Martinez‐Thompson, Jennifer M.

ABSTRACTIntroduction/AimsHealthcare utilization and costs in myotonic dystrophy (DM) are not well understood. This study describes the burden of DM and its associated costs.MethodsWe performed a retrospective study using data from a large U.S. administrative claims database to identify commercially insured individuals with DM and compared healthcare utilization and cost with a matched cohort. Analyses were performed between the cohorts with ≥ 3 years of insured follow‐up.ResultsWe identified 1182 DM individuals with coverage at least 3 year prior and 3 years following an index DM diagnosis from January 1, 2009 to December 31, 2018. Compared to controls, DM individuals were 3.7 times more likely to be hospitalized (p < 0.0001), 2.4 times more likely to visit an emergency department (p < 0.0001), and had twice as many outpatient visits (p < 0.0001) in the first year post‐diagnosis, with similar utilization at 2‐ and 3‐years post‐diagnosis. Annual mean costs were 3.9 times higher for health plan paid costs (p < 0.0001) and 2.6 times higher for patient‐paid costs (p < 0.0001) for DM individuals than controls in the first year post‐diagnosis, with similar costs at 2‐ and 3‐years post‐diagnosis. Factors associated with higher costs included the need for durable medical equipment, including gait aids or respiratory support devices.DiscussionIndividuals with DM experience significantly higher healthcare utilization and associated healthcare costs than controls of similar age, sex, race, and census region. The findings show the high clinical and economic burden of DM, highlighting the importance of improving cost‐effective care delivery in this population.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR &amp;lt;1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Abstract Nerve conduction F-wave studies contain crucial information about subclinical motor dysfunction that can be used to diagnose patients with amyotrophic lateral sclerosis (ALS). However, F-wave responses are highly variable in morphology, making waveform interpretation challenging. Artificial intelligence techniques can extract time–frequency features to provide new insights into ALS diagnosis and prognosis. A retrospective analysis was performed on F-wave responses from 46 802 patients. Discrete wavelet transforms were applied to time-series waveform responses after stimulating ulnar, median, fibular and tibial nerves. Wavelet coefficient statistics, onset age, sex and body mass index were features for training a Gradient Boosting Machine model on 40 095 patients (5329 diagnosed with motor neuron disease). Model performance was tested on responses from 689 ALS patients meeting Gold Coast criteria and 689 age- and sex-matched controls. An exploratory analysis examined model performance on cohorts of patients with inclusion body myositis, cervical radiculopathy, lumbar radiculopathy or peripheral neuropathy, which can mimic ALS symptoms. Factors affecting survival were estimated through Cox proportional hazards regression. The model trained using wavelet features on the full waveform had 90% recall, 87% precision and 88% accuracy. Similar model performance was measured using features from only the M-wave or F-wave. Classification probabilities for ALS patients were statistically different from the diagnoses mimicking ALS symptoms (P &lt; 0.001, ANOVA, Tukey’s post hoc test). Higher model classification probabilities of ALS, older age at onset, and family history of ALS alone or with frontotemporal dementia were factors decreasing survival. Longer diagnostic delay and upper limb onset site were factors increasing survival. Model scores two standard deviations below the mean had 4 months increased survival (two standard deviations below had 3 months decreased survival). Artificial intelligence techniques extracted important information from F-wave responses to estimate a patient’s likelihood of ALS and their survival risks. Although the model can make predictions at a specific decision threshold as presented here, the true strength of such a model lies in its ability to provide probabilities about whether a patient is likely to have ALS in comparison to other mimicking diagnoses, such as inclusion body myositis, cervical or lumbar radiculopathy or peripheral neuropathy. These probabilities provide clinicians with additional information that they can use to make the final diagnosis with greater confidence and precision. Integrating such a model into the clinical workflow could help clinicians to diagnose ALS sooner and manage treatment based on estimated survival, which might improve outcomes and the quality of life of patients.