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Background: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. Methods: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18?74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0?3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period?study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. Findings: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (?15?1% [IQR ?31?1 to 3?2] in the zilucoplan group vs ?16?3% [?43?8 to 5?9] in the placebo group; p=0?46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). Interpretation: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. Funding: Ra Pharmaceuticals (now part of UCB Pharma).

Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN).We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected.Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy.Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.

INTRODUCTION/AIMS: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics. METHODS: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in 2 sequential cohorts: 500 mg (Cohort 1) and 1000 mg (Cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale-revised, and forced vital capacity. RESULTS: Six and eight participants were enrolled in cohorts 1 and 2 respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% CI 39 to 70.8%) and severity decreased by 46.3% (95% CI 29.5 to 63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change. DISCUSSION: Ranolazine was well tolerated in ALS up to 2000 mg daily with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial.

The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM.We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups.The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells.We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types. This article is protected by copyright. All rights reserved.

Objective: The aim of the study was to estimate the exacerbation incidence rate (IR) in acetylcholine receptor antibody (AChR)-positive generalized myasthenia gravis (MG) and its predictors. Methods: The primary outcome in this retrospective study was to estimate moderate-to-severe (M-S) exacerbations IR in the early course of generalized MG. The secondary outcome was to explore the predictors of MG exacerbations. Results: Between 1999 and 2015, we identified 78 AChR-positive generalized MG patients and 37 M-S exacerbations over the first 6 years following the onset of generalized MG symptoms. The M-S exacerbation IR was 12.2 per 100 person years (95% confidence interval [CI] 8.8–16.8). Any exacerbation (including mild) IR was 24.4 per 100 person years (95% CI 19.4–30.7). After controlling for confounding factors, MG exacerbation IR predictors included gender, disease severity at onset, and prednisone dose reduction with risk ratio of 0.34 (male gender), 2.67, and 20.8, respectively (all p values Conclusion: More than half of newly diagnosed AChR + MG cases experience an exacerbation in the first 6 years. Gender, disease severity at onset and prednisone dose reduction are predictors that could inform clinical practice and future research.

Introduction: Amyloid myopathy is a rare presentation of systemic amyloidosis. Amyloid myopathy can be initially misdiagnosed as sporadic inclusion body myositis (IBM). Methods: We report 4 cases of amyloid myopathy clinically mimicking inclusion body myositis and initially thought to be phenotypically IBM by neuromuscular experts. Results: Case 1 is an 81-year-old woman who presented with distal arm and proximal leg asymmetric weakness (myopathy pattern 4). Case 2 is a 76-year-old man with primary systemic amyloidosis who presented with myopathy pattern 4 and progressive dysphagia for four years. Case 3 is an 82-year-old man with progressive myopathy pattern 4 weakness and swallowing difficulty. Case 4 is a 62-year-old man with progressive bilateral finger flexor weakness. Muscle biopsies in all 4 cases showed perivascular amyloid deposits Discussion: Amyloid myopathy may be clinically indistinguishable from IBM. Muscle biopsy is of critical importance in the evaluation of patients suspected to have IBM.

Introduction: Diagnostic criteria for CIDP have been proven useful for clinical trials. However, use of these criteria in clinics has been limited by time constraints and unknown usefulness in predicting outcomes. Methods: A retrospective chart review of CIDP patients at the University of Kansas seen between 2008 and 2014 was performed. We determined the diagnostic criteria fulfilled by each patient and assessed treatment responses. A positive response was defined by improvement sensory or motor examination as determined by a neuromuscular physician.Results: There were 38 total patients included in the study. The response rate to IVIG in patients who fulfilled EFNS/PNS criteria was 20/22 (90.1%). Among patients who fulfilled AAN criteria, 8/9 (88.9%) responded positively to IVIG. Slightly lower response rates were seen in patients fulfilling INCAT criteria and Saperstein criteria at 10/15 (66.7%) and 12/17 (70.6%), respectively.Discussion: EFNS/PNS and AAN criteria can similarly predict IVIG treatment response.

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.

Introduction. Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods.xAn analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion. There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes.

Introduction. Daily oral beta-adrenoreceptor antagonist has been shown to be effective in preventing migraine headaches. Timolol 0.5% ophthalmic solution is a non-selective beta-adrenoreceptor antago- nist, where the primary use is for glaucoma. There have been case reports that timolol is effective in aborting or improving an acute migraine headache. The objective of this study was to assess the efficacy (decrease of ≥ 50% in pain scale at 120 minutes) of timolol 0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. Methods.We performed a randomized, double-blind, crossover, placebo-controlled, study. Study entry criteria required subjects to have one to eight migraine episodes per month. The primary outcome was comparison of the change in a visual analog pain scale (VAS) at 120 minutes after taking the study medication. Study subjects were given a pain scale with a range of 1 (no pain) to 10 (most severe pain) to complete after onset of migraine but before administration of study drops and 120 minutes after administration of study drops. Improve- ment was defined as a ≥ 50% decrease in pain scale. Results. Nineteen subjects completed the study and were used for analysis. The primary outcome changes in pain scale, 120 minutes after dose, showed a similar decrease for placebo and drug with a slightly wider 95% CI for placebo. Six subjects in each arm experi- enced a ≥ 50% decrease in pain scale. Conclusion. These results support that timolol 0.5% ophthalmic solution is not an efficacious treatment for acute migraine headache.

Background and ObjectiveTo determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG).MethodsThe B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase 2 trial that utilized a futility design. Individuals 21–90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II–IV) and receiving prednisone ≥15 mg/d were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The coprimary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to a 2-cycle rituximab/placebo regimen, with follow-up through 52 weeks.ResultsOf the 52 participants included, mean ± SD age at enrollment was 55.1 ± 17.1 years; 23 (44.2%) were women and 31 (59.6%) were Myasthenia Gravis Foundation of America Class II. The mean ± SD baseline prednisone dose was 22.1 ± 9.7 mg/d. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs 56% on placebo. The study reached its futility endpoint (p = 0.03), suggesting that the predefined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues were identified.DiscussionAlthough rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase 3 trial of mild to moderately symptomatic AChR-Ab+ gMG.Classification of EvidenceThis study provides Class I evidence that for mild to moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.Trial Registration InformationClinicalTrials.gov identifier: NCT02110706.

Aim: Compare efficacies of deflazacort and prednisone/prednisolone in providing clinically meaningful delays in loss of physical milestones in patients with nonsense mutation Duchenne muscular dystrophy. Materials & methods: Placebo data from Phase IIb (ClinicalTrials.gov Identifier: NCT00592553) and ACT DMD (ClinicalTrials.gov Identifier: NCT01826487) ataluren nonsense mutation Duchenne muscular dystrophy clinical trials were retrospectively combined in meta-analyses (intent-to-treat population; for change from baseline to week 48 in 6-min walk distance [6MWD] and timed function tests). Results: Significant improvements in change in 6-min walk distance with deflazacort versus prednisone/prednisolone (least-squares mean difference 39.54 m [95% CI: 13.799, 65.286; p = 0.0026]). Significant and clinically meaningful improvements in 4-stair climb and 4-stair descend for deflazacort versus prednisone/prednisolone. Conclusion: Deflazacort provides clinically meaningful delays in loss of physical milestones over 48 weeks compared with prednisone/prednisolone for patients with nonsense mutation Duchenne muscular dystrophy.

Background. Neuronal Ceroid Lipofuscinosis, or Batten disease, is a neurodegenerative disorder that results in seizures, vision loss, vegetative state, and premature death. This project aims to understand the value of disease organizations in the management of Batten disease progression. Methods. Seven semi-structured interviews with caregivers of children with Batten disease were conducted at a national family conference. Also, five semi-structured telephone interviews with disease organizations were conducted, two of which were Batten disease specific. Results. Most caregiver participants reported difficulties in getting a diagnosis. All participants reported significant benefit from involvement in the Batten Disease Support and Research Association (BDSRA) and associated family conference. Some of the most challenging aspects of care centered around a lack of in-home aid, medical equipment, and the education system. The disease advocacy organizations included Rare KC, the National Organization for Rare Disorders (NORD), Global Genes, Noah’s Hope, and Taylor’s Tale. Disease organizations encourage rare disease families to thrive by providing the bridge that connects patients, physicians, and researchers. A central organization implements an avenue for individuals to share information and meet people in the rare disease community. Conclusions. The participants provided clear examples of the benefits families received from being involved in a rare disease organization.

Background and ObjectivesPompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.MethodsNEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of −0.473 per year (−1.188 to 0.242) and −0.648 per year (−1.061 to −0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of −0.701 per year (−1.571 to 0.169) and −0.846 per year (−1.567 to −0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.Trial Registration InformationNCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1—August 19, 2013; NEO-EXT—February 27, 2014.

Background: Isolated bulbar amyotrophic lateral sclerosis (IBALS) is a regional variant of amyotrophic lateral sclerosis (ALS) with weakness restricted to the bulbar muscles for at least 2 years, and slower progression than generalized ALS. Bulbar-onset generalized ALS, by contrast, typically has a more rapid progression than limb-onset ALS.Objective: To characterize patients with IBALS and compare them to patients with isolated bulbar disease at presentation who progress to generalized ALS.Methods: We performed a retrospective chart review of patients seen in our ALS specialty clinic at the University of Kansas Medical Center between 2001-2011. Results: Of 543 patients seen in the ALS clinic, 150 presented with bulbar symptoms at disease onset: 28 (18.7%) had bulbar signs and no evidence of extremity involvement on exam or electrodiagnostic testing at their initial visit; and 14 (9.3%) had weakness restricted to the bulbar muscles after 2 years of follow up (IBALS). IBALS patients were 57.1% male, with a mean age of symptom onset of 60.8 years (range 39-77 years). The mean disease duration was 3.1 years (range of 2-8 years), with 50% mortality at a mean follow up of 3.5 years. Minimal denervation changes were seen in at least one limb in 6 subjects (42.9%). Other clinical features included: 4 subjects (28.6%) had cognitive impairment, 4 (28.6%) had pseudo-bulbar affect, and 5 subjects (35.7%) had impaired eye movements on smooth pursuit.Conclusion: Isolatred bulbar ALS IBALS is an identifiable restricted regional ALS pattern if there is no clinical limb weakness 2 years after symptom onset. It may have a slower progression from typical ALS. The biologic factors that account for the IBALS restricted pattern are unknown.

Isolated bilateral ptosis as an initial sign of Guillain-Barré Syndrome (GBS) with subsequent limb paralysis or paresis has been reported. However, to our knowledge, bilateral ptosis with subsequent limb myokymia but without ophthalmoplegia, facial or extremity weakness has not been observed. Our patient developed severe bilateral ptosis over several days. There was no facial or extremity weakness although limb myokymia was seen. Laboratory studies excluded common causes of ptosis and were suggestive of GBS. We believe our patient extends the clinical spectrum of GBS, and that binocular ptosis represents a mild regional variant of this neuropathy.

While traditional immunosuppressive and immunomodulatory therapies remain the cornerstone of immune-mediated neuromuscular disease management, new and novel agents including antigen-specific, monoclonal antibody drugs, have emerged as important treatment options. This article is the second of a two-part series that reviews immune-based therapies in neuromuscular diseases. The first article provides an update on the use of traditional immune-based therapies such as corticosteroids, plasma exchange, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin G. This second article focuses on new and novel immune-based therapies, including eculizumab, a complement inhibitor approved for acetylcholine receptor antibody-positive myasthenia gravis; rituximab, a B-cell depletion therapy with evolving indications in neuromuscular diseases; and the subcutaneous formulation of immunoglobulin G that gained approval for use in chronic inflammatory demyelinating polyradiculoneuropathy in 2018. Finally, several novel antigen-specific drugs at different stages of investigation in neuromuscular disease are also reviewed.

Limited resources are a challenge when planning comparative effectiveness studies of multiple promising treatments, often prompting study planners to reduce the sample size to meet the financial constraints. The practical solution is often to increase the efficiency of this sample size by selecting a pair of treatments among the pool of promising treatments before the clinical trial begins. The problem with this approach is that the investigator may inadvertently leave out the most beneficial treatment. This paper demonstrates a possible solution to this problem by using Bayesian adaptive designs. We use a planned comparative effectiveness clinical trial of treatments for sialorrhea in amyotrophic lateral sclerosis as an example of the approach. Rather than having to guess at the two best treatments to compare based on limited data, we suggest putting more arms in the trial and letting response adaptive randomization (RAR) determine better arms. To ground this study relative to previous literature we first compare RAR, adaptive equal randomization (ER), arm(s) dropping, and a fixed design. Given the goals of this trial we demonstrate that we may avoid 'type III errors' - inadvertently leaving out the best treatment - with little loss in power compared to a two-arm design, even when choosing the correct two arms for the two-armed design. There are appreciable gains in power when the two arms are prescreened at random.

Introduction A randomized trial demonstrated benefit from thymectomy in nonthymomatous acetylcholine receptor (AChR)-antibody positive myasthenia gravis (MG). Uncontrolled observational and histologic studies suggest thymectomy may not be efficacious in anti-muscle-specific kinase (MuSK)-MG. Methods The therapeutic impact of thymectomy was evaluated from data collected for a multicenter, retrospective blinded review of rituximab in MuSK-MG. Results Baseline characteristics were similar between thymectomy (n = 26) and nonthymectomy (n = 29) groups, including treatment with rituximab (42% vs. 45%). At last visit, 35% of thymectomy subjects reached the primary endpoint, a Myasthenia Gravis Foundation of America (MGFA) post-intervention status (PIS) score of minimal manifestations (MM) or better, compared with 55% of controls (P = 0.17). After controlling for age at onset of MG, rituximab, prednisone, and intravenous immunoglobulin/plasma exchange treatment, thymectomy was not associated with greater likelihood of favorable clinical outcome (odds ratio = 0.43, 95% confidence interval 0.12-1.53, P = 0.19). Discussion Thymectomy was not associated with additional clinical improvement in this multicenter cohort of MuSK-MG patients. Muscle Nerve 59:404-410, 2019.

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published