initial functional improvements and their disease has remained stable (i.e., no symptom progression) after two years. These results suggest that long-term use of GM1 is safe and may work to partially reverse the degenerative process in established Parkinson's disease patients.

GM1 ganglioside for acute ischemic stroke. Trial design issues.

GM1 ganglioside decreases the severity of ischemic brain lesions in experimental models, although the mechanism is uncertain. In clinical trials involving patients with stroke, efficacy has been reported in some but not in others. However, some of the latter also showed efficacy after analyses not planned before the trial began. Analyses of the trials done to date revealed design differences sufficiently large so as to preclude meta-analysis of the results. Moreover, flaws in these studies may account for some of their failure to demonstrate that GM1 therapy is efficacious in ischemic stroke. Several of these flaws are discussed, including small sample size; attrition of the study cohort; inclusion of stroke severity and type that made demonstrations of a beneficial effect difficult; use of inappropriate clinical and outcome measuring instruments; delay in enrollment; inappropriate statistical analyses; inadequate dose; inappropriate route of administration; a too short duration of treatment. Improvements in these design features in future clinical trials of GM1 may yet demonstrate efficacy of this drug in acute ischemic stroke.

Intracerebroventricular administration of GM1 ganglioside to presenile Alzheimer patients.

We have conducted a preliminary study of the optimum conditions for a therapeutic effect of ganglioside GM1 in Alzheimer's disease. Five patients with the early onset form of Alzheimer's disease (AD type I) received the ganglioside by intracerebroventricular administration for 12 months. Bilateral stereotactic punction of the frontal horns of the ventricular system was performed, and shunt catheters were implanted and connected to a programmable pump. The optimum GM1 dose varied between 20 and 30 mg/24 h. Neurological neuropsychological, psychiatric and neurochemical examinations were performed 7 days before surgery and on days 30, 90, 180 and 360. No patient found the surgery difficult and no patient or relative regretted that they participated in the study. The patients became more active and safer in relation to others and to performance of various activities from day 90. The cerebrospinal fluid level of the monoamine metabolites homovanillic acid and 5-hydroxyindoleacetic acid and the neuropeptide somatostatin increased.

GM1 ganglioside treatment of Parkinson's disease: an open pilot study of safety and efficacy.

We performed an open-label study testing the effects of GM1 ganglioside on 10 Parkinson's disease (PD) patients. Patients received 1,000 mg of GM1 by IV infusion after the last of three baseline functional assessments. Patients then self-administered GM1 at a dose of 200 mg/d, by subcutaneous injection, for 18 weeks. Under these conditions, GM1 ganglioside proved to be safe and well tolerated. There were no serious adverse events and none of the patients developed elevated anti-GM1 antibody titers. Improvements on at least some functional measures were present in most patients, beginning after 4 to 8 weeks of GM1 treatment. When functional improvements occurred, they lasted for the duration of the study. These results suggest that GM1 ganglioside is well tolerated and may be a useful adjunct to the treatment of PD, and that a double-blind, placebo-controlled study is now warranted.

Early treatment of stroke with monosialoganglioside GM-1. Efficacy and safety results of the Early Stroke Trial.

BACKGROUND AND PURPOSE: The Early Stroke Trial (EST) is a randomized, double-blind, placebo-controlled trial to assess the effect of monosialoganglioside GM-1 in improving recovery in patients who experienced an ischemic supratentorial stroke. METHODS: Sixteen clinical centers recruited 805 patients, of whom 792 were confirmed to be eligible. Treatment, consisting of a first dose of either 200 mg GM-1 or placebo, was initiated within 5 hours of the onset of stroke; a second dose of either 100 mg GM-1 or placebo was administered 12 hours later. Thereafter, patients received a daily injection of 100 mg GM-1 or placebo intravenously from day 2 through 10 and intramuscularly from day 11 through 21. Patients were followed up for a total of 4 months. RESULTS: Survival was similar in the two treatment groups. Improvement in neurological status, as measured by the change in Canadian Neurological Scale score between baseline and 4-month assessments, was greater in the group receiving GM-1; the observed difference between treatment groups was 0.22 (P = .06). A post hoc analysis in the subgroup of patients treated within 4 hours showed a statistically significant difference, with Canadian Neurological Scale mean improvement of 0.41 (P = .016). GM-1 use was not associated with differences in frequency, nature, or severity of adverse experiences. CONCLUSIONS: These findings suggest that GM-1 is safe in the dose and treatment schedule used and that its efficacy in ischemic stroke is greater when given soon after onset of stroke.

Ganglioside GM1 in acute ischemic stroke. The SASS Trial.

BACKGROUND AND PURPOSE: We sought to assess the safety and efficacy of ganglioside GM1 in acute (< or = 48 hours), anterior circulation ischemic stroke. METHODS: We screened more than 5000 patients at 13 centers in a randomized, double-blind, placebo-controlled, parallel-treatment, clinical trial and enrolled 287 patients. They received 100 mg GM1 or placebo intramuscularly daily for 28 days and were evaluated regularly for 84 days. Number of deaths, the Toronto Stroke Scale, and the Barthel Index were primary outcomes; improvements on the Fugl-Meyer Scale and on a neuropsychological battery were secondary outcomes. RESULTS: The groups were balanced for severity, side of stroke, age, sex, race, years of schooling, prior illness, and depression scores. Analyzable data were available on 275 patients; 217 patients completed the trial. Protocol-specified primary and secondary outcome measures showed no significant difference between treatment arms. However, improvement from baseline in the motor component of the Toronto Stroke Scale favored the GM1-treated group at day 28 when GM1 treatment stopped (P = .020); at day 84, the difference still favored the GM1-treated group (P = .057). All 10 components of the Barthel Index, the Fugl-Meyer Scale, and four of the five tests in the neuropsychological battery also favored the GM1 group. Adverse experiences were similar in the two groups. CONCLUSIONS: GM1 is safe. However, since only certain post hoc tests showed statistically significant differences or trends favoring GM1, another clinical trial is needed to demonstrate efficacy.

GM-1 ganglioside and motor recovery following human spinal cord injury.

Neurological deficit resulting from spinal cord injury varies widely in severity, ranging from transient abnormal reflexes to lifelong complete absence of motor and sensory function. Medical treatment to aid damaged neurons to recover function has been very limited; therapeutic efforts have focused primarily on initial stabilization of fractures, hemodynamic resuscitation, and then aggressive rehabilitation to enhance the full development of any remaining neuronal activity. Pharmacological treatment to improve restoration of neurological function may be possible, however, as indicated by many animal studies and a few clinical studies with a number of agents. A recent clinical trial of GM-1 ganglioside conducted in patients with spinal cord injuries showed that GM-1 ganglioside enhanced the recovery of neurological function 1 year after major spinal cord injury. In addition to GM-1 ganglioside treatment, these patients received aggressive medical and surgical treatment, as well as methylprednisolone. Neurological recovery was assessed with the Frankel scale and the American Spinal Injury Association (ASIA) motor scale. The findings show enhanced motor recovery compared with placebo in the lower extremities, but not in the upper extremities, over time. This corresponds to improved function of axons passing through the site of injury. Analysis of individual motor groups showed that neurological recovery in the GM-1 ganglioside-treated patients increased in initially paralyzed muscles, enabling them to regain useful motor function; paretic muscles were not found to be strengthened. The study provides the basis for larger studies of GM-1 ganglioside and methylprednisolone, which are currently under way.

Design and baseline results of the monosialoganglioside early stroke trial. The EST Study Group.

BACKGROUND AND PURPOSE: The Early Stroke Trial is a randomized, placebo-controlled, double-masked, multicenter study to assess the safety and efficacy of monosialoganglioside in patients who have suffered an ischemic stroke of the cerebral hemispheres. METHODS: Only patients who could be evaluated and treated within 5 hours after the onset of stroke were considered; within each center, subjects were stratified by age, sex, and clinical severity. Patients were randomly allocated to receive a specified sequence of intravenous and intramuscular doses of either monosialoganglioside or identical-appearing placebo for 21 days. Patients were followed up for 4 months after randomization. Neurological status was measured primarily by using the Canadian Neurological Scale. After assessing the effect of treatment on survival, the principal measure of efficacy will be the change in neurological status between baseline and the 4-month follow-up among survivors. RESULTS: Sixteen clinical centers, 15 in Europe and one in North America, entered a total of 792 eligible patients during a 36-month recruitment period (from May 1987 to April 1990). In our series there were more men than women, and the relative frequency of patients increased with advancing age. The most frequently associated cardiovascular conditions were hypertension, atrial fibrillation, and peripheral vascular disease. Approximately 46% of the patients were admitted to a hospital within 1 hour and 81%, within 2 hours after the onset of stroke. About 22% first received the study treatment within 3 hours and 57%, within 4 hours. CONCLUSIONS: This study demonstrates the feasibility of large-scale trials with the onset of treatment within 5 hours after an ischemic stroke.

Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside.

BACKGROUND: Spinal-cord injury is devastating; until recently, there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons. METHODS: A prospective, randomized, placebo-controlled, double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study, 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses, with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100, derived from strength tests of 20 specific muscles, each scored from 0 to 5). RESULTS: There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0, 1, 2, and 3 grades in 13, 4, 1, and 0 patients, respectively, in the placebo group and 8, 1, 6, and 1 patients, respectively, in the GM-1 group; P = 0.034 by the Cochran-Mantel-Haenszel chi-square test). The GM-1-treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles. CONCLUSIONS: This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted, however, before GM-1 is considered efficacious and safe in treating spinal-cord injury.

Pharmacokinetics of GM1 ganglioside following parenteral administration.

The pharmacokinetic parameters of monosialotetrahexosylganglioside (GM1) have been determined in healthy volunteers at 3 dose levels: 100, 200, 300 mg. Each dose was administered to separate groups of 12 volunteers. GM1 levels were determined in plasma, urine, and faeces by a method based on the property of the cholera toxin beta subunit to react specifically with GM1 ganglioside. A non-compartmental model was applied to determine standard pharmacokinetic parameters. The average AUC increased with dose (1002 +/- 121.2, 1306 +/- 146.1, 3155 +/- 121.6 micrograms mL-1 h after 100, 200, 300 mg, respectively). Plasma clearance was less than 3 mL min-1 and the distribution volume was close to the plasma volume (on average between 4.3 and 7.2 L). Mean residence time was about 43 h for all doses. GM1 was not detected in urine, while in faeces the amount of GM1 determined was similar to the baseline values obtained before dosing.