High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation. Double blind cross over trial with deprenyl in amyotrophic lateral sclerosis. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis.
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. Increasing evidence suggests 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 paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS.
                Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment.
                After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole.
                Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints. The activity of glutathione peroxidase (GSH-Px) as well as the activities of other antioxidative enzymes: CuZn superoxide dismutase (CuZn SOD), catalase (CAT), glutathione reductase (GR) in erythrocytes, as well as the activity of plasma glutathione transferase (GST), and the plasma content of vitamins E and C were evaluated in 35 sporadic amyotrophic lateral sclerosis (sALS) patients. The results revealed significantly decreased activity of both GSH-Px and CuZn SOD in sALS patients compared with the control. These data showed that a disturbed oxidative/antioxidative balance in sALS patients exists not only in motoneurons but also in the blood. The effect of exogenously administered selenium (Se), antioxidants, amino acids, a Ca2+ channel blocker such as nimodipine, and their combination in Alsamin was evaluated by screening parameter levels after 9 weeks of treatment. Only the use of all components together enhanced the activity of GSH-Px and the amount of vitamin E in sALS patients. Judging by the results of clinical trials, this treatment slowed the course of the disease. In this paper we present results from a double blind cross over trial with deprenyl, a selective and irreversible monoamine oxidase-B (MAO-B) inhibitor, in 10 patients suffering from amyotrophic lateral sclerosis. The patients were randomised in such a way that half of the patients started with the active drug and half with the placebo treatment. Each patient was given 10 mg deprenyl (eldepryl, 10 mg tablets) per day for 12 weeks and then placebo for the same length of time. There was a drug free period of 12 weeks between the courses. The neurological status of the patients were evaluated every six weeks by using Norris, spinal and bulbar scores and it was observed that all cases deteriorated in their clinical status during the 36 weeks of the controlled study. MAO-B activity in blood platelets was completely inhibited during treatment with deprenyl. In the preliminary analysis performed so far, no obvious retardation in the progress of the disease could be observed with deprenyl treatment. Free radicals may play a role in the pathogenesis of amyotrophic lateral sclerosis.
                To investigate the efficacy of the free radical scavenging agent acetylcysteine in patients with amyotrophic lateral sclerosis.
                Randomized, double-blind, placebo-controlled clinical trial to assess the effect of treatment with acetylcysteine on survival and disease progression.
                A university hospital referral setting.
                One hundred ten consecutive patients who fulfilled the diagnostic criteria for amyotrophic lateral sclerosis, followed up at monthly intervals for 12 months.
                Acetylcysteine or placebo in a dose of 50 mg/kg per day subcutaneously for 12 months.
                Survival.
                After 12 months, 35 patients (65%) treated with acetylcysteine and 30 (54%) given placebo were still alive (hazard ratio, 0.74 in the acetylcysteine group relative to the placebo group; 95% confidence interval, 0.41 to 1.33; log-rank test, P = .31). Rates of disease progression, as expressed by decline in muscle strength, pulmonary function, disability, and bulbar function were similar in both groups. In the subgroup of 81 patients with limb onset of the disease, 28 patients (74%) in the acetylcysteine group and 22 (51%) in the placebo group survived 12 months (hazard ratio, 0.50; 95% confidence interval, 0.24 to 1.04; P = .06). In the bulbar subgroup of 29 patients, seven patients (44%) receiving acetylcysteine and eight (62%) receiving placebo were alive at the end of the study (hazard ratio, 1.66; 95% confidence interval, 0.56 to 4.99; P = .36).
                In this trial, treatment with the free radical scavenger acetylcysteine did not result in a major increase in 12-month survival or a reduction in disease progression in patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.
                We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.
                Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.
                CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.
There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect but this was not supported in our analysis. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trials. The high tolerance and safety, and relatively low cost of vitamins C and E, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.