A phase 1 trial of riluzole in spinal muscular atrophy. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excision. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Results of the European Glaucoma Prevention Study. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Neuronavigator-guided percutaneous radiofrequency thermocoagulation in the treatment of intractable trigeminal neuralgia. Double-masked prospective ocular safety study of a lens epithelial cell antibody to prevent posterior capsule opacification. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized 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. Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. Three to 6 million people in the United States are at increased risk for developing POAG because of elevated intraocular pressure (IOP), or ocular hypertension. There is no consensus on the efficacy of medical treatment in delaying or preventing the onset of POAG in individuals with elevated IOP. Therefore, we designed a randomized clinical trial, the Ocular Hypertension Treatment Study.
                To determine the safety and efficacy of topical ocular hypotensive medication in delaying or preventing the onset of POAG.
                A total of 1636 participants with no evidence of glaucomatous damage, aged 40 to 80 years, and with an IOP between 24 mm Hg and 32 mm Hg in one eye and between 21 mm Hg and 32 mm Hg in the other eye were randomized to either observation or treatment with commercially available topical ocular hypotensive medication. The goal in the medication group was to reduce the IOP by 20% or more and to reach an IOP of 24 mm Hg or less.
                The primary outcome was the development of reproducible visual field abnormality or reproducible optic disc deterioration attributed to POAG. Abnormalities were determined by masked certified readers at the reading centers, and attribution to POAG was decided by the masked Endpoint Committee.
                During the course of the study, the mean +/- SD reduction in IOP in the medication group was 22.5% +/- 9.9%. The IOP declined by 4.0% +/- 11.6% in the observation group. At 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio, 0.40; 95% confidence interval, 0.27-0.59; P<.0001). There was little evidence of increased systemic or ocular risk associated with ocular hypotensive medication.
                Topical ocular hypotensive medication was effective in delaying or preventing the onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG. An accelerated prescription for whole brain irradiation (WBI) in the treatment of brain metastases has been reported to provide favourable survival in good performance status patients. Because it was not known whether this outcome represented patient selection or a radiobiologically advantageous regimen, a phase III study to compare overall survival following accelerated and conventional hypofractionated daily WBI was proposed.
                Ninety patients were randomized between 1996 and 2003 at two centres. The investigational arm received 40 Gy in 20 fractions of 2 Gy twice daily. The control arm received 20 Gy in 5 daily fractions. The study was designed to detect an increase in median survival of 1.75x. Outcome measures included acute side effects (WHO epilation score), neurological function (modified Barthel Index) and late toxicity (LENT/SOMA score for the CNS).
                Both arms of the study were balanced by RPA class. The median survival was 19 weeks in both arms. Subset analysis showed time to retreatment for intracranial relapse was 14 weeks in the control arm and 32 weeks in the accelerated arm (p=0.03). Trends for more severe epilation and improved neurological function in the accelerated arm did not reach statistical significance. Overall survival was associated with RPA class and colorectal pathology.
                Although accelerated WBI may improve local control this did not translate into improved overall survival in the patients studied. Few patients with amyotrophic lateral sclerosis currently receive non-invasive ventilation (NIV), reflecting clinical uncertainty about the role of this intervention. We aimed to assess the effect of NIV on quality of life and survival in amyotrophic lateral sclerosis in a randomised controlled trial.
                92 of 102 eligible patients participated. They were assessed every 2 months and randomly assigned to NIV (n=22) or standard care (n=19) when they developed either orthopnoea with maximum inspiratory pressure less than 60% of that predicted or symptomatic hypercapnia. Primary validated quality-of-life outcome measures were the short form 36 mental component summary (MCS) and the sleep apnoea quality-of-life index symptoms domain (sym). Both time maintained above 75% of baseline (T(i)MCS and T(i)sym) and mean improvement (microMCS and microsym) were measured.
                NIV improved T(i)MCS, T(i)sym, microMCS, microsym, and survival in all patients and in the subgroup with better bulbar function (n=20). This subgroup showed improvement in several measures of quality of life and a median survival benefit of 205 days (p=0.006) with maintained quality of life for most of this period. NIV improved some quality-of-life indices in those with poor bulbar function, including microsym (p=0.018), but conferred no survival benefit.
                In patients with amyotrophic lateral sclerosis without severe bulbar dysfunction, NIV improves survival with maintenance of, and improvement in, quality of life. The survival benefit from NIV in this group is much greater than that from currently available neuroprotective therapy. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage. The European Glaucoma Prevention Study (EGPS) seeks to evaluate the efficacy of reduction of intraocular pressure (IOP) by dorzolamide in preventing or delaying primary open-angle glaucoma (POAG) in patients affected by ocular hypertension (OHT).
                Randomized, double-masked, controlled clinical trial.
                One thousand eighty-one patients (age, > or =30 years) were enrolled by 18 European centers. The patients fulfilled a series of inclusion criteria, including: IOP 22 to 29 mmHg; 2 normal and reliable visual fields (on the basis of mean deviation and corrected pattern standard deviation or corrected loss variance of standard 30/II Humphrey or Octopus perimetry); normal optic disc as determined by the Optic Disc Reading Center.
                Patients were randomized to treatment with dorzolamide or placebo (the vehicle of dorzolamide).
                Efficacy end points were visual field, optic disc changes, or both. A visual field change during follow-up had to be confirmed by 2 further positive tests. Optic disc change was defined on the basis of the agreement of 2 of 3 independent observers evaluating optic disc stereo slides. The safety end point was an IOP of more than 35 mmHg on 2 consecutive examinations.
                During the course of the study, the mean percent reduction in IOP in the dorzolamide group was 15% after 6 months and 22% after 5 years. Mean IOP declined by 9% after 6 months and by 19% after 5 years in the placebo group. At 60 months, the cumulative probability of converting to an efficacy end point was 13.4% in the dorzolamide group and 14.1% in the placebo group (hazard ratio, 0.86; 95% confidence interval [CI], 0.58-1.26; P = 0.45). The cumulative probability of developing an efficacy or a safety end point was 13.7% in the dorzolamide group and 16.4% in the placebo group (hazard ratio, 0.73; 95% CI, 0.51-1.06; P = 0.1).
                Dorzolamide reduced IOP by 15% to 22% throughout the 5 years of the trial. However, the EGPS failed to detect a statistically significant difference between medical therapy and placebo in reducing the incidence of POAG among a large population of OHT patients at moderate risk for developing POAG, because placebo also significantly and consistently lowered IOP. To report interim outcome data, using all available follow-up through 5 years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS).
                Randomized clinical trial.
                Six hundred seven newly diagnosed glaucoma patients.
                In a randomized clinical trial, 607 patients with newly diagnosed open-angle glaucoma were initially treated with either medication or trabeculectomy (with or without 5-fluorouracil). After treatment onset and early follow-up, patients were evaluated clinically at 6-month intervals. In addition, quality of life telephone interviews were conducted at similar frequency to the clinical visits. Patients in both arms of CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined target pressure specific for each individual eye. Visual field (VF) scores were analyzed by time-specific comparisons and by repeated measures models.
                VF loss was the primary outcome variable in CIGTS. Secondary outcomes of visual acuity (VA), IOP, and cataract were also studied.
                On the basis of completed follow-up through 4 years and partially completed through 5 years, VF loss did not differ significantly by initial treatment. Over the entire period of follow-up, surgical patients had a greater risk of substantial VA loss compared with medical patients. However, by 4 years after treatment, the average VA in the two groups was about equal. Over the course of follow-up, IOP in the medicine group has averaged 17 to 18 mmHg, whereas that in the surgery group averaged 14 to 15 mmHg. The rate of cataract requiring removal was greater in the surgically treated group.
                Both initial medical or initial surgical therapy result in about the same VF outcome after up to 5 years of follow-up. VA loss was greater in the surgery group, but the differences between groups seem to be converging as follow-up continues. When aggressive treatment aimed at substantial reduction in IOP from baseline is used, loss of VF can be seen to be minimal in general. Because 4 to 5 years of follow-up in a chronic disease is not adequate to draw treatment conclusions, these interim CIGTS outcomes do not support altering current treatment approaches to open-angle glaucoma. Percutaneous radiofrequency thermocoagulation of the trigeminal ganglion (PRTTG) is regarded as the first choice for most patients with trigeminal neuralgia (TN) because of its safety and feasibility. However, neuronavigator-guided PRTTG has been seldom reported. The purpose of this study was to assess the safety and efficacy of neuronavigator-guided PRTTG for the treatment of intractable TN.
                Between January 2000 and December 2004, 54 patients with intractable TN were enrolled into this study and were randomly divided into two groups. The patients in navigation group (n = 26) underwent PRTTG with frameless neuronavigation, and those in control group (n = 28) received PRTTG without neuronavigation. Three months after the operation, the efficacy, side effects, and complications of the surgery were recorded. The patients in the control group were followed up for 10 to 54 months (mean, 34 +/- 5), and those in the navigation group were followed up for 13 to 58 months (mean, 36 +/- 7). Kaplan-Meier analyses of the pain-free survival curves were used for the censored survival data, and the log-rank test was used to compare survival curves of the two groups.
                The immediate complete pain-relief rate of the navigation group was 100%, whereas it was 95% in the control. The proportion of sustained pain-relief rates at 12, 24 and 36 months after the procedure were 85%, 77%, and 62% in the navigation group, and 54%, 40%, and 35% in the control. Recurrences in the control group were more common than that in the navigation group. Annual recurrence rate in the first and second years were 15% and 23% in the navigation group, and 46%, 60% in the control group. No side-effect and complication was noted in the navigation group except minimal facial hypesthesia.
                Neuronavigator-guided PRTTG is a safe and promising method for treatment of intractable TN with better short- and long-term outcomes and lower complication rate than PRTTG without neuronavigation. To evaluate the intraocular safety of an immunoconjugate (MDX-RA) developed to prevent posterior capsule opacification (PCO) in human eyes.
                St. Thomas's Hospital Eye Department, London, United Kingdom.
                Twenty-six patients had phacoemulsification and implantation of an intraocular lens (IOL). All were randomly allocated at the end of surgery to receive a 0.1 mL placebo or 0.1 mL of the immunotoxin MDX-RA intracamerally. Two doses of the drug were tested: 8 patients with a low dose (50 units), 9 patients with a high dose (100 units), and 9 with placebo. Follow-up at days 1, 14, 30, 60, 90, and 180 consisted of visual acuity measured by the Early Treatment of Diabetic Retinopathy Study test, contrast sensitivity, aqueous flare, specular microscopy of the IOL's anterior surface, and corneal endothelial counts. The percentage area of PCO was measured from retroillumination images of the posterior capsule.
                There was no decrease in corneal endothelial cell count in toxin-treated patients. Early postoperative flare, anterior chamber cell count, and corneal pachymetry were higher in toxin-treated patients. The median percentage area of PCO at 1 year was 32.0 in the placebo group, 3.8 in the low-dose group, and 7.4 in the high-dose group (P = .06).
                This prospective, randomized, placebo-controlled trial confirmed that MDX-RA is safe for intraocular use and is of potential value for further clinical trials of the prevention of PCO. 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.
Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, this trial did not provide evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in people with OAG. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. Since OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents would require long-term follow up (more than four years) in order to detect clinically meaningful effects.