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.).

Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment.

INTRODUCTION/AIMS: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone. METHODS: This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone. RESULTS: The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug. DISCUSSION: This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.

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.

Harnessing the power of the electronic health record for ALS research and quality improvement: CReATe CAPTURE-ALS and the ALS Toolkit.

The electronic health record (EHR) is designed principally to support the provision and documentation of clinical care, as well as billing and insurance claims. Broad implementation of the EHR, however, also yields an opportunity to use EHR data for other purposes, including research and quality improvement. Indeed, effective use of clinical data for research purposes has been a long-standing goal of physicians who provide care for patients with ALS, but the quality and completeness of clinical data, as well as the burden of double data entry into the EHR and into a research database, have been persistent barriers. These factors provided motivation for the development of the ALS Toolkit, a set of interactive digital forms within the EHR that enable easy, consistent, and structured capture of information relevant to ALS patient care (as well as research and quality improvement) during clinical encounters. Routine use of the ALS Toolkit within the context of the CReATe Consortium's institutional review board-approved Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study protocol, permits aggregation of structured ALS patient data, with the goals of empowering research and driving quality improvement. Widespread use of the ALS Toolkit through the CAPTURE-ALS protocol will help to ensure that ALS clinics become a driving force for collecting and aggregating clinical data in a way that reflects the true diversity of the populations affected by this disease, rather than the restricted subset of patients that currently participate in dedicated research studies.

Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset.

BACKGROUND: Prior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results. We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field. METHODS: ALS patients diagnosed within 12 months and their spouses as healthy controls (n = 150 couples) were screened. For eligible sALS and bALS patients (n = 36) and healthy controls (n = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences. Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels. ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R). RESULTS: sALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes-ratio (F/B-ratio). In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral F/B-ratio. For sALS patients, gut-dysbiosis (a shift in fecal F/B-ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.8006, P < 0.0001) and more severe symptoms (r = 0.9470, P < 0.0001). In contrast, for bALS patients, oral-dysbiosis (a shift in oral F/B-ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.9860, P < 0.0001) and greater disease severity (r = 0.9842, P < 0.0001). For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r = 0.7924, P < 0.0001; bALS: r = 0.7496, P = 0.0067). Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS. This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS. CONCLUSIONS: We found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients. Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease. Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.

Embedded Psychiatric Services in a Multidisciplinary Amyotrophic Lateral Sclerosis Clinic: An Assessment of Patient Needs and Perceptions.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is often associated with a range of difficult neuropsychiatric symptoms and conditions, including depression, apathy, pseudobulbar affect, and frontotemporal dementia (FTD). Despite the potential role for psychiatrists in the treatment of ALS, they are not typically involved in the ALS clinical team. The investigators describe a quality improvement intervention providing embedded psychiatric services within a multidisciplinary clinic (MDC). METHODS: A psychiatrist working within an ALS MDC evaluated patients (N=116) over a 1-year period. The clinic assessed the prevalence of neuropsychiatric symptoms and conditions in patients with ALS (depression, anxiety, pseudobulbar affect, and cognitive impairment, including FTD) using standardized screening methods. Fifty-five patients and 47 family members completed surveys about perceptions of their need for psychiatric care, their experience of meeting with a psychiatrist, and their desire for future access to psychiatric care. RESULTS: Prevalence rates for neuropsychiatric symptoms were 14.9% for depression, 11.3% for anxiety, 19% for cognitive impairment (including FTD, 8.6%), and 36.2% for pseudobulbar affect; 62.0% of patients were being prescribed at least one psychotropic medication. Both patients and family members reported that meeting with a psychiatrist was helpful, that the treatment provided was helpful, and that they would prefer continued availability of psychiatric services in the future. The presence of cognitive impairment and use of antidepressants increased the likelihood of patients reporting a benefit from psychiatric care. CONCLUSIONS: Patients with ALS report a benefit from increased access to psychiatric services. The inclusion of a psychiatrist within the ALS MDC model should be considered to improve quality of care for this patient population.

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.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Post-Traumatic brain injury (TBI) presenting with Guillain-Barré syndrome and elevated anti-ganglioside antibodies: a case report and review of the literature.

Guillain-Barré Syndrome (GBS) is a demyelinating polyneuropathy resulting in sensory, motor and autonomic symptoms. The severity of the disease can range from mild to severe but it is classically described as an ascending demyelinating process. Initially thought to be the sequelae of a bacterial or viral infection, the clinical symptoms of post-infective GBS can present up to 4 weeks after sentinel injury. A rarely defined post-surgical GBS has been since described after major cranial, cardiothoracic and gastro-intestinal surgery. Post traumatic GBS is an even more unusual presentation with very few cases reported in contemporary academic literature. We present a case of GBS presenting two weeks after non-operative traumatic brain injury (TBI) and a review of the literature.

Primary progressive aphasia and amyotrophic lateral sclerosis (PPA-ALS): A longitudinal case study.

OBJECTIVE: Approximately 50% of patients with amyotrophic lateral sclerosis (ALS) experience cognitive decline, with frontotemporal dementia (FTD) accounting for up to 15% of these cases. Despite this, there is considerable delay in diagnosis, which affects patient care. METHODS: We report longitudinal results of neuropsychological evaluations in a patient diagnosed with non-fluent/agrammatic primary progressive aphasia (nfvPPA) and amyotrophic lateral sclerosis (ALS). The patient, Ms. X, presented with progressive speech difficulties starting in her late-60's. Initial diagnosis was nfvPPA. After 4-5 years of progressive swallowing difficulties, as well as facial weakness, her diagnosis was modified to PPA-ALS. RESULTS: Ms. X underwent neuropsychological evaluations three times over a period of five years. Results of evaluations were intact and stable over time, except for progressive loss of speech impacting her performance on a sentence repetition task. CONCLUSION: This case study provides valuable insight into the overlap between PPA-ALS from a neuropsychological standpoint. The results reflect preserved cognitive skills in the context of loss of speech and motor abilities. This case study also shows the length of time between onset of symptoms and clear diagnosis, which often requires an immense amount of health literacy and personal advocacy on the part of the patient.

Sexual Intimacy in Persons with Amyotrophic Lateral Sclerosis and their Partners: A Pilot Study.

OBJECTIVE: The objective of this study was to describe concerns experienced among persons with amyotrophic lateral sclerosis (PALS) and their partners regarding sexual intimacy, as well as preferences regarding discussion of the topic with healthcare providers. METHODS: A total of 27 survey responses including 13 PALS and 14 partners were received. Surveys included both quantitative and qualitative data addressing the importance of sexual intimacy to quality of life, assistance required to participate in sexual intimacy, concerns for safety, and preferred timing and method of discussing/receiving information from healthcare professionals. RESULTS: 100% of respondents stated they had never been asked about sexual intimacy by any healthcare provider. 92% of participants agreed ALS had affected their ability to express sexual intimacy. Participants discussed loss of intimacy as due to muscle weakness, respiratory concerns, and role change among other contributors to the overall experienced change in expression of sexual intimacy. With regards to their preferred method of receiving/discussing information on the effect of ALS on sexual intimacy, 48% of participants preferred use of an online video series, 44% chose a pamphlet, 24% chose a one-on-one discussion with a healthcare provider, and 12% chose a private conversation with their partner and healthcare provider. CONCLUSIONS: The findings greatly illustrate the difficulties and concerns experienced with sexual intimacy among PALS and their partners as well as the preferred methods for receiving information on the topic.

Clinical effectiveness of medical marijuana in patients with amyotrophic lateral sclerosis.

Following legalization, Medical Marijuana (MM), has been used to treat the symptoms of Amyotrophic Lateral Sclerosis (ALS), yet data regarding Medical Marijuana's efficacy is lacking. Thus, we conducted a retrospective cohort study to assess Medical Marijuana's impact on ALS symptoms and progression. We reviewed the charts of all ALS patients treated in our clinic over a two-year period to collect data related to the primary outcome measures of symptoms of pain, poor appetite, anxiety, spasticity, insomnia, ALSFRS-R score, BMI, and MM use. Two groups were defined: a control group with target symptoms but no MM prescription, and a test group that filled a MM prescription, including a subgroup on MM for ≥3 visits. Outcomes were correlations between MM usage and symptom prevalence, and between MM usage and BMI and ALSFRS-R decline slope, analyzed using descriptive statistics and qualitative analysis via local regression. Data included 344 ALS patients. We found MM use correlated with alleviation of pain, poor appetite, and anxiety in the short term, but not with spasticity or insomnia. There was no correlation between MM use BMI maintenance. Notably, MM usage correlated with faster ALS progression, although patients using MM exhibited higher symptom burden and progressed faster than controls even pre-MM prescription. In conclusion, MM shows correlation with managing pain, poor appetite, and short-term anxiety in ALS, but is also correlated with faster disease progression based on ALSFRS-R scores. We suggest a multi-center, randomized controlled trial to evaluate both the clinical efficacy and safety of MM in the treatment of ALS.

ALSUntangled #76: Wahls protocol.

The Wahls diet is a modified Paleolithic diet that emphasizes dark green leafy vegetables, colorful fruits, high-quality animal proteins, and omega-3 polyunsaturated fatty acids, while limiting grains, legumes, dairy products, sugar, and processed foods containing proinflammatory omega-6 fatty acids. The Wahls diet may reduce inflammation, oxidative stress, and mitochondrial dysfunction and has plausible mechanisms for slowing amyotrophic lateral sclerosis (ALS) progression. However, research on its dietary components in the ALS animal models has yielded conflicting results. Though multiple cohort studies suggest high carotenoids, omega-3 fatty acids and fruit intake are associated with reduced ALS risks, neither the diet nor its components has been demonstrated to slow down ALS progression in case studies or clinical trials. On the contrary, the Wahls diet, a restrictive, low-carbohydrate and low glycemic index diet, caused an average weight loss of 7.2% BMI in multiple sclerosis clinical trials, which is a significant concern for people living with amyotrophic lateral sclerosis (PALS) as weight loss is associated with faster ALS progression and shorter survival. Considering the above, we cannot endorse the Wahls diet for slowing ALS progression.

ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Oral Edaravone - Introducing a Flexible Treatment Option for Amyotrophic Lateral Sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. While pharmacotherapy options remain limited, the Food and Drug Administration (FDA) approved intravenous (IV) and oral edaravone for the treatment of ALS in 2017 and 2022, respectively. With the addition of oral edaravone, patients with ALS may exclusively use oral medications. AREAS COVERED: The authors performed a review of the published literature using the United States (US) National Library of Medicine's PubMed.gov resource to describe the pharmacokinetics, pharmacodynamics, safety, and efficacy of oral edaravone, as well as pertinent completed and ongoing clinical trials, including the oral edaravone clinical trial development program. The clinical profile of oral edaravone is also discussed. EXPERT OPINION: Edaravone has been shown to slow the rate of motor function deterioration experienced by patients with ALS. As the oral formulation has been approved, patients with ALS may use it alone or in combination with other approved therapeutics. Additional clinical trials and real-world evidence are ongoing to gain further understanding of the clinical profile of oral edaravone.

MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial.

OBJECTIVE: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. METHODS: This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. RESULTS: The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's. CONCLUSION: This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving reldesemtiv or placebo in FORTITUDE-ALS.

AIMS: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving reldesemtiv versus placebo in FORTITUDE-ALS. MATERIALS AND METHODS: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated reldesemtiv in patients with ALS. Health utilities from the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) were estimated using ALS Functional Rating Scale-Revised (ALSFRS-R) scores collected during the trial. QALYs were estimated using the area under the curve method. RESULTS: The full analysis set consisted of 456 patients (reldesemtiv n = 342, placebo n = 114), who received at least one dose of the double-blind study drug, and had ALSFRS-R assessed at baseline and at least one post-baseline assessment. The difference in EQ-5D-5L utility least-squares (LS) mean change from baseline to week 12 for reldesemtiv versus placebo, adjusted for baseline values, was statistically significant (0.03, 95% confidence interval [CI]: 0.01, 0.05; p = .0008). The incremental QALY of reldesemtiv versus placebo adjusted for baseline utility values showed a modest, but statistically significant, difference (0.004, 95% CI: 0.001, 0.007; p = .0058). CONCLUSIONS: This post hoc analysis of FORTITUDE-ALS suggests that reldesemtiv showed a modest but significant benefit in health utilities and QALYs compared with placebo. Future long-term studies that include direct collection of EQ-5D-5L data will be needed to confirm our findings. CLINICALTRIALS.GOV IDENTIFIER: NCT03160898.

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success.

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS).Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial.Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort.Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS).

Role of disease severity, illness perceptions, and mood on quality of life in muscle disease.

INTRODUCTION: The aim of this study was to describe the effect of muscle disease upon QoL and to explore the influence of disease severity, mood, and illness perception on the QoL of these patients. METHODS: Validated questionnaires assessing QoL (Individualized Neuromuscular QoL and SF-36), disease severity (Health Assessment Questionnaire), mood (Hospital Anxiety and Depression Scale) and illness perception (Illness Perception Questionnaire) were sent to adults with muscle disease. RESULTS: We received 302 responses (return rate 75%). QoL was reduced, particularly for "physical" domains, but "psychological" domains were also affected. Disease severity was the main determinant for the "physical" domains of QoL, but mood and illness perception played a part. Conversely, mood and illness perception were the main determinants for the "psychological" domains of QoL. CONCLUSIONS: Because mood and illness perception explain significant variance in QoL in muscle disease, there is scope for devising psychosocial interventions that may improve QoL for those with muscle disease.