المؤلفون: Sheela Sitaraman, Richard Roxburgh, Kristina Gutschmidt, Ela Stefanescu, Drago Bratkovic, Thomas Burrow, Kornblum Cornelia, Kristl Claeys, Miriam Freimer, Ozlem Goker-Alpan, Srilakshmi Kuchipudi, Alan Pestronk, Wolfgang Löscher, Francoise Bouhour, Maria Judit Molnar, Ans T. van der Ploeg, Halina Bartosik-Psujek, Mitchell Goldman, Robert D. Henderson, Stephanie Dearmey, Colin Quinn, Paula R. Clemens, Priya S. Kishnani, Jennifer B Avelar, Nicola Longo, Shahram Attarian, Robert Hopkin, Tomo Sawada, Blaž Koritnik, George Konstantinos Papadimas, Hideaki Shiraishi, Christopher Lindberg, Jin-Hong Shin, Ivaylo Tarnev, Tahseen Mozaffar, Heather Lau, Michel Tchan, Jozsef Janszky, Tobias Ruck, Sabrina Sacconi, Benedikt Schoser, Hashiguchi Akihiro, Patrick Deegan, Ernest Butler, Nuria Vidal-Fernandez, Antonio Toscano, Tarekegn Hiwot, Gee Kim, Emmanuelle Salort-Campana, Jeff Castelli, Pascal Laforet, Céline Tard, Crystal Eldridge, Aneal Khan, Stephan Wenninger, Simona Fecarotta, Jordi Díaz-Manera, Jorge Alonso-Pérez, Yin-Hsiu Chien, Mark Tarnopolsky, Olimpia Musumeci, Hiroshi Kobayashi, Helio Pedro, Jonathan Cauci, Agnes Sebok, Cynthia Bodkin, Hai Jiang, Julie Berthy, Vescei Laszlo, Derralynn Hughes, David Reyes-Leiva, Aleksandra Dominovic-Kovacevic, Mazen M. Dimachkie, Hernan Amartino, Hani Kushlaf, Barry J. Byrne, Giancarlo Parenti, Henning Andersen, Mark Roberts, Marie Wencel, Jaime Vengoechea

المساهمون: Schoser, B., Roberts, M., Byrne, B. J., Sitaraman, S., Jiang, H., Laforet, P., Toscano, A., Castelli, J., Diaz-Manera, J., Goldman, M., van der Ploeg, A. T., Bratkovic, D., Kuchipudi, S., Mozaffar, T., Kishnani, P. S., Sebok, A., Pestronk, A., Dominovic-Kovacevic, A., Khan, A., Koritnik, B., Tard, C., Lindberg, C., Quinn, C., Eldridge, C., Bodkin, C., Reyes-Leiva, D., Hughes, D., Stefanescu, E., SALORT-CAMPANA, E., Butler, E., Bouhour, F., Kim, G., Konstantinos Papadimas, G., Parenti, G., Bartosik-Psujek, H., Kushlaf, H., Akihiro, H., Lau, H., Pedro, H., Andersen, H., Amartino, H., Shiraishi, H., Kobayashi, H., Tarnev, I., Vengoechea, J., Avelar, J., Shin, J. -H., Cauci, J., Alonso-Perez, J., Janszky, J., Berthy, J., Cornelia, K., Gutschmidt, K., Claeys, K., Judit Molnar, M., Wencel, M., Tarnopolsky, M., Dimachkie, M., Tchan, M., Freimer, M., Longo, N., Vidal-Fernandez, N., Musumeci, O., Goker-Alpan, O., Deegan, P., Clemens, P. R., Roxburgh, R., Henderson, R., Hopkin, R., Sacconi, S., Fecarotta, S., Attarian, S., Wenninger, S., Dearmey, S., Hiwot, T., Burrow, T., Ruck, T., Sawada, T., Laszlo, V., Loscher, W., Chien, Y. -H., Pediatrics

المصدر: LANCET NEUROLOGY
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
The Lancet Neurology, 20(12), 1027-1037. Lancet Publishing Group
PROPEL Study Group 2021, ' Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL) : an international, randomised, double-blind, parallel-group, phase 3 trial ', The Lancet Neurology, vol. 20, no. 12, pp. 1027-1037 . https://doi.org/10.1016/S1474-4422Test(21)00331-8

مصطلحات موضوعية: education.field_of_study, medicine.medical_specialty, 1-Deoxynojirimycin, Adolescent, Glycogen Storage Disease Type II, business.industry, Population, alpha-Glucosidases, Enzyme replacement therapy, Placebo, Treatment Outcome, Double-Blind Method, SDG 3 - Good Health and Well-being, Internal medicine, Miglustat, medicine, Clinical endpoint, Humans, Respiratory function, Neurology (clinical), Adverse effect, education, business, Alglucosidase alfa, medicine.drug

الوصف: Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7ca8d17d8a65ecd5fd078c358714459bTest
https://doi.org/10.1016/s1474-4422Test(21)00331-8

المؤلفون: Stella Mazurová, John W. Day, Mazen M. Dimachkie, Sónia Tizon, Anna Kostera-Pruszczyk, Tahseen Mozaffar, Joel Charrow, Chafic Karam, Ricardo Maré, Jean-Baptiste Noury, Dewi Guellec, Jorge Alonso-Pérez, Acary Souza Bulle Oliveira, Loren D M Pena, Tianyue Zhou, Sergey Illarioshkin, Nathan Thibault, Marcelo Rugiero, Can Ebru Bekircan-Kurt, Lauren Chase, Monica Sciacco, Mamatha Pasnoor, Jenny Billy, Mark Tarnopolsky, Fabien Zagnoli, Marie Wencel, Sevim Erdem-Ozdamar, Erin Hatcher, Madoka Mori, Céline Tard, Nicolas Mavroudakis, Emmanuelle Salort-Campana, Antonio Toscano, Shafeeq Ladha, Angela Genge, Ans T. van der Ploeg, Michela Guglieri, Judith Johnson, Fanny Duval, Loïc Danjoux, Christopher Hug, Robert D. Henderson, Robert Neel, Luca Solera, Aleksandra Nadaj-Pakleza, Silvia Boschi, Nizar Chahin, Maurizio Gualtiero Moggio, Peter Young, Priya S. Kishnani, Yin-Hsiu Chien, Alexandra Kautzky-Willer, Claire Questienne, Francoise Bouhour, Gabriela A Niizawa, Ekaterina Fedotova, Tiziana Enrica Mongini, Harmke A. van Kooten, Vera Malinova, Sina Helms, Shahram Attarian, Patrick Deegan, Guilhem Sole, Hamilton Cirne, Ludwig Gutmann, Kenneth I. Berger, Laura Carrera Garcia, N A M E van der Beek, Stephanie Dearmey, Suzara Souto Lopes, Anna Potulska-Chromik, Joao Lindolfo Borges, Yesim Parman, Michaela Riedl, Sergey A. Klyushnikov, Olivier Huynh-Ba, Gauthier Remiche, Paula R. Clemens, Andrea Swenson, Stephan Wenninger, Miriam Hufgard-Leitner, Eugen Mengel, Kristina An Haack, Eve Gandolfo, David Reyes-Leiva, Jean-Baptiste Davion, Chester Whitley, Young Chul Choi, Patricia Altemus, Maria Judit Molnar, Perry B. Shieh, Matthias Vorgerd, Julia B Hennermann, Cheryl Smith, Volker Straub, Lauren Noll, Pascal Laforet, Andres Nascimento Osorio, Clarisa Maxit, Anne-Catherine Aubé-Nathier, Ozlem Goker-Alpan, Olimpia Musumeci, Louisa Müller-Miny, Tarekegn Hiwot, Jacqui Langton, Christopher Nance, Daniel Natera-de Benito, Jeffrey Statland, Nicola Longo, Vivien Pautot, Zoltan Grosz, Thomas Stulnig, Matthias Boentert, Anne-Katrin Guettsches, Chong Yew Tan, Erik Ortega, Derralynn Hughes, Hacer Durmus Tekce, Mark Roberts, Lenka Linková, Amel Karaa, Hani Kushlaf, Anthony Behin, Margarida Ramos Lopes, Jordi Diaz-Manera, Alessia Pugliese, Paulo Victor Sgobbi Souza, Carrie Bailey, Jennifer B Avelar, Hirofumi Komaki, Frederic Taithe, Benedikt Schoser, Sabine Specht, Kathryn E Brown, Gerson Carvalho

المساهمون: Pediatrics

المصدر: The Lancet Neurology, 20(12), 1012-1026. Lancet Publishing Group

مصطلحات موضوعية: medicine.medical_specialty, Population, Walking, FEV1/FVC ratio, stomatognathic system, SDG 3 - Good Health and Well-being, Double-Blind Method, Internal medicine, Statistical significance, Child, Preschool, Enzyme Replacement Therapy, Humans, Treatment Outcome, Glycogen Storage Disease Type II, alpha-Glucosidases, medicine, Respiratory function, Adverse effect, education, Child, Preschool, Alglucosidase alfa, education.field_of_study, business.industry, Standard treatment, virus diseases, Enzyme replacement therapy, Neurology (clinical), business, medicine.drug

الوصف: Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::070f1f6f1e025674e4ced58aa9218fbfTest
http://hdl.handle.net/11570/3218654Test