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1. A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.

Author

Bhai, Salman, Levine, Todd, Moore, Dan, Bowser, Robert, Heim, Andrew, Walsh, Maureen, Shibani, Aziz, Simmons, Zachary, Grogan, James, Goyal, Namita, Govindarajan, Raghav, Hussain, Yessar, Papsdorf, Tania, Schwasinger-Schmidt, Tiffany, Olney, Nick, Goslin, Kim, Pulley, Michael, Kasarskis, Edward, Weiss, Michael, Katz, Susan, Moser, Suzan, Jabari, Duaa, Jawdat, Omar, Statland, Jeffrey, Dimachkie, Mazen, and Barohn, Richard

Subjects
amyotrophic lateral sclerosis (ALS), biomarkers, memantine, motor neuron disease (MND), neurofilament, Humans, Memantine, Amyotrophic Lateral Sclerosis, Male, Female, Double-Blind Method, Middle Aged, Aged, Adult, Aged, 80 and over, Disease Progression, Treatment Outcome, Young Adult, Excitatory Amino Acid Antagonists
Abstract

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies. AIMS: This study investigated memantines impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis. RESULTS: Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline. DISCUSSION: In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.

Published
2025

2. The Effectiveness of NP001 on the Long-Term Survival of Patients with Amyotrophic Lateral Sclerosis.

Author

Forrest, Bruce, Goyal, Namita, Fleming, Thomas, Bracci, Paige, Brett, Neil, Khan, Zaeem, Robinson, Michelle, Azhir, Ari, and McGrath, Michael

Subjects
amyotrophic lateral sclerosis, innate immunity, neuroinflammation, overall survival, sodium chlorite
Abstract

BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities. RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. CONCLUSIONS: The findings from this study suggest that a 6 months treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.

Published
2024

4. Conception of Indian Monsoon Prediction Methods

Author

Goyal, Namita, Mahajan, Aparna N., Tripathi, K. C., Kacprzyk, Janusz, Series Editor, Gomide, Fernando, Advisory Editor, Kaynak, Okyay, Advisory Editor, Liu, Derong, Advisory Editor, Pedrycz, Witold, Advisory Editor, Polycarpou, Marios M., Advisory Editor, Rudas, Imre J., Advisory Editor, Wang, Jun, Advisory Editor, Sharma, Harish, editor, Shrivastava, Vivek, editor, Tripathi, Ashish Kumar, editor, and Wang, Lipo, editor

Published
2024
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6. Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial

Author

Perrin, Steven, Ladha, Shafeeq, Maragakis, Nicholas, Rivner, Michael H., Katz, Jonathan, Genge, Angela, Olney, Nicholas, Lange, Dale, Heitzman, Daragh, Bodkin, Cynthia, Jawdat, Omar, Goyal, Namita A., Bornstein, Jeffrey D., Mak, Carmen, Appel, Stanley H., and Paganoni, Sabrina

Subjects
Drug therapy, Testing, Physiological aspects, Patient outcomes, Amyotrophic lateral sclerosis -- Drug therapy -- Patient outcomes, Monoclonal antibodies -- Testing -- Patient outcomes -- Physiological aspects
Abstract

Author(s): Steven Perrin 1, Shafeeq Ladha 2, Nicholas Maragakis 3, Michael H. Rivner 4, Jonathan Katz 5, Angela Genge 6, Nicholas Olney 7, Dale Lange 8, Daragh Heitzman 9, Cynthia [...], Background The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). Methods and findings In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. Conclusions Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Trial registration Clintrials.gov ID:NCT04322149.

Published
2024
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7. Correlations of disease severity outcome measures in inclusion body myositis.

Author

Greenberg, Steven, Cauchi, Jonathan, Araujo, Nadia, Li, Vivian, Wencel, Marie, Irani, Tyler, Wang, Leo, Palma, Anton, Mozaffar, Tahseen, Villalta, Sergio, and Goyal, Namita

Subjects
Clinical trials, IBMFRS, Inclusion body myositis, Outcome measures, Humans, Myositis, Inclusion Body, Hand Strength, Cross-Sectional Studies, Severity of Illness Index, Outcome Assessment, Health Care
Abstract

This study aimed to evaluate the correlation between various outcome measures used to assess disease severity and progression in inclusion body myositis (IBM) clinical trials. A cross-sectional study, involving 51 IBM patients meeting the European Neuromuscular Center (ENMC) 2011 criteria for clinically defined or probable IBM, was completed at the University of California, Irvine. Clinical details, demographic data, and functional data including timed get up (TGU), manual muscle testing, hand grip, pinch dynamometry, as well as IBM functional rating scale (IBMFRS), modified Rankin score, forced vital capacity (FVC), and modified ocular bulbar facial respiratory scale (mOBFRS) were collected on all patients. Descriptive statistics and Pearsons r correlation were performed to analyze the data. Age of the patient did not correlate with any of the outcome measures. Greater severity of IBMFRS scores correlated with longer disease duration as well as greater severity for FVC, strength outcomes, TGU, modified Rankin, and mOBFRS. Additionally, TGU strongly correlated with muscle strength measurements, modified Rankin, and mOBFRS. mOBFRS moderately correlated with IBMFRS, muscle strength, FVC, TGU and modified Rankin score. We demonstrate moderate to strong correlations among the disease severity outcome measures in this study.

Published
2022

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

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry D, Jackson, Carlayne, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq S, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita, Pattee, Gary L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Mathew, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Yu, Hong, Cohen, Joshua, Klee, Justin, Tanzi, Rudolph, Gilbert, Walter, Yeramian, Patrick, and Cudkowicz, Merit

Subjects
Rare Diseases, ALS, Neurosciences, Clinical Research, Clinical Trials and Supportive Activities, Neurodegenerative, Brain Disorders, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, MOTOR NEURON DISEASE, NEUROMUSCULAR, RANDOMISED TRIALS, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults 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.ResultsRisk 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.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration numberNCT03127514; NCT03488524.

Published
2022

10. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Author

Granit, Volkan, Steele, Julie, Levy, Wendy, Paredes, Maria Elena, Hernandez, Jessica, Bilsker, Martin, Szacka, Katarzyna, Ronert, Adam, Jablońska, Dorota, Łuczak, Alina Zuzanna, Chaverri, Delia, Janse van Mantgem, Mark R, Bunte, Tommy M, Broere, Bianca, de Fockert, Arianne, Sanchez-Tejerina, Daniel, Landabaso, Carmen, Calvo, Andrea, Moglia, Cristina, Manera, Umberto, Canosa, Antonio, Vasta, Rosario, Salamone, Paolina, Fuda, Giuseppe, DeMarco, Giovanni, Casale, Federico, ME Forsberg, Karin, Winroth, Ivar, Almgren Stenberg, Erica, Holmgren, Monica, Amador, Maria del Mar, Lenglet, Timothee, Querin, Giorgia, Coudoin, Sylvie, Pavlakis, Pantelis, Holzberg, Shara, Sideri, Riccardo, Marinou, Kalliopi, Czarnecki, Maciej, Ługiewicz, Renata, Biel-Czarnecka, Marta, Boczkowska, Marcelina, Schotte, Caroline, Vynckier, Jan, Van Daele, Sien, Claeys, Thomas, Delmotte, Koen, Swinnen, Bart, Serrien, Anouk, D'Hondt, Ann, Lamaire, Nikita, Debien, Elisa, Jones, Sarah, Vachon, Chris, Grogan, James, Solorzano, Guillermo, Crowell, Allison, Rakocevic, Goran, Wagoner, Mary, Alma, Osmanovic, Flavia, Wiehler, Sonja, Körner, Olivia, Schreiber-Katz, Camilla, Wohnrade, Anastasia, Sarikidi, Carola, Kassebaum, Chantal, Fischer, Adamo, Ashley, Turcotte, Nicole, Duncan, Jessie, Turner, Ivone, Elman, Lauren, Massie, Rami, Berube, Maxime, Saunders, Natalie, Salmon, Kristiana, Foucher, Juliette, Agessandro, Abrahao, Shirley, Pham, Jahan, Mookshah, Phung, Liane, Statland, Jeffrey, Jawdat, Omar, Dimachkie, Mazen, Pasnoor, Mamatha, Farmakidis, Constantine, Heim, Andrew, Lillig, Katie, Lackey, Alyssa, Weber, Markus, Kurz, Martina, Levine, Todd, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A, Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H, Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M, Pradat, Pierre-Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A, Meyer, Thomas, Hanna, Michael G, Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C, Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M, Turner, Martin R, Wuu, Joanne, Bennett, Richard, Dang, Hoang, and Sundgreen, Claus

Published
2024
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11. Immunophenotyping of Inclusion Body Myositis Blood T and NK Cells

Author

Goyal, Namita A, Coulis, Gérald, Duarte, Jorge, Farahat, Philip K, Mannaa, Ali H, Cauchii, Jonathan, Irani, Tyler, Araujo, Nadia, Wang, Leo, Wencel, Marie, Li, Vivian, Zhang, Lishi, Greenberg, Steven A, Mozaffar, Tahseen, and Villalta, S Armando

Subjects
Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, CD8-Positive T-Lymphocytes, Humans, Immunologic Memory, Immunophenotyping, Killer Cells, Natural, Leukocytes, Mononuclear, Myositis, Inclusion Body, Clinical Sciences, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Background and objectivesTo evaluate the therapeutic potential of targeting highly differentiated T cells in patients with inclusion body myositis (IBM) by establishing high-resolution mapping of killer cell lectin-like receptor subfamily G member 1 (KLRG1+) within the T and natural killer (NK) cell compartments.MethodsBlood was collected from 51 patients with IBM and 19 healthy age-matched donors. Peripheral blood mononuclear cells were interrogated by flow cytometry using a 12-marker antibody panel. The panel allowed the delineation of naive T cells (Tn), central memory T cells (Tcm), 4 stages of effector memory differentiation T cells (Tem 1-4), and effector memory re-expressing CD45RA T cells (TemRA), as well as total and subpopulations of NK cells based on the differential expression of CD16 and C56.ResultsWe found that a population of KLRG1+ Tem and TemRA were expanded in both the CD4+ and CD8+ T-cell subpopulations in patients with IBM. KLRG1 expression in CD8+ T cells increased with T-cell differentiation with the lowest levels of expression in Tn and highest in highly differentiated TemRA and CD56+CD8+ T cells. The frequency of KLRG1+ total NK cells and subpopulations did not differ between patients with IBM and healthy donors. IBM disease duration correlated with increased CD8+ T-cell differentiation.DiscussionOur findings reveal that the selective expansion of blood KLRG1+ T cells in patients with IBM is confined to the TemRA and Tem cellular compartments.

Published
2022

12. A randomized placebo‐controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis

Author

Cudkowicz, Merit E, Lindborg, Stacy R, Goyal, Namita A, Miller, Robert G, Burford, Matthew J, Berry, James D, Nicholson, Katharine A, Mozaffar, Tahseen, Katz, Jonathan S, Jenkins, Liberty J, Baloh, Robert H, Lewis, Richard A, Staff, Nathan P, Owegi, Margaret A, Berry, Donald A, Gothelf, Yael, Levy, Yossef S, Aricha, Revital, Kern, Ralph Z, Windebank, Anthony J, and Brown, Robert H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Stem Cell Research, Brain Disorders, Clinical Trials and Supportive Activities, Stem Cell Research - Nonembryonic - Human, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Prevention, ALS, Neurosciences, Neurodegenerative, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Neurological, Amyotrophic Lateral Sclerosis, Double-Blind Method, Humans, Mesenchymal Stem Cells, Nerve Growth Factors, Transplantation, Autologous, ALSFRS-R, amyotrophic lateral sclerosis, biomarker, clinical trial, stem cells, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

Introduction/aimsAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.MethodsThis randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold.ResultsOverall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged.DiscussionThe study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

Published
2022

13. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

Author

Tawil, Rabi, Wagner, Kathryn R, Hamel, Johanna I, Leung, Doris G, Statland, Jeffrey M, Wang, Leo H, Genge, Angela, Sacconi, Sabrina, Lochmüller, Hanns, Reyes-Leiva, David, Diaz-Manera, Jordi, Alonso-Perez, Jorge, Muelas, Nuria, Vilchez, Juan J, Pestronk, Alan, Gibson, Summer, Goyal, Namita A, Hayward, Lawrence J, Johnson, Nicholas, LoRusso, Samantha, Freimer, Miriam, Shieh, Perry B, Subramony, S H, van Engelen, Baziel, Kools, Joost, Leinhard, Olof Dahlqvist, Widholm, Per, Morabito, Christopher, Moxham, Christopher M, Cadavid, Diego, Mellion, Michelle L, Odueyungbo, Adefowope, Tracewell, William G, Accorsi, Anthony, Ronco, Lucienne, Gould, Robert J, Shoskes, Jennifer, Rojas, Luis Alejandro, and Jiang, John G

Published
2024
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14. Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices: The IPaNeMA Study.

Author

Wencel, Marie, Shaibani, Aziz, Goyal, Namita A, Dimachkie, Mazen M, Trivedi, Jaya, Johnson, Nicholas E, Gutmann, Laurie, Wicklund, Matthew P, Bandyopadhay, Sankar, Genge, Angela L, Freimer, Miriam L, Goyal, Neelam, Pestronk, Alan, Florence, Julaine, Karam, Chafic, Ralph, Jeffrey W, Rasheed, Zinah, Hays, Melissa, Hopkins, Steve, and Mozaffar, Tahseen

Subjects
Genetic Testing, Liver Disease, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Genetics, Rare Diseases, Clinical Research, Neurosciences
Abstract

Background and objectivesWe investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada.MethodsAll successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine.ResultsGAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic.DiscussionThe prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles.Trial registration informationClinical trial registration number: NCT02838368.

Published
2021

15. Subcutaneous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy

Author

Goyal, Namita A, Karam, Chafic, Sheikh, Kazim A, and Dimachkie, Mazen M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Humans, Immunization, Passive, Immunoglobulin G, Infusions, Subcutaneous, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating, CIDP, immunoglobulin therapy, IVIg, SCIg, transition, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

Immunoglobulin G (IgG) therapy is an established long-term treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) that is commonly administered intravenously (IVIg). The subcutaneous immunoglobulin (SCIg) administration route is a safe and effective alternative option, approved by the United States Food and Drug Administration (FDA) in 2018, for maintenance treatment of adults with CIDP. Physicians and patients alike need to be aware of all their treatment options in order to make informed decisions and plan long-term treatment strategies. In this review, we collate the evidence for SCIg in CIDP from all published studies and discuss their implications and translation to clinical practice. We also provide guidance on the practicalities of how and when to transition patients from IVIg to SCIg and ongoing patient support. Evidence suggests that IVIg and SCIg have comparable long-term efficacy in CIDP. However, SCIg can provide additional benefits for some patients, including no requirement for venous access or premedication, and reduced frequency of systemic adverse events. Local-site reactions are more common with SCIg than IVIg, but these are mostly well-tolerated and abate with subsequent infusions. Data suggest that many patients prefer SCIg following transition from IVIg. SCIg preference may be a result of the independence and flexibility associated with self-infusion, whereas IVIg preference may be a result of familiarity and reliance on a healthcare professional for infusions. In practice, individualizing maintenance dosing based on disease behavior and determining the minimally effective IgG dose for individuals are key considerations irrespective of the administration route chosen.

Published
2021

16. Efficacy and Safety of Bimagrumab in Sporadic Inclusion Body Myositis: Long-term Extension of RESILIENT.

Author

Amato, Anthony A, Hanna, Michael G, Machado, Pedro M, Badrising, Umesh A, Chinoy, Hector, Benveniste, Olivier, Karanam, Ananda Krishna, Wu, Min, Tankó, László B, Schubert-Tennigkeit, Agnes Annette, Papanicolaou, Dimitris A, Lloyd, Thomas E, Needham, Merrilee, Liang, Christina, Reardon, Katrina A, de Visser, Marianne, Ascherman, Dana P, Barohn, Richard J, Dimachkie, Mazen M, Miller, James AL, Kissel, John T, Oskarsson, Björn, Joyce, Nanette C, Van den Bergh, Peter, Baets, Jonathan, De Bleecker, Jan L, Karam, Chafic, David, William S, Mirabella, Massimiliano, Nations, Sharon P, Jung, Hans H, Pegoraro, Elena, Maggi, Lorenzo, Rodolico, Carmelo, Filosto, Massimiliano, Shaibani, Aziz I, Sivakumar, Kumaraswamy, Goyal, Namita A, Mori-Yoshimura, Madoka, Yamashita, Satoshi, Suzuki, Naoki, Aoki, Masashi, Katsuno, Masahisa, Morihata, Hirokazu, Murata, Kenya, Nodera, Hiroyuki, Nishino, Ichizo, Romano, Carla D, Williams, Valerie SL, Vissing, John, and Zhang Auberson, Lixin

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Accidental Falls, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Double-Blind Method, Female, Humans, Male, Middle Aged, Muscle Strength, Myositis, Inclusion Body, Time, Treatment Outcome, Walk Test, RESILIENT Study Extension Group, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM).MethodsParticipants (aged 36-85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co-primary outcome measures were 6-minute walk distance (6MWD) and safety.ResultsBetween November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24-104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively).ConclusionExtended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint.Clinical trial registrationClinicaltrials.gov identifier NCT02573467.Classification of evidenceThis study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.

Published
2021

17. Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

Author

Weiss, Michael D, Macklin, Eric A, McIlduff, Courtney E, Vucic, Steve, Wainger, Brian J, Kiernan, Matthew C, Goutman, Stephen A, Goyal, Namita A, Rutkove, Seward B, Ladha, Shafeeq S, Chen, I‐Hweii Amy, Harms, Matthew B, Brannagan, Thomas H, Lacomis, David, Zivkovic, Sasha, Ma, Maxwell, Wang, Leo H, Simmons, Zachary, Rivner, Michael H, Shefner, Jeremy M, Cudkowicz, Merit E, Atassi, Nazem, and Group, for the Mexiletine‐2 ALS Study

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Research, ALS, Neurosciences, Clinical Trials and Supportive Activities, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Axons, Cortical Excitability, Double-Blind Method, Electrodiagnosis, Electromyography, Evoked Potentials, Motor, Female, Humans, Male, Median Nerve, Mexiletine, Middle Aged, Neural Conduction, Preliminary Data, Transcranial Magnetic Stimulation, Voltage-Gated Sodium Channel Blockers, amyotrophic lateral sclerosis, axonal excitability, outcome research, randomized controlled clinical trial, transcranial magnetic stimulation, Mexiletine-2 ALS Study Group, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundTo collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial.MethodsTwenty ALS subjects were randomized to placebo and mexiletine 300 or 600 mg daily for 4 wk and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT).ResultsRMT was unchanged with 4 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk on mexiletine.ConclusionsThe relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine.

Published
2021

18. Clinical utility of anti‐cytosolic 5’‐nucleotidase 1A antibody in idiopathic inflammatory myopathies

Author

Ikenaga, Chiseko, Findlay, Andrew R, Goyal, Namita A, Robinson, Sarah, Cauchi, Jonathan, Hussain, Yessar, Wang, Leo H, Kershen, Joshua C, Beson, Brent A, Wallendorf, Michael, Bucelli, Robert C, Mozaffar, Tahseen, Pestronk, Alan, and Weihl, Conrad C

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Rare Diseases, Autoimmune Disease, Inflammatory and immune system, 5'-Nucleotidase, Adult, Aged, Autoantibodies, Female, Humans, Male, Middle Aged, Myositis, Myositis, Inclusion Body, Retrospective Studies, Clinical Sciences, Neurosciences, Clinical and health psychology
Abstract

ObjectiveTo define the clinicopathologic features and diagnostic utility associated with anti-cytosolic 5'-nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs).MethodsAnti-NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases.ResultsOf 593 patients, anti-NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti-NT5C1A antibody seropositive patients had more cytochrome oxidase-negative fibers compared with anti-NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti-NT5C1A antibody, three patients (21%) converted to positive. Anti-NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs.InterpretationAnti-NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non-IBM IIMs and it does not correlate with any prognostic factors or survival.

Published
2021

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

Author

Paganoni, Sabrina, Hendrix, Suzanne, Dickson, Samuel P, Knowlton, Newman, Macklin, Eric A, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret Ayo, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman‐Patterson, Terry D, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Hall, Meghan, Kittle, Gale, Eydinov, Matthew, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, St Pierre, Maria E, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Yu, Zi‐Fan, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Brain Disorders, Rare Diseases, Neurodegenerative, Clinical Trials and Supportive Activities, Clinical Research, ALS, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Double-Blind Method, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Phenylbutyrates, Taurochenodeoxycholic Acid, Time, Young Adult, amyotrophic lateral sclerosis, CENTAUR, motor neuron disease, sodium phenylbutyrate&#8208, taurursodiol, survival analysis, sodium phenylbutyrate-taurursodiol, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

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.

Published
2021

20. Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis

Author

Paganoni, Sabrina, Macklin, Eric A, Hendrix, Suzanne, Berry, James D, Elliott, Michael A, Maiser, Samuel, Karam, Chafic, Caress, James B, Owegi, Margaret A, Quick, Adam, Wymer, James, Goutman, Stephen A, Heitzman, Daragh, Heiman-Patterson, Terry, Jackson, Carlayne E, Quinn, Colin, Rothstein, Jeffrey D, Kasarskis, Edward J, Katz, Jonathan, Jenkins, Liberty, Ladha, Shafeeq, Miller, Timothy M, Scelsa, Stephen N, Vu, Tuan H, Fournier, Christina N, Glass, Jonathan D, Johnson, Kristin M, Swenson, Andrea, Goyal, Namita A, Pattee, Gary L, Andres, Patricia L, Babu, Suma, Chase, Marianne, Dagostino, Derek, Dickson, Samuel P, Ellison, Noel, Hall, Meghan, Hendrix, Kent, Kittle, Gale, McGovern, Michelle, Ostrow, Joseph, Pothier, Lindsay, Randall, Rebecca, Shefner, Jeremy M, Sherman, Alexander V, Tustison, Eric, Vigneswaran, Prasha, Walker, Jason, Yu, Hong, Chan, James, Wittes, Janet, Cohen, Joshua, Klee, Justin, Leslie, Kent, Tanzi, Rudolph E, Gilbert, Walter, Yeramian, Patrick D, Schoenfeld, David, and Cudkowicz, Merit E

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Neurodegenerative, Rare Diseases, Clinical Research, ALS, Brain Disorders, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Amyotrophic Lateral Sclerosis, Disease Progression, Double-Blind Method, Drug Combinations, Female, Humans, Intention to Treat Analysis, Male, Middle Aged, Phenylbutyrates, Severity of Illness Index, Taurochenodeoxycholic Acid, Treatment Outcome, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundSodium 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.MethodsIn 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.ResultsA 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.ConclusionsSodium 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.).

Published
2020

21. Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Author

Goyal, Namita A, Berry, James D, Windebank, Anthony, Staff, Nathan P, Maragakis, Nicholas J, Berg, Leonard H, Genge, Angela, Miller, Robert, Baloh, Robert H, Kern, Ralph, Gothelf, Yael, Lebovits, Chaim, and Cudkowicz, Merit

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Orphan Drug, Clinical Research, Rare Diseases, ALS, Brain Disorders, Neurodegenerative, Clinical Trials and Supportive Activities, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Good Health and Well Being, Amyotrophic Lateral Sclerosis, Biological Variation, Population, Biomarkers, Clinical Trials as Topic, Disease Progression, Drug Development, Humans, Muscle Strength, Outcome Assessment, Health Care, Physical Functional Performance, Precision Medicine, Prognosis, Reproducibility of Results, Respiratory Function Tests, Risk Assessment, Speech, Transcranial Magnetic Stimulation, amyotrophic lateral sclerosis, biomarkers, clinical trials, disease heterogeneity, enrichment strategies, outcome measures, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.

Published
2020

22. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study

Author

Sembinelli, Dylan, Teitelbaum, Jeanne, Nicolle, Michael, Bernard, Emilien, Svahn, Juliette, Spinazzi, Marco, Stojkovic, Tanya, Demeret, Sophie, Weiss, Nicolas, Le Guennec, Loïc, Messai, Sihame, Tranchant, Christine, Nadaj-Pakleza, Aleksandra, Chanson, Jean-Baptiste, Suliman, Muhtadi, Zaidi, Leila, Tard, Celine, Lecointe, Peggy, Zschüntzsch, Jana, Schmidt, Jens, Glaubitz, Stefanie, Zeng, Rachel, Scholl, Matthias, Kowarik, Markus, Ziemann, Ulf, Krumbholz, Markus, Martin, Pascal, Ruschil, Christoph, Dünschede, Jutta, Kemmner, Roswitha, Rumpel, Natalie, Berger, Benjamin, Totzeck, Andreas, Hagenacker, Tim, Stolte, Benjamin, Iorio, Raffaele, Evoli, Amelia, Falso, Silvia, Antozzi, Carlo, Frangiamore, Rita, Vanoli, Fiammetta, Rinaldi, Elena, Deguchi, Kazushi, Minami, Naoya, Nagane, Yuriko, Suzuki, Yasushi, Ishida, Sayaka, Suzuki, Shigeaki, Nakahara, Jin, Nagaoka, Astushi, Yoshimura, Shunsuke, Konno, Shingo, Tsuya, Youko, Uzawa, Akiyuki, Kubota, Tomoya, Takahashi, Masanori, Okuno, Tatsusada, Murai, Hiroyuki, Gilhus, Nils Erik, Boldingh, Marion, Rønning, Tone Hakvåg, Chyrchel-Paszkiewicz, Urszula, Kumor, Klaudiusz, Zielinski, Tomasz, Banaszkiewicz, Krzysztof, Błaż, Michał, Kłósek, Agata, Świderek-Matysiak, Mariola, Szczudlik, Andrzej, Paśko, Aneta, Szczechowski, Lech, Banach, Marta, Ilkowski, Jan, Kapetanovic Garcia, Solange, Ortiz Bagan, Patricia, Belén Cánovas Segura, Ana, Turon Sans, Joana, Vidal Fernandez, Nuria, Cortes Vicente, Elena, Rodrigo Armenteros, Patricia, Ashraghi, Mohammad, Cavey, Ana, Haslam, Liam, Emery, Anna, Liow, Kore, Yegiaian, Sharon, Barboi, Alexandru, Vazquez, Rosa Maria, Lennon, Joshua, Pascuzzi, Robert M, Bodkin, Cynthia, Guingrich, Sandra, Comer, Adam, Bromberg, Mark, Janecki, Teresa, Saba, Sami, Tellez, Marco, Elsheikh, Bakri, Freimer, Miriam, Heintzman, Sarah, Govindarajan, Raghav, Guptill, Jeffrey, Massey, Janice M, Juel, Vern, Gonzalez, Natalia, Habib, Ali A, Mozaffar, Tahseen, Korb, Manisha, Goyal, Namita, Machemehl, Hannah, Manousakis, Georgios, Allen, Jeffrey, Harper, Emily, Farmakidis, Constantine, Saavedra, Lilli, Dimachkie, Mazen, Pasnoor, Mamatha, Akhter, Salma, Beydoun, Said, McIlduff, Courtney, Nye, Joan, Roy, Bhaskar, Munro Sheldon, Bailey, Nowak, Richard, Barnes, Benjamin, Rivner, Michael, Suresh, Niraja, Shaw, Jessica, Harvey, Brittany, Lam, Lucy, Thomas, Nikki, Chopra, Manisha, Traub, Rebecca E, Jones, Sarah, Wagoner, Mary, Smajic, Sejla, Aly, Radwa, Katz, Jonathan, Chen, Henry, Miller, Robert G, Jenkins, Liberty, Khan, Shaida, Khatri, Bhupendra, Sershon, Lisa, Pavlakis, Pantelis, Holzberg, Shara, Li, Yuebing, Caristo, Irys B, Marquardt, Robert, Hastings, Debbie, Rube, Jacob, Lisak, Robert P, Choudhury, Aparna, Ruzhansky, Katherine, Sachdev, Amit, Shin, Susan, Bratton, Joan, Fetter, Mary, McKinnon, Naya, McKinnon, Jonathan, Sissons-Ross, Laura, Sahu, Amos, Distad, B Jane, Howard, James F, Jr, Bresch, Saskia, Genge, Angela, Hewamadduma, Channa, Hinton, John, Hussain, Yessar, Juntas-Morales, Raul, Kaminski, Henry J, Maniaol, Angelina, Mantegazza, Renato, Masuda, Masayuki, Sivakumar, Kumaraswamy, Śmiłowski, Marek, Utsugisawa, Kimiaki, Vu, Tuan, Weiss, Michael D, Zajda, Małgorzata, Boroojerdi, Babak, Brock, Melissa, de la Borderie, Guillemette, Duda, Petra W, Lowcock, Romana, Vanderkelen, Mark, and Leite, M Isabel

Published
2023
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23. Variable clinical features and genotype-phenotype correlations in 18 patients with late-onset Pompe disease.

Author

Alandy-Dy, Jousef, Wencel, Marie, Hall, Kathy, Simon, Julie, Chen, Yanjun, Valenti, Erik, Yang, Jade, Bali, Deeksha, Lakatos, Anita, Mozaffar, Tahseen, Kimonis, Virginia, and Goyal, Namita

Subjects
Pompe disease, aneurysm, enzyme replacement therapy (ERT), genotype-phenotype correlation, newborn screening, novel GAA variants, pulmonary function studies, six-minute walk test (6MWT), testicular cancer
Abstract

BACKGROUND: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. METHODS: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. RESULTS: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves disease and testicular cancer. CONCLUSIONS: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

Published
2019

25. Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

Author

Grunseich, Christopher, Miller, Ram, Swan, Therese, Glass, David J, Mouelhi, Mohamed El, Fornaro, Mara, Petricoul, Olivier, Vostiar, Igor, Roubenoff, Ronenn, Meriggioli, Matthew N, Kokkinis, Angela, Guber, Robert D, Budron, Maher S, Vissing, John, Soraru, Gianni, Mozaffar, Tahseen, Ludolph, Albert, Kissel, John T, Fischbeck, Kenneth H, group, BVS857 study, Dahlqvist, Julia, Witting, Nanna, Martinelli, Ilaria, Querin, Giorgia, Goyal, Namita A, Cash, Tiyonnoh M, Minton, Brian, Rosenbohm, Angela, Weiland, Ulrike, Weydt, Patrick, Chelnick, Sharon, Iyadurai, Stanley, and King, Wendy

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Rare Diseases, Clinical Research, Neurosciences, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Musculoskeletal, Adult, Aged, Biomimetics, Bulbo-Spinal Atrophy, X-Linked, Cohort Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Insulin-Like Growth Factor I, International Cooperation, Magnetic Resonance Imaging, Male, Middle Aged, Muscular Atrophy, Treatment Outcome, BVS857 study group, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundSpinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932.Findings31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function.InterpretationTMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease.FundingNovartis Pharmaceuticals and the US National Institutes of Health.

Published
2018

26. A cross-sectional analysis of clinical evaluation in 35 individuals with mutations of the valosin-containing protein gene.

Author

Plewa, Jake, Surampalli, Abhilasha, Wencel, Marie, Milad, Merit, Donkervoort, Sandra, Kimonis, Virginia, Mozaffar, Tahseen, Caiozzo, Vincent, and Goyal, Namita

Subjects
Dynamometry, IBMFRS, IBMPFD, Inclusion Body Myopathy, Paget disease, VCP, Adult, Cross-Sectional Studies, Female, Frontotemporal Dementia, Humans, Male, Middle Aged, Muscular Dystrophies, Limb-Girdle, Mutation, Myositis, Inclusion Body, Osteitis Deformans, Severity of Illness Index, Valosin Containing Protein
Abstract

Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale questionairres, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), and pulmonary function studies. Strong correlation was observed between the IBMFRS and measurements of muscle strength with dynamometry and the other functional tests, indicating that it may be utilized in long-term follow-up assessments due to its relative simplicity. This cross-section study represents the most comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals.

Published
2018

27. Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial

Author

Oskarsson, Björn, Moore, Dan, Mozaffar, Tahseen, Ravits, John, Wiedau-Pazos, Martina, Parziale, Nicholas, Joyce, Nanette C, Mandeville, Ross, Goyal, Namita, Cudkowicz, Merit E, Weiss, Michael, Miller, Robert G, and McDonald, Craig M

Subjects
Muscle cramp, amyotrophic lateral sclerosis, fasciculations, neuromuscular, quality of life
Abstract

INTRODUCTION:More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.METHODS:A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.RESULTS:Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P

Published
2018

28. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Kiernan, Matthew, Mathers, Susan, Henderson, Robert, Needham, Merrilee, Schultz, David, Löscher, Wolfgang, Mitrovic, Nenad, Rath, Jakob, Damme, Philip Van, De Bleecker, Jan L., Delstanche, Stéphanie, Johnston, Wendy, Zinman, Lorne, O'Connell, Colleen, Matte, Genevieve, Dionne, Annie, Korngut, Lawrence, Turnbull, John, Laaksovirta, Hannu, Jokela, Manu, Tapiola, Tero, Soriani, Marie-Hélène, Couratier, Philippe, Camu, William, Corcia, Philippe, Ludolph, Albert, Großkreutz, Julian, Meyer, Thomas, Boentert, Matthias, Schrank, Berthold, Prudlo, Johannes, Untucht, Robert, Hardiman, Orla, Siciliano, Gabriele, Chio', Adriano, Mazzini, Letizia, Inghilleri, Maurizio, Caponnetto, Claudia, Mora, Gabriele, Mora Pardina, Jesús S, Farrero Munoz, Eva, Vázquez Costa, Juan F, Aguera Morales, Eduardo, Varona, Luis, Andersen, Peter, Ingre, Caroline, Johansson, Rune, Radunovic, Aleksandar, Young, Carolyn, Babu, Suma, Shaibani, Aziz, Staff, Nathan, Vu, Tuan, Rivner, Michael, Scelsa, Stephen, Sivakumar, Kumaraswamy, Waheed, Waqar, Heitzman, Daragh, Rana, Sandeep, Pattee, Gary, Ajroud-Driss, Senda, Bayat, Elham, Kasarskis, Edward, Lange, Dale J, Elliott, Michael, Harris, Brent, Felice, Kevin, Pulley, Michael T, Kwan, Justin, Brown, Martin, Ravits, John, Burford, Matthew, Karam, Chafic, Miller, Timothy, Andrews, Jinsy, Levine, Todd, Locatelli, Eduardo, Wymer, James, Bedlack, Richard, Fee, Dominic, Goyal, Namita, Oskarsson, Bjorn, McCluskey, Leo, Caress, James, Weiss, Michael, Quick, Adam, Bromberg, Mark, Lacomis, David, Goutman, Stephen, Rezania, Kourosh, Guliani, Gaurav, Goslin, Kimberly, Katz, Jonathan S, Cudkowicz, Merit, Genge, Angela, Maragakis, Nicholas, Petri, Susanne, van den Berg, Leonard, Aho, Valtteri V, Sarapohja, Toni, Kuoppamäki, Mikko, Garratt, Chris, and Al-Chalabi, Ammar

Published
2021
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30. A Hemizygous Deletion Within the PGK1 Gene in Males with PGK1 Deficiency

Author

Behlmann, Andrea Medrano, Goyal, Namita A, Yang, Xiaoyu, Chen, Ping H, and Ankala, Arunkanth

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Metabolic and endocrine, 3′UTR, Deletion, PGK1, Poly-A tail, Polyadenylation, Regulatory element, X-linked disorder, Clinical sciences
Abstract

Phosphoglycerate kinase-1 (PGK1) deficiency is a rare X-linked disorder caused by pathogenic variants in the PGK1 gene. Complete loss-of-function variants have not been reported in this gene, indicating that residual enzyme function is critical for viability in males. Therefore, copy number variants (CNVs) that include single exon or multiple exon deletions or duplications are generally not expected in individuals with PGK1 deficiency. Here we describe a 64-year-old male presenting with a family history (three additional affected males) and a personal history of childhood-onset metabolic myopathy that involves episodes of muscle pain, stiffness after activity, exercise intolerance, and myoglobinuria after exertion. Biochemical analysis on a muscle biopsy indicated significantly reduced activity (15% compared to normal) for phosphoglycerate kinase (PGK1), a glycolytic enzyme encoded by PGK1. A diagnosis of PGK1 deficiency was established by molecular analysis which detected an approximately 886 kb deletion involving the polyadenylation site in the 3'UTR of the PGK1 gene. RNA analysis showed significantly reduced PGK1 transcript levels (30% compared to normal). This is the first deletion reported in the PGK1 gene and is the first pathogenic variant involving the 3'UTR polyadenylation site of this gene. Our report emphasizes the role of 3'UTR variants in human disorders and underscores the need for exploring noncoding regions of disease-associated genes when seeking a molecular diagnosis.

Published
2018

31. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial

Author

De Bleecker, Jan L., De Koning, Kathy, De Mey, Katrien, De Pue, Annelien, Mercelis, Rudolf, Wyckmans, Maren, Vinck, Caroline, Wagemaekers, Linda, Baets, Jonathan, Ng, Eduardo, Shabanpour, Jafar, Daniyal, Lubna, Mannan, Shabber, Katzberg, Hans D., Genge, Angela, Siddiqi, Zaeem, Junkerová, Jana, Horakova, Jana, Reguliova, Katerina, Tyblova, Michaela, Jurajdova, Ivana, Novakova, Iveta, Jakubikova, Michala, Pitha, Jiri, Vohanka, Stanislav, Havelkova, Katerina, Horak, Tomas, Bednarik, Josef, Horakova, Mageda, Meisel, Andreas, Remstedt, Dike, Heibutzki, Claudia, Kohler, Siegfried, Gerischer, Lea, Hoffman, Sarah, Stascheit, Frauke, Vissing, John, Zafirakos, Lizzie, Khatri, Kuldeep Kumar, Autzen, Anne, Godtfeldt Stemmerik, Mads Peter, Andersen, Henning, Attarian, Shahram, Salort-Campana, Emmanuelle, Delmont, Emilien, Grapperon, Aude-Marie, Kouton, Ludivine, Tsiskaridze, Alexander, Rózsa, Csilla, Jakab, Gedeonne Margo, Toth, Szilvia, Szabo, Gyorgyi, Bors, David, Szabo, Eniko, Campanella, Angela, Vanoli, Fiammetta, Frangiamore, Rita, Antozzi, Carlo, Bonanno, Silvia, Maggi, Lorenzo, Giossi, Riccardo, Saccà, Francesco, Marsili, Angela, Pane, Chiara, Puorro, Giorgia, Reia, Antonio, Antonini, Giovanni, Alfieri, Girolamo, Morino, Stefania, Garibaldi, Matteo, Fionda, Laura, Leonardi, Luca, Konno, Shingo, Uzawa, Akiyuki, Sakuma, Kaoru, Watanabe, Chiho, Ozawa, Yukiko, Yasuda, Manato, Onishi, Yosuke, Samukawa, Makoto, Tsuda, Tomoko, Suzuki, Yasushi, Ishida, Sayaka, Watanabe, Genya, Takahashi, Masanori, Nakamura, Hiroko, Sugano, Erina, Kubota, Tomoya, Imai, Tomihiro, Suzuki., Mari, Mori, Ayako, Yamamoto, Daisuke, Ikeda, Kazuna, Hisahara, Shin, Masuda, Masayuki, Takaki, Miki, Minemoto, Kanako, Ido, Nobuhiro, Naito, Makiko, Okubo, Yoshihiko, Sugimoto, Takamichi, Takematsu, Yuka, Kamei, Ayumi, Shimizu, Mihiro, Naito, Hiroyuki, Nomura, Eiichi, Van Heur, Marjolein, Peters, Anne-Marie, Tannemaat, Martijn, Ruiter, Annabel, Keene, Kevin, Halas, Marek, Szczudlik, Andrzej, Pinkosz, Marta, Frasinska, Monika, Zwolinska, Grazyna, Kostera-Pruszczyk, Anna, Golenia, Aleksandra, Szczudlik, Piotr, Szczechowski, Lech, Pasko, Aneta, Poverennova, Irina, Urtaeva, Lubov, Kuznetsova, Nadezhda, Romanova, Tatiana, Nadezhda, Malkova, Lapochka, Elena, Korobko, Denis, Vergunova, Ilona, Melnikova, Anna, Bulatova, Ekaterina, Antipenko, Elena, Basta, Ivana, Bozovic, Ivo, Lavrnic, Dragana, Stojanovic, Vidosava Rakocevic, Beydoun, Said, Akhter, Salma, Malekniazi, Ali, Darki, Leila, Pimentel, Norianne, Cannon, Victoria, Chopra, Manisha, Traub, Rebecca, Mozaffar, Tahseen, Hernandez, Isela, Turner, Ivonne, Habib, Ali, Goyal, Namita, Kak, Manisha, Velasquez, Erik, Lam, Lucy, Suresh, Niraja, Farias, Jerrica, Jones, Sarah, Wagoner, Mary, Eggleston, Debbie, Bertorini, Tulio, Benzel, Cindy, Henegar, Robert, Pillai, Rekha, Bharavaju-Sanka, Ratna, Paiz, Carolyn, Jackson, Carlayne, Ruzhansky, Katherine, Dimitrova, Diana, Visser, Amy, Chahin, Nizar, Levine, Todd, Lisak, Robert, Jia, Kelly, Mada, Flicia, Bernitsas, Evanthia, Pasnoor, Mamatha, Roath, Katherine, Colgan, Samantha, Currence, Melissa, Heim, Andrew, Barohn, Richard, Dimachkie, Mazen, Statland, Jeffrey, Jawdat, Omar, Jabari, Duaa, Farmakidis, Constantine, Gilchrist, James, Li, Yuebing, Caristo, Irys, Hastings, Debbie, Morren, John Anthony, Weiss, Michael, Muppidi, Srikanth, Nguyen, Tia, Welsh, Lesly, So, Yuen, Goyal, Neelam, Pulley, Michael, Bailey, Cathy, Quraishi, Zubair, Berger, Alan, Sahagian, Gregory, Camberos, Yasmin, Frishberg, Benjamin, Howard, James F, Jr, Bril, Vera, Vu, Tuan, Karam, Chafic, Peric, Stojan, Margania, Temur, Murai, Hiroyuki, Bilinska, Malgorzata, Shakarishvili, Roman, Smilowski, Marek, Guglietta, Antonio, Ulrichts, Peter, Vangeneugden, Tony, Utsugisawa, Kimiaki, Verschuuren, Jan, and Mantegazza, Renato

Published
2021
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32. Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability.

Author

Berry, James D, Paganoni, Sabrina, Atassi, Nazem, Macklin, Eric A, Goyal, Namita, Rivner, Michael, Simpson, Ericka, Appel, Stanley, Grasso, Daniela L, Mejia, Nicte I, Mateen, Farrah, Gill, Alan, Vieira, Fernando, Tassinari, Valerie, and Perrin, Steven

Subjects
Adult, Aged, Amyotrophic Lateral Sclerosis: diagnosis, drug therapy, Bradycardia: chemically induced, Fatigue: chemically induced, Female, Fingolimod Hydrochloride: adverse effects, therapeutic use, Humans, Immunosuppressive Agents: adverse effects, therapeutic use, Male, Middle Aged, Single-Blind Method
Abstract

Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS.Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression.Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P

Published
2017

33. Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

Author

Dyck, Peter J, Kincaid, John C, Dyck, P James B, Chaudhry, Vinay, Goyal, Namita A, Alves, Christina, Salhi, Hayet, Wiesman, Janice F, Labeyrie, Celine, Robinson‐Papp, Jessica, Cardoso, Márcio, Laura, Matilde, Ruzhansky, Katherine, Cortese, Andrea, Brannagan, Thomas H, Khoury, Julie, Khella, Sami, Waddington‐Cruz, Márcia, Ferreira, João, Wang, Annabel K, Pinto, Marcus V, Ayache, Samar S, Benson, Merrill D, Berk, John L, Coelho, Teresa, Polydefkis, Michael, Gorevic, Peter, Adams, David H, Plante‐Bordeneuve, Violaine, Whelan, Carol, Merlini, Giampaolo, Heitner, Stephen, Drachman, Brian M, Conceição, Isabel, Klein, Christopher J, Gertz, Morie A, Ackermann, Elizabeth J, Hughes, Steven G, Mauermann, Michelle L, Bergemann, Rito, Lodermeier, Karen A, Davies, Jenny L, Carter, Rickey E, and Litchy, William J

Subjects
Neurodegenerative, Peripheral Neuropathy, Neurosciences, Chronic Pain, Clinical Research, Pain Research, Adult, Aged, Aged, 80 and over, Amyloid Neuropathies, Familial, Cohort Studies, Diagnostic Techniques, Neurological, Disability Evaluation, Female, Humans, International Cooperation, Male, Middle Aged, Neural Conduction, Neurologists, Oligonucleotides, Outcome Assessment, Health Care, Severity of Illness Index, disability, familial amyloidotic polyneuropathy, neurophysiologic tests, oligonucleotide trials, peripheral neuropathy, polyneuropathy signs, proficiency, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

IntroductionPolyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.MethodsWe assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores.ResultsThe mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.ConclusionsSpecially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Published
2017

36. Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes

Author

Lindborg, Stacy R., primary, Goyal, Namita A., additional, Katz, Jonathan, additional, Burford, Matthew, additional, Li, Jenny, additional, Kaspi, Haggai, additional, Abramov, Natalie, additional, Boulanger, Bruno, additional, Berry, James D., additional, Nicholson, Katharine, additional, Mozaffar, Tahseen, additional, Miller, Robert, additional, Jenkins, Liberty, additional, Baloh, Robert H., additional, Lewis, Richard, additional, Staff, Nathan P., additional, Owegi, Margaret Ayo, additional, Dagher, Bob, additional, Blondheim‐Shraga, Netta R., additional, Gothelf, Yael, additional, Levy, Yossef S., additional, Kern, Ralph, additional, Aricha, Revital, additional, Windebank, Anthony J., additional, Bowser, Robert, additional, Brown, Robert H., additional, and Cudkowicz, Merit E., additional

Published
2024
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37. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis.

Author

Pasnoor, Mamatha, He, Jianghua, Herbelin, Laura, Burns, Ted M, Nations, Sharon, Bril, Vera, Wang, Annabel K, Elsheikh, Bakri H, Kissel, John T, Saperstein, David, Shaibani, J Aziz, Jackson, Carlayne, Swenson, Andrea, Howard, James F, Goyal, Namita, David, William, Wicklund, Matthew, Pulley, Michael, Becker, Mara, Mozaffar, Tahseen, Benatar, Michael, Pazcuzzi, Robert, Simpson, Ericka, Rosenfeld, Jeffrey, Dimachkie, Mazen M, Statland, Jeffrey M, Barohn, Richard J, and Methotrexate in MG Investigators of the Muscle Study Group

Subjects
Methotrexate in MG Investigators of the Muscle Study Group, Humans, Myasthenia Gravis, Methotrexate, Prednisone, Receptors, Cholinergic, Immunosuppressive Agents, Autoantibodies, Treatment Outcome, Severity of Illness Index, Area Under Curve, Double-Blind Method, Adult, Aged, Aged, 80 and over, Middle Aged, Canada, United States, Female, Male, Clinical Trials and Supportive Activities, Rare Diseases, Autoimmune Disease, Neurosciences, Clinical Research, Orphan Drug, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).MethodsWe performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.ResultsFifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).ConclusionsWe found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.Classification of evidenceThis study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

Published
2016

39. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Author

Neurologen, Projectafdeling ALS, Brain, Opleiding Neurologie, ALS Trial team, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A., Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H., Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M., Pradat, Pierre Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A., Meyer, Thomas, Hanna, Michael G., Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C., Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M., Turner, Martin R., Wuu, Joanne, Bennett, Richard, Dang, Hoang, Sundgreen, Claus, ORARIALS-01 trial team, Neurologen, Projectafdeling ALS, Brain, Opleiding Neurologie, ALS Trial team, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A., Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H., Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M., Pradat, Pierre Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A., Meyer, Thomas, Hanna, Michael G., Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C., Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M., Turner, Martin R., Wuu, Joanne, Bennett, Richard, Dang, Hoang, Sundgreen, Claus, and ORARIALS-01 trial team

Published
2024

41. Tongue atrophy and fasciculations in transthyretin familial amyloid neuropathy: An ALS mimicker.

Author

Goyal, Namita A and Mozaffar, Tahseen

Subjects
Genetics, Neurosciences
Abstract

ObjectiveMacroglossia is a well-known feature of amyloidosis; however, tongue atrophy and fasciculations are rarely seen and can lead to the misdiagnosis of amyotrophic lateral sclerosis (ALS).MethodsWe identified 2 unrelated patients with atypical features of tongue atrophy and fasciculations in the setting of a severe neuropathy.ResultsBoth patients were confirmed to have transthyretin-related familial amyloid polyneuropathy (TTR-FAP) by genetic testing.ConclusionsTTR-FAP should be considered as a possible mimicker of ALS when tongue atrophy and fasciculations are seen in the setting of a severely progressive polyneuropathy. Other atypical mimickers of ALS include polyglucosan body disease, hexosaminidase A deficiency, multisystem proteinopathy, and Allgrove syndrome.

Published
2015

42. An overview of polymyositis and dermatomyositis

Author

Findlay, Andrew R, Goyal, Namita A, and Mozaffar, Tahseen

Subjects
Autoimmune Disease, Rare Diseases, Clinical Research, Adrenal Cortex Hormones, Biological Products, Dermatomyositis, Humans, Immunosuppressive Agents, Polymyositis, Prevalence, Prognosis, Treatment Outcome, dermatomyositis, inclusion-body myositis, inflammatory myopathy, polymyositis, myositis-specific autoantibodies, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

Polymyositis and dermatomyositis are inflammatory myopathies that differ in their clinical features, histopathology, response to treatment, and prognosis. Although their clinical pictures differ, they both present with symmetrical, proximal muscle weakness. Treatment relies mainly upon empirical use of corticosteroids and immunosuppressive agents. A deeper understanding of the molecular pathways that drive pathogenesis, careful phenotyping, and accurate disease classification will aid clinical research and development of more efficacious treatments. In this review we address the current knowledge of the epidemiology, clinical characteristics, diagnostic evaluation, classification, pathogenesis, treatment, and prognosis of polymyositis and dermatomyositis.

Published
2015

43. Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

Author

Mazia, Claudio Gabriel, Wilken, Miguel, Barroso, Fabio, Saba, Juliet, Rugiero, Marcelo, Bettini, Mariela, Chaves, Marcelo, Vidal, Gonzalo, Garcia, Alejandra Dalila, De Bleecker, Jan, Van den Abeele, Guy, de Koning, Kathy, De Mey, Katrien, Mercelis, Rudy, Mahieu, Délphine, Wagemaekers, Linda, Van Damme, Philip, Depreitere, Annelies, Schotte, Caroline, Smetcoren, Charlotte, Stevens, Olivier, Van Daele, Sien, Vandenbussche, Nicolas, Vanhee, Annelies, Verjans, Sarah, Vynckier, Jan, D'Hondt, Ann, Tilkin, Petra, Alves de Siqueira Carvalho, Alzira, Dias Brockhausen, Igor, Feder, David, Ambrosio, Daniel, César, Pamela, Melo, Ana Paula, Martins Ribeiro, Renata, Rocha, Rosana, Bezerra Rosa, Bruno, Veiga, Thabata, da Silva, Luiz Augusto, Santos Engel, Murilo, Gonçalves Geraldo, Jordana, Ananias Morita, Maria da Penha, Nogueira Coelho, Erica, Paiva, Gabriel, Pozo, Marina, Prando, Natalia, Martineli Torres, Debora Dada, Butinhao, Cristiani Fernanda, Duran, Gustavo, Gomes da Silva, Tamires Cristina, Otavio Maia Gonçalves, Luiz, Pazetto, Lucas Eduardo, Fialho, Tomás Augusto Suriane, Renata Cubas Volpe, Luciana, Souza Duca, Luciana, Souza Bulle Oliveira, Acary, Amaral Andrade, Ana Carolina, Annes, Marcelo, Duarte Silva, Liene, Cavalcante Lino, Valeria, Pinto, Wladimir, Assis, Natália, Carrara, Fernanda, Miranda, Carolina, Souza, Iandra, Fernandes, Patricia, Siddiqi, Zaeem, Phan, Cecile, Narayan, Jeffrey, Blackmore, Derrick, Mallon, Ashley, Roderus, Rikki, Watt, Elizabeth, Junkerova, Jana, Kurkova, Barbora, Reguliova, Katarina, Zapletalova, Olga, Pitha, Jiri, Novakova, Iveta, Tyblova, Michaela, Jurajdova, Ivana, Wolfova, Marcela, Andersen, Henning, Harbo, Thomas, Vinge, Lotte, Krogh, Susanne, Mogensen, Anita, Vissing, John, Højgaard, Joan, Witting, Nanna, Mette Ostergaard Autzen, Anne, Pedersen, Jane, Eralinna, Juha-Pekka, Laaksonen, Mikko, Oksaranta, Olli, Harrison, Tuula, Eriksson, Jaana, Rozsa, Csilla, Horvath, Melinda, Lovas, Gabor, Matolcsi, Judit, Szabo, Gyorgyi, Jakab, Gedeonne, Szabadosne, Brigitta, Antonini, Giovanni, Di Pasquale, Antonella, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Fionda, Laura, Filla, Allessandro, Costabile, Teresa, Marano, Enrico, Saccà, Francesco, Fasanaro, Angiola, Marsili, Angela, Puorro, Giorgia, Mantegazza, Renato, Antozzi, Carlo, Bonanno, Silvia, Camera, Giorgia, Locatelli, Alberta, Maggi, Lorenzo, Pasanisi, Maria, Campanella, Angela, Evoli, Amelia, Alboini, Paolo Emilio, D'Amato, Valentina, Iorio, Raffaele, Kanai, Tetsuya, Kawaguchi, Naoki, Mori, Masahiro, Kaneko, Yoko, Kanzaki, Akiko, Kobayashi, Eri, Masaki, Katsuhisa, Matsuse, Dai, Matsushita, Takuya, Uehara, Taira, Shimpo, Misa, Jingu, Maki, Kikutake, Keiko, Nakamura, Yumiko, Sano, Yoshiko, Nagane, Yuriko, Kamegamori, Ikuko, Tsuda, Tomoko, Fujii, Yuko, Futono, Kazumi, Ozawa, Yukiko, Mizugami, Aya, Saito, Yuka, Morikawa, Miyuki, Samukawa, Makoto, Kamakura, Sachiko, Miyawaki, Eriko, Mitazaki, Teiichiro, Motomura, Masakatsu, Mukaino, Akihiro, Yoshimura, Shunsuke, Asada, Shizuka, Yoshida, Seiko, Amamoto, Shoko, Kobashikawa, Tomomi, Koga, Megumi, Maeda, Yasuko, Takada, Kazumi, Takada, Mihoko, Tsurumaru, Masako, Yamashita, Yumi, Akiyama, Tetsuya, Narikawa, Koichi, Tano, Ohito, Tsukita, Kenichi, Kurihara, Rikako, Meguro, Fumie, Fukuda, Yusuke, Sato, Miwako, Funaka, Soichiro, Kawamura, Tomohiro, Makamori, Masayuki, Takahashi, Masanori, Taichi, Namie, Hasuike, Tomoya, Higuchi, Eriko, Kobayashi, Hisako, Osakada, Kaori, Tsuda, Emiko, Shimohama, Shun, Hayashi, Takashi, Hisahara, Shin, Kawamata, Jun, Murahara, Takashi, Saitoh, Masaki, Suzuki, Shuichiro, Yamamoto, Daisuke, Ishiyama, Yoko, Ishiyama, Naoko, Noshiro, Mayuko, Takeyama, Rumi, Uwasa, Kaori, Yasuda, Ikuko, van der Kooi, Anneke, de Visser, Marianne, Gibson, Tamar, Casasnovas, Carlos, Alberti Aguilo, Maria Antonia, Homedes-Pedret, Christian, Julia Palacios, Natalia, Diez Porras, Laura, Velez Santamaria, Valentina, Lazaro, Ana, Diez Tejedor, Exuperio, Gomez Salcedo, Pilar, Fernandez-Fournier, Mireya, Lopez Ruiz, Pedro, Rodriguez de Rivera, Francisco Javier, Sastre, Maria, Gamez, Josep, Sune, Pilar, Salvado, Maria, Gili, Gisela, Mazuela, Gonzalo, Illa, Isabel, Cortes Vicente, Elena, Diaz-Manera, Jordi, Querol Gutierrez, Luis Antonio, Rojas Garcia, Ricardo, Vidal, Nuria, Arribas-Ibar, Elisabet, Piehl, Fredrik, Hietala, Albert, Bjarbo, Lena, Sengun, Ihsan, Meherremova, Arzu, Ozcelik, Pinar, Balkan, Bengu, Tuga, Celal, Ugur, Muzeyyen, Erdem-Ozdamar, Sevim, Bekircan-Kurt, Can Ebru, Acar, Nazire Pinar, Yilmaz, Ezgi, Caliskan, Yagmur, Orsel, Gulsah, Efendi, Husnu, Aydinlik, Seda, Cavus, Hakan, Kutlu, Ayse, Becerikli, Gulsah, Semiz, Cansu, Tun, Ozlem, Terzi, Murat, Dogan, Baki, Onar, Musa Kazim, Sen, Sedat, Kirbas Cavdar, Tugce, Veske, Adife, Norwood, Fiona, Dimitriou, Aikaterini, Gollogly, Jakit, Mahdi-Rogers, Mohamed, Seddigh, Arshira, Sokratous, Giannis, Maier, Gal, Sohail, Faisal, Jacob, Saiju, Sadalage, Girija, Torane, Pravin, Brown, Claire, Shah, Amna, Sathasivam, Sivakumar, Arndt, Heike, Davies, Debbie, Watling, Dave, Amato, Anthony, Cochrane, Thomas, Salajegheh, Mohammed, Roe, Kristen, Amato, Katherine, Toska, Shirli, Wolfe, Gil, Silvestri, Nicholas, Patrick, Kara, Zakalik, Karen, Katz, Jonathan, Miller, Robert, Engel, Marguerite, Forshew, Dallas, Bravver, Elena, Brooks, Benjamin, Plevka, Sarah, Burdette, Maryanne, Cunningham, Scott, Sanjak, Mohammad, Kramer, Megan, Nemeth, Joanne, Schommer, Clara, Tierney, Scott, Juel, Vern, Guptill, Jeffrey, Hobson-Webb, Lisa, Massey, Janice, Beck, Kate, Carnes, Donna, Loor, John, Anderson, Amanda, Pascuzzi, Robert, Bodkin, Cynthia, Kincaid, John, Snook, Riley, Guingrich, Sandra, Micheels, Angela, Chaudhry, Vinay, Corse, Andrea, Mosmiller, Betsy, Kelley, Andrea, Ho, Doreen, Srinivasan, Jayashri, Vytopil, Michal, Jara, Jordan, Ventura, Nicholas, Scala, Stephanie, Carter, Cynthia, Donahue, Craig, Herbert, Carol, Weiner, Elaine, Alam, Sharmeen, McKinnon, Jonathan, Haar, Laura, McKinnon, Naya, Alcon, Karan, McKenna, Kaitlyn, Sattar, Nadia, Daniels, Kevin, Jeffery, Dennis, Freimer, Miriam, Hoyle, Joseph Chad, Kissel, John, Agriesti, Julie, Chelnick, Sharon, Mezache, Louisa, Pineda, Colleen, Muharrem, Filiz, Karam, Chafic, Khoury, Julie, Marburger, Tessa, Kaur, Harpreet, Dimitrova, Diana, Gilchrist, James, Agrawal, Brajesh, Elsayed, Mona, Kohlrus, Stephanie, Andoin, Angela, Darnell, Taylor, Golden, Laura, Lokaitis, Barbara, Seelback, Jenna, Muppidi, Srikanth, Goyal, Neelam, Sakamuri, Sarada, So, Yuen T., Paulose, Shirley, Pol, Sabrina, Welsh, Lesly, Bhavaraju-Sanka, Ratna, Tobon Gonzales, Alejandro, Dishman, Lorraine, Jones, Floyd, Gonzalez, Anna, Padilla, Patricia, Saklad, Amy, Silva, Marcela, Kazamel, Mohamed, Alsharabati, Mohammad, Lu, Liang, Nozaki, Kenkichi, Mumfrey-Thomas, Sandi, Woodall, Amy, Mozaffar, Tahseen, Cash, Tiyonnoh, Goyal, Namita, Roy, Gulmohor, Mathew, Veena, Maqsood, Fatima, Minton, Brian, Jones, H. James, Rosenfeld, Jeffrey, Garcia, Rebekah, Echevarria, Laura, Garcia, Sonia, Pulley, Michael, Aranke, Shachie, Berger, Alan Ross, Shah, Jaimin, Shabbir, Yasmeen, Smith, Lisa, Varghese, Mary, Gutmann, Laurie, Gutmann, Ludwig, Jerath, Nivedita, Nance, Christopher, Swenson, Andrea, Olalde, Heena, Kressin, Nicole, Sieren, Jeri, Barohn, Richard, Dimachkie, Mazen, Glenn, Melanie, McVey, April, Pasnoor, Mamatha, Statland, Jeffery, Wang, Yunxia, Liu, Tina, Emmons, Kelley, Jenci, Nicole, Locheke, Jerry, Fondaw, Alex, Johns, Kathryn, Rico, Gabrielle, Walsh, Maureen, Herbelin, Laura, Hafer-Macko, Charlene, Kwan, Justin, Zilliox, Lindsay, Callison, Karen, Young, Valerie, DiSanzo, Beth, Naunton, Kerry, Benatar, Michael, Bilsker, Martin, Sharma, Khema, Cooley, Anne, Reyes, Eliana, Michon, Sara-Claude, Sheldon, Danielle, Steele, Julie, Howard Jr, James, Chopra, Manisha, Traub, Rebecca, Vu, Tuan, Katzin, Lara, McClain, Terry, Harvey, Brittany, Hart, Adam, Huynh, Kristin, Beydoun, Said, Chilingaryan, Amaiak, Doan, Victor, Droker, Brian, Gong, Hui, Karimi, Sanaz, Lin, Frank, Pokala, Krishna, Shah, Akshay, Tran, Anh, Akhter, Salma, Malekniazi, Ali, Tandan, Rup, Hehir, Michael, Waheed, Waqar, Lucy, Shannon, Weiss, Michael, Distad, Jane, Strom, Susan, Downing, Sharon, Kim, Bryan, Nowak, Richard, Dicapua, Daniel, Keung, Benison, Kumar, Aditya, Patwa, Huned, Robeson, Kimberly, Yang, Irene, Nye, Joan, Vu, Hong, Murai, Hiroyuki, Uzawa, Akiyuki, Suzuki, Yasushi, Imai, Tomihiro, Shiraishi, Hirokazu, Suzuki, Hidekazu, Okumura, Meinoshin, O’Brien, Fanny, Wang, Jing-Jing, Fujita, Kenji P., and Utsugisawa, Kimiaki

Published
2019
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44. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial

Author

Hanna, Michael G, Badrising, Umesh A, Benveniste, Olivier, Lloyd, Thomas E, Needham, Merrilee, Chinoy, Hector, Aoki, Masashi, Machado, Pedro M, Liang, Christina, Reardon, Katrina A, de Visser, Marianne, Ascherman, Dana P, Barohn, Richard J, Dimachkie, Mazen M, Miller, James A L, Kissel, John T, Oskarsson, Björn, Joyce, Nanette C, Van den Bergh, Peter, Baets, Jonathan, De Bleecker, Jan L, Karam, Chafic, David, William S, Mirabella, Massimiliano, Nations, Sharon P, Jung, Hans H, Pegoraro, Elena, Maggi, Lorenzo, Rodolico, Carmelo, Filosto, Massimiliano, Shaibani, Aziz I, Sivakumar, Kumaraswamy, Goyal, Namita A, Mori-Yoshimura, Madoka, Yamashita, Satoshi, Suzuki, Naoki, Katsuno, Masahisa, Murata, Kenya, Nodera, Hiroyuki, Nishino, Ichizo, Romano, Carla D, Williams, Valerie S L, Vissing, John, Auberson, Lixin Zhang, Wu, Min, de Vera, Ana, Papanicolaou, Dimitris A, and Amato, Anthony A

Published
2019
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45. ALS Identified: two‐year findings from a sponsored ALS genetic testing program.

Author

Goutman, Stephen A., Goyal, Namita A., Payne, Katelyn, Paisán‐Ruiz, Coro, Kupelian, Varant, Kang, Melissa L., Mitchell, Adele A., and Fecteau, Teresa E.

Subjects
*AMYOTROPHIC lateral sclerosis, *MEDICAL personnel, *GENETIC testing, *GENETIC variation, UNITED States. Racketeer Influenced & Corrupt Organizations Act
Abstract

Objective: To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease‐causing variants. Methods: ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS‐associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen. Results: As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS‐associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population. Interpretation: Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Author

Mazia, Claudio Gabriel, Wilken, Miguel, Ortea, Carolina, Saba, Juliet, Rugiero, Marcelo, Bettini, Mariela, Vidal, Gonzalo, Garcia, Alejandra Dalila, Lamont, Phillipa, Leong, Wai-Kuen, Boterhoven, Heidi, Fyfe, Beverly, Roberts, Leslie, Jasinarachchi, Mahi, Willlems, Natasha, Wanschitz, Julia, Löscher, Wolfgang, De Bleecker, Jan, Van den Abeele, Guy, de Koning, Kathy, De Mey, Katrien, Mercelis, Rudy, Wagemaekers, Linda, Mahieu, Delphine, Van Damme, Philip, Smetcoren, Charlotte, Stevens, Olivier, Verjans, Sarah, D'Hondt, Ann, Tilkin, Petra, Alves de Siqueira Carvalho, Alzira, Hasan, Rosa, Dias Brockhausen, Igor, Feder, David, Ambrosio, Daniel, Melo, Ana Paula, Rocha, Rosana, Rosa, Bruno, Veiga, Thabata, Augusto da Silva, Luiz, Gonçalves Geraldo, Jordana, da Penha Morita Ananias, Maria, Nogueira Coelho, Erica, Paiva, Gabriel, Pozo, Marina, Prando, Natalia, Dada Martineli Torres, Debora, Fernanda Butinhao, Cristiani, Coelho, Erica, Renata Cubas Volpe, Luciana, Duran, Gustavo, Gomes da Silva, Tamires Cristina, Otavio Maia Gonçalves, Luiz, Pazetto, Lucas Eduardo, Souza Duca, Luciana, Suriane Fialho, Tomás Augusto, Gheller Friedrich, Maurício André, Guerreiro, Alexandre, Mohr, Henrique, Pereira Martins, Maurer, da Cruz Pacheco, Daiane, Macagnan, Ana Paula, de Cassia Santos, Aline, Bulle Oliveira, Acary Souza, Amaral de Andrade, Ana Carolina, Annes, Marcelo, Cavalcante Lino, Valeria, Pinto, Wladimir, Miranda, Carolina, Carrara, Fernanda, Souza, Iandra, Genge, Angela, Massie, Rami, Campbell, Natasha, Bril, Vera, Katzberg, Hans, Soltani, Mehran, Ng, Eduardo, Siddiqi, Zaeem, Phan, Celile, Blackmore, Derrick, Vohanka, Stanislav, Bednarik, Josef, Chmelikova, Magda, Cierny, Marek, Toncrova, Stanislava, Junkerova, Jana, Kurkova, Barbora, Reguliova, Katarina, Zapletalova, Olga, Pitha, Jiri, Novakova, Iveta, Tyblova, Michaela, Wolfova, Marcela, Jurajdova, Ivana, Andersen, Henning, Harbo, Thomas, Vinge, Lotte, Mogensen, Anita, Højgaard, Joan, Witting, Nanna, Autzen, Anne Mette, Pedersen, Jane, Färkkilä, Markus, Atula, Sari, Nyrhinen, Anne, Erälinna, Juha-Pekka, Laaksonen, Mikko, Oksaranta, Olli, Eriksson, Jaana, Harrison, Tuula, Desnuelle, Claude, Sacconi, Sabrina, Soriani, Marie-Hélène, Decressac, Sonia, Moutarde, Julie, Lahaut, Pauline, Solé, Guilhem, Le Masson, Gwendal, Wielanek-Bachelet, Anne-Cécile, Gaboreau, Morgane, Moreau, Caroline, Wilson, Amy, Vial, Christophe, Bouhour, Françoise, Gervais-Bernard, Helene, Merle, Hélène, Hourquin, Caroline, Lacour, Arnaud, Outteryck, Olivier, Vermersch, Patrick, Zephir, Hélène, Millois, Edouard, Deneve, Michel, Deruelle, Fabienne, Schoser, Benedikt, Wenninger, Stephan, Stangel, Martin, Alvermann, Sascha, Gingele, Stefan, Skripuletz, Thomas, Suehs, Kurt-Wolfram, Trebst, Corinna, Fricke, Karin, Papagiannopoulos, Sotirios, Bostantzopoulou, Sevasti, Vlaikidis, Nicholas, Zampaki, Martha, Papadopoulou, Nikoletta, Mitsikostas, Dimos-Dimitrios, Kasioti, Eleni, Mitropoulou, Efstathia, Charalambous, Despoina, Rozsa, Csilla, Horvath, Melinda, Lovas, Gabor, Matolcsi, Judit, Szabo, Gyorgyi, Szabadosne, Brigitta, Vecsei, Laszlo, Dezsi, Livia, Varga, Edina, Konyane, Monika, Gross, Bella, Azrilin, Olga, Greenbereg, Nelly, Bali Kuperman, Hila, Antonini, Giovanni, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Di Pasquale, Antonella, Filla, Alessandro, Costabile, Teresa, Marano, Enrico, Sacca, Francesco, Marsil, Angela, Puorro, Giorgia, Maestri Tassoni, Michelangelo, De Rosa, Anna, Bonanno, Silvia, Antozzi, Carlo, Maggi, Lorenzo, Campanella, Angela, Angelini, Corrado, Cudia, Paola, Pegoraro, Valentina, Pinzan, Elena, Bevilacqua, Francesca, Orrico, Daniele, Bonifati, Domenico Marco, Evoli, Amelia, Alboini, Paolo Emilio, D'Amato, Valentina, Iorio, Raffaele, Inghilleri, Maurizio, Fionda, Laura, Frasca, Vittorio, Giacomelli, Elena, Gori, Maria, Lopergolo, Diego, Onesti, Emanuela, Gabriele, Maria, Patti, Francesco, Salvatore Caramma, Andrea, Messina, Silvia, Reggio, Ester, Caserta, Cinzia, Uzawa, Akiyuki, Kanai, Tetsuya, Mori, Masahiro, Kaneko, Yoko, Kanzaki, Akiko, Kobayashi, Eri, Masaki, Katsuhisa, Matsuse, Dai, Matsushita, Takuya, Uehara, Taira, Shimpo, Misa, Jingu, Maki, Kikutake, Keiko, Nakamura, Yumiko, Sano, Yoshiko, Nagane, Yuriko, Kamegamori, Ikuko, Fujii, Yuko, Futono, Kazumi, Tsuda, Tomoko, Saito, Yuka, Suzuki, Hidekazu, Morikawa, Miyuki, Samukawa, Makoto, Kamakura, Sachiko, Shiraishi, Hirokazu, Mitazaki, Teiichiro, Motomura, Masakatsu, Mukaino, Akihiro, Yoshimura, Shunsuke, Asada, Shizuka, Kobashikawa, Tomomi, Koga, Megumi, Maeda, Yasuko, Takada, Kazumi, Takada, Mihoko Takada, Yamashita, Yumi, Yoshida, Seiko, Suzuki, Yasushi, Akiyama, Tetsuya, Narikawa, Koichi, Tsukita, Kenichi, Meguro, Fumie, Fukuda, Yusuke, Sato, Miwako, Matsuo, Hidenori, Fukudome, Takayasu, Gondo, Yuichiro, Maeda, Yasuhiro, Nagaishi, Akiko, Nakane, Shunya, Okubo, Yoshinori, Okumura, Meinoshin, Funaka, Soichiro, Kawamura, Tomohiro, Makamori, Masayuki, Takahashi, Masanori, Hasuike, Tomoya, Higuchi, Eriko, Kobayashi, Hisako, Osakada, Kaori, Taichi, Namie, Tsuda, Emiko, Hayashi, Takashi, Hisahara, Shin, Imai, Tomihiro, Kawamata, Jun, Murahara, Takashi, Saitoh, Masaki, Shimohama, Shun, Suzuki, Shuichiro, Yamamoto, Daisuke, Konno, Shingo, Imamura, Tomomi, Inoue, Masashi, Murata, Mayumi, Nakazora, Hiroshi, Nakayama, Ritsu, Ikeda, Yasuko, Ogawa, Miki, Shirane, Maoko, Kanda, Takashi, Kawai, Motoharu, Koga, Michiaki, Ogasawara, Junichi, Omoto, Masatoshi, Sano, Yasuteru, Arima, Hideki, Fukui, Sachie, Shimose, Shigemi, Shinozaki, Hirokazu, Watanabe, Masanori, Yoshikawa, Chieko, van der Kooi, Anneke, de Visser, Marianne, Gibson, Tamar, Maessen, Jos, de Baets, Marc, Faber, Catherine, Keijzers, Maria Johanna, Miesen, Monique, Kostera-Pruszczyk, Anna, Kaminska, Anna, Kim, Byung-Jo, Lee, Chang Nyoung, Koo, Yong Seo, Seok, Hung Youl, Kang, Hoo Nam, Ra, HyeJin, Kim, Byoung Joon, Cho, Eun Bin, Lee, HyeLim, Min, Ju-Hong, Seok, Jinmyoung, Koh, Da Yoon, Kwon, JuYoung, Lee, JiEun, Park, SangAe, Hong, Yoon-Ho, Lim, Jae-Sung, Kim, MiRi, Kim, Seung Min, Kim, Yool-hee, Lee, Hyung Seok, Shin, Ha Young, Hwang, Eun Bi, Shin, MiJu, Sazonov, Denis, Yarmoschuk, Asya, Babenko, Larisa, Malkova, Nadezhda, Melnikova, Anna, Korobko, Denis, Kosykh, Evgeniya, Pokhabov, Dmitry, Nesterova, Yulia, Abramov, Vladislav, Balyazin, Victor, Casasnovas Pons, Carlos, Alberti Aguilo, Maria, Homedes-Pedret, Christian, Palacios, Natalia Julia, Lazaro, Ana, Diez Tejedor, Exuperio, Fernandez-Fournier, Mireya, Lopez Ruiz, Pedro, Rodriguez de Rivera, Francisco Javier, Salvado Figueras, Maria, Gamez, Josep, Salvado, Maria, Cortes Vicente, Elena, Diaz-Manera, Jordi, Querol Gutierrez, Luis, Rojas Garcia, Ricardo, Vidal, Nuria, Arribas-Ibar, Elisabet, Piehl, Fredrik, Hietala, Albert, Bjarbo, Lena, Lindberg, Christopher, Jons, Daniel, Andersson, Blanka, Sengun, Ihsan, Ozcelik, Pinar, Tuga, Celal, Ugur, Muzeyyen, Boz, Cavit, Altiparmak, Didem, Gazioglu, Sibel, Ozen Aydin, Cigdem, Erdem-Ozdamar, Sevim, Bekircan-Kurt, Can Ebru, Yilmaz, Ezgi, Acar, Nazire Pinar, Caliskan, Yagmur, Efendi, Husnu, Aydinlik, Seda, Cavus, Hakan, Semiz, Cansu, Tun, Ozlem, Terzi, Murat, Dogan, Baki, Onar, Musa Kazim, Sen, Sedat, Cavdar, Tugce Kirbas, Norwood, Fiona, Dimitriou, Aikaterini, Gollogly, Jakit, Mahdi-Rogers, Mohamed, Seddigh, Arshira, Maier, Gal, Sohail, Faisal, Sathasivam, Sivakumar, Arndt, Heike, Davies, Debbie, Watling, Dave, Rivner, Michael, Hartmann, J. Edward, Quarles, Brandy, Smalley, Nicole, Amato, Anthony, Cochrane, Thomas, Salajegheh, Mohammed, Roe, Kristen, Amato, Katherine, Toska, Shirli, Wolfe, Gil, Silvestri, Nicholas, Patrick, Kara, Zakalik, Karen, Katz, Jonathan, Miller, Robert, Engel, Marguerite, Bravver, Elena, Brooks, Benjamin, Plevka, Sarah, Burdette, Maryanne, Sanjak, Mohammad, Kramer, Megan, Nemeth, Joanne, Schommer, Clara, Juel, Vern, Guptill, Jeffrey, Hobson-Webb, Lisa, Beck, Kate, Carnes, Donna, Loor, John, Anderson, Amanda, Lange, Dale, Agopian, Eliz, Goldstein, Jonathan, Manning, Erin, Kaplan, Lindsay, Holzberg, Shara, Kassebaum, Nicole, Pascuzzi, Robert, Bodkin, Cynthia, Kincaid, John, Snook, Riley, Guinrich, Sandra, Micheels, Angela, Chaudhry, Vinay, Corse, Andrea, Mosmiller, Betsy, Ho, Doreen, Srinivasan, Jayashri, Vytopil, Michael, Ventura, Nicholas, Scala, Stephanie, Carter, Cynthia, Donahue, Craig, Herbert, Carol, Weiner, Elaine, McKinnon, Jonathan, Haar, Laura, McKinnon, Naya, Alcon, Karan, Daniels, Kevin, Sattar, Nadia, Jeffery, Dennis, McKenna, Kaitlyn, Guidon, Amanda, David, William, Dheel, Christina, Levine-Weinberg, Mark, Nigro, Catherine, Simpson, Ericka, Appel, Stanley H, Lai, Eugene, Lay, Jr, Luis, Pleitez, Milvia, Halton, Sharon, Faigle, Casey, Thompson, Lisa, Sivak, Mark, Shin, Susan, Bratton, Joan, Jacobs, Daniel, Brown, Gavin, Bandukwala, Ibrez, Brown, Morris, Kane, Jennifer, Blount, Ira, Freimer, Miriam, Hoyle, J. Chad, Agriesti, Julie, Khoury, Julie, Marburger, Tessa, Kaur, Harpreet, Dimitrova, Diana, Mellion, Michelle, Sachs, George, Crabtree, Brigid, Keo, Roseann, Perez, Ele Kim, Taber, Sandra, Gilchrist, James, Andoin, Angela, Darnell, Taylor, Goyal, Neelam, Sakamuri, Sarada, So, Yuen T, Welsh, Lesly Welsh, Bhavaraju-Sanka, Ratna, Tobon Gonzalez, Alejandro, Jones, Floyd, Saklad, Amy, Nations, Sharon, Trivedi, Jaya, Hopkins, Steve, Kazamel, Mohamed, Alsharabati, Mohammad, Lu, Liang, Mumfrey-Thomas, Sandi, Woodall, Amy, Richman, David, Butters, Janelle, Lindsay, Molly, Mozaffar, Tahseen, Cash, Tiyonnoh, Goyal, Namita, Roy, Gulmohor, Mathew, Veena, Maqsood, Fatima, Minton, Brian, Jones, H. James, Rosenfeld, Jeffrey, Garcia, Rebekah, Garcia, Sonia, Echevarria, Laura, Pulley, Michael, Aranke, Shachie, Berger, Alan Ross, Shah, Jaimin, Shabbir, Yasmeen, Smith, Lisa, Varghese, Mary, Gutmann, Laurie, Gutmann, Ludwig, Swenson, Andrea, Olalde, Heena, Hafer-Macko, Charlene, Kwan, Justin, Zilliox, Lindsay, Callison, Karen, DiSanzo, Beth, Naunton, Kerry, Bilsker, Martin, Sharma, Khema, Reyes, Eliana, Cooley, Anne, Michon, Sara-Claude, Steele, Julie, Karam, Chafic Karam, Chopra, Manisha, Bird, Shawn, Kaufman, Jacob, Gallatti, Nichole, Vu, Tuan, Katzin, Lara, McClain, Terry, Harvey, Brittany, Hart, Adam, Huynh, Kristin, Beydoun, Said, Chilingaryan, Amaiak, Droker, Brian, Lin, Frank, Shah, Akshay, Tran, Anh, Akhter, Salma, Malekniazi, Ali, Tandan, Rup, Hehir, Michael, Waheed, Waqar, Lucy, Shannon, Weiss, Michael, Distad, Jane, Downing, Sharon, Strom, Susan, Lisak, Robert, Bernitsas, Evanthia, Khan, Omar, Kumar Sriwastava, Shitiz, Tselis, Alexandros, Jia, Kelly, Bertorini, Tulio, Arnold, Thomas, Henderson, Kendrick, Pillai, Rekha, Liu, Ye, Wheeler, Lauren, Hewlett, Jasmine, Vanderhook, Mollie, Dicapua, Daniel, Keung, Benison, Kumar, Aditya, Patwa, Huned, Robeson, Kimberly, Nye, Joan, Vu, Hong, Howard, James F, Jr, Utsugisawa, Kimiaki, Benatar, Michael, Murai, Hiroyuki, Barohn, Richard J, Illa, Isabel, Jacob, Saiju, Vissing, John, Burns, Ted M, Kissel, John T, Muppidi, Srikanth, Nowak, Richard J, O'Brien, Fanny, Wang, Jing-Jing, and Mantegazza, Renato

Published
2017
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