Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial.

BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.

Eye-controlled, power wheelchair performs well for ALS patients.

BACKGROUND: Our pilot study tested the feasibility and performance of an eye-controlled power wheelchair for amyotrophic lateral sclerosis (ALS) patients. METHODS: In this prospective pilot study, participants drove the wheelchair three times around an indoor course. We assessed the time to complete the course; starting and stopping on command; turning 90, 135, and 180 degrees; time to backup; and obstacle negotiation. Following their use of the wheelchair, subjects were given a questionnaire to assess user experience. RESULTS: Twelve patients participated, and all were able to complete three trials without difficulty. Eight participants completed all of the individual tasks (eg, turning, stopping, etc.) without any errors. Overall performance ratings were high across all participants (4.6/5-excellent). CONCLUSIONS: Our eye-controlled power wheelchair prototype is feasible and has a very favorable user experience. This system has the potential to improve the mobility and independence of ALS patients, and other groups with motor impairments.

Contact Sports as a Risk Factor for Amyotrophic Lateral Sclerosis: A Systematic Review.

STUDY DESIGN: Systematic review. INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, ultimately resulting in paralysis and death. The condition is considered to be caused by a complex interaction between environmental and genetic factors. Although vast genetic research has deciphered many of the molecular factors in ALS pathogenesis, the environmental factors have remained largely unknown. Recent evidence suggests that participation in certain types of sporting activities are associated with increased risk for ALS. OBJECTIVE: To test the hypothesis that competitive sports at the highest level that involve repetitive concussive head and cervical spinal trauma result in an increased risk of ALS compared with the general population or nonsport controls. METHODS: Electronic databases from inception to November 22, 2017 and reference lists of key articles were searched to identify studies meeting inclusion criteria. RESULTS: Sixteen studies met the inclusion criteria. Sports assessed (professional or nonprofessional) included soccer (n = 5), American football (n = 2), basketball (n = 1), cycling (n = 1), marathon or triathlon (n = 1), skating (n = 1), and general sports not specified (n = 11). Soccer and American football were considered sports involving repetitive concussive head and cervical spinal trauma. Professional sports prone to repetitive concussive head and cervical spinal trauma were associated with substantially greater effects (pooled rate ratio [RR] 8.52, 95% CI 5.18-14.0) compared with (a) nonprofessional sports prone to repetitive concussive head and cervical spinal trauma (pooled RR 0.60, 95% CI 0.12-3.06); (b) professional sports not prone to repetitive head and neck trauma (pooled RR 1.35, 95% CI 0.67-2.71); or (c) nonprofessional sports not prone to repetitive concussive head and cervical spinal trauma (pooled RR 1.17, 95% CI 0.79-1.71). CONCLUSIONS: Our review suggests that increased susceptibility to ALS is significantly and independently associated with 2 factors: professional sports and sports prone to repetitive concussive head and cervical spinal trauma. Their combination resulted in an additive effect, further increasing this association to ALS.

Death with dignity in Washington patients with amyotrophic lateral sclerosis.

OBJECTIVES: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. METHODS: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. RESULTS: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46-86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. CONCLUSIONS: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients' goals without complications.

"Shiatsu sympathectomy": ICA dissection associated with a shiatsu massager.

Carotid dissection is a well-described complication of head and neck trauma. Two cases of carotid dissection that occurred after use of shiatsu-type massagers are described. This potential cause should be considered when evaluating patients with idiopathic carotid dissection.

Citalopram treatment of compulsive shopping: an open-label study.

BACKGROUND: Compulsive shopping, a DSM-IV impulse-control disorder not otherwise specified, is characterized by preoccupation with shopping and inability to resist buying unneeded items, with resulting marked distress, social or occupational impairment, and financial and/or familial problems. Because an open-label trial suggested that fluovaxamine, a selective serotonin reuptake inhibitor (SSRI), is effective for this disorder, we tested the effectiveness of the SSRI citalopram. METHOD: We enrolled adults meeting formal diagnostic criteria (as defined by McElroy and colleagues) in a 12-week open-label trial. We excluded subjects with obsessive-compulsive disorder, bipolar disorder, substance abuse or dependence, or psychotic disorders. Citalopram treatment was begun at 20 mg/day and increased every 2 weeks by 20 mg/day, absent marked response and limiting side effects, to 60 mg/day. At endpoint, all subjects were asked to give written informed consent for follow-up telephone interviews at 3-month intervals for 12 months. RESULTS: We enrolled 24 subjects, 22 women and 2 men, whose mean +/- SD age was 43.7 +/- 8.1 years; most had been shopping compulsively for 2 decades or more. Citalopram (mean +/- SD endpoint dose = 35.4 +/- 21.4 mg/day) produced rapid, marked, sustained improvements on both the Yale-Brown Obsessive Compulsive Scale-Shopping Version and the Clinical Global Impressions-Improvement (CGI-I) scale in subjects with and without comorbid conditions. Seventeen subjects (71%) were responders, achieving ratings of much or very much improved on the CGI-I, including 2 of the 3 subjects who discontinued for adverse events (sedation or agitation). During a 6-month follow-up period, those continuing citalopram therapy were less likely to relapse than those discontinuing the medication. CONCLUSION: Citalopram appears to be a safe and effective treatment for compulsive shopping. Acute and long-term, double-blind, placebo-controlled trials of citalopram and other SSRIs for the treatment of this disorder are indicated.