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

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Benatar, MichaelDepartment of Neurology, University of Miami Miller School of Medicine, FL, Miami, United States (författare)

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

Artikel/kapitelEngelska2024

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Elsevier,2024
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LIBRIS-ID:oai:DiVA.org:umu-226731
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-226731URI
https://doi.org/10.1016/S1474-4422(24)00134-0DOI

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Språk:engelska
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Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Neurologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Neurology hsv//eng

Biuppslag (personer, institutioner, konferenser, titlar ...)

Hansen, ThomasOrphazyme, Copenhagen, Denmark (författare)
Rom, DrorProsoft Clinical, PA, Chesterbrook, United States (författare)
Geist, Marie AOrphazyme, Copenhagen, Denmark (författare)
Blaettler, ThomasOrphazyme, Copenhagen, Denmark (författare)
Camu, WilliamDepartment of Neurology University of Montpellier, CHU Montpellier, INM INSERM, Montpellier, France (författare)
Kuzma-Kozakiewicz, MagdalenaDepartment of Neurology, Medical University of Warsaw, Warsaw, Poland (författare)
van den Berg, Leonard HDepartment of Neurology, University Medical Center Utrecht, Utrecht, Netherlands (författare)
Morales, Raul JuntasDepartment of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain (författare)
Chio, AdrianoRita Levi Montalcini Department of Neuroscience, University of Torino, Torino, Italy (författare)
Andersen, Peter M.,1962-Umeå universitet,Neurovetenskaper(Swepub:umu)pean0001 (författare)
Pradat, Pierre-FrancoisAPHP, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France (författare)
Lange, DaleDepartment of Neurology, Hospital for Special Surgery, NY, New York, United States (författare)
Van Damme, PhilipDepartment of Neurology, University Hospital Leuven, KU Leuven, Leuven, Belgium (författare)
Mora, GabrieleIstituti Clinici Scientifici Maugeri, IRCCS Milano, Milan, Italy (författare)
Grudniak, MariuszResearch and Development Department, Polish Stem Cell Bank, Warsaw, Poland (författare)
Elliott, MatthewUniversity of Virginia Medical Center, VA, Charlottesville, United States (författare)
Petri, SusanneDepartment of Neurology, Hannover Medical School, Hannover, Germany (författare)
Olney, NicholasProvidence Portland Medical Center, Providence Brain and Spine Institute, OR, Portland, United States (författare)
Ladha, ShafeeqDepartment of Neurology, Barrow Neurological Institute, AZ, Phoenix, United States (författare)
Goyal, Namita ADepartment of Neurology, University of California Irvine, CA, Irvine, United States (författare)
Meyer, ThomasDepartment of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany (författare)
Hanna, Michael GUniversity College London, National Hospital for Neurology and Neurosurgery, London, United Kingdom (författare)
Quinn, ColinDepartment of Neurology, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United States (författare)
Genge, AngelaDepartment of Neurology, Montreal Neurological Institute, QC, Montreal, Canada (författare)
Zinman, LorneSunnybrook Health Sciences Centre, ON, Toronto, Canada (författare)
Jabari, DuaaDepartment of Neurology, The University of Kansas Medical Center, KS, Kansas City, United States (författare)
Shoesmith, ChristenDepartment of Clinical Neurological Sciences, London Health Sciences Centre, Western University, ON, London, Canada (författare)
Ludolph, Albert CDepartment of Neurology, University of Ulm, Ulm, Germany (författare)
Neuwirth, ChristophNeuromuscular Disease Unit/ALS Clinic, Kantonspital St Gallen, St Gallen, Switzerland (författare)
Nations, SharonUniversity of Texas Southwestern, TX, Dallas, United States (författare)
Shefner, Jeremy MDepartment of Neurology, Barrow Neurological Institute, AZ, Phoenix, United States (författare)
Turner, Martin RNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom (författare)
Wuu, JoanneDepartment of Neurology, University of Miami Miller School of Medicine, FL, Miami, United States (författare)
Bennett, RichardOrphazyme, Copenhagen, Denmark (författare)
Dang, HoangOrphazyme, Copenhagen, Denmark (författare)
Sundgreen, ClausOrphazyme, Copenhagen, Denmark (författare)
Granit, Volkan[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Steele, Julie[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Levy, Wendy[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Paredes, Maria Elena[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Hernandez, Jessica[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Bilsker, Martin[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Szacka, Katarzyna[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Ronert, Adam[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Jablońska, Dorota[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Łuczak, Alina Zuzanna[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Chaverri, Delia[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Janse van Mantgem, Mark R[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Bunte, Tommy M[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Broere, Bianca[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Salamone, Paolina[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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ME Forsberg, Karin[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Winroth, Ivar[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Almgren Stenberg, Erica[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Holmgren, Monica[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Amador, Maria del Mar[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Lenglet, Timothee[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Querin, Giorgia[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Pavlakis, Pantelis[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Van Daele, Sien[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Claeys, Thomas[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Delmotte, Koen[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Serrien, Anouk[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Rakocevic, Goran[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Wagoner, Mary[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Alma, Osmanovic[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Flavia, Wiehler[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Sonja, Körner[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Olivia, Schreiber-Katz[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Camilla, Wohnrade[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Anastasia, Sarikidi[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Carola, Kassebaum[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Chantal, Fischer[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Adamo, Ashley[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Turcotte, Nicole[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Duncan, Jessie[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Turner, Ivone[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Massie, Rami[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
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Salmon, Kristiana[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Foucher, Juliette[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Agessandro, Abrahao[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Shirley, Pham[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Jahan, Mookshah[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Phung, Liane[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Statland, Jeffrey[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Jawdat, Omar[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Dimachkie, Mazen[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Pasnoor, Mamatha[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Farmakidis, Constantine[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Heim, Andrew[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Lillig, Katie[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Lackey, Alyssa[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Weber, Markus[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Kurz, Martina[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Levine, Todd[NO CONNECTION TO ANY AFFILIATION IN XML] (författare)
Department of Neurology, University of Miami Miller School of Medicine, FL, Miami, United StatesOrphazyme, Copenhagen, Denmark (creator_code:org_t)

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Ingår i:Lancet Neurology: Elsevier23:7, s. 687-6991474-44221474-4465

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Av författaren/redakt...: Benatar, Michael; Hansen, Thomas; Rom, Dror; Geist, Marie A; Blaettler, Thoma ...; Camu, William; visa fler...; Kuzma-Kozakiewic ...; van den Berg, Le ...; Morales, Raul Ju ...; Chio, Adriano; Andersen, Peter ...; Pradat, Pierre-F ...; Lange, Dale; Van Damme, Phili ...; Mora, Gabriele; Grudniak, Marius ...; 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, Chris ...; Ludolph, Albert ...; Neuwirth, Christ ...; Nations, Sharon; Shefner, Jeremy ...; Turner, Martin R; Wuu, Joanne; Bennett, Richard; Dang, Hoang; Sundgreen, Claus; Granit, Volkan; Steele, Julie; Levy, Wendy; Paredes, Maria E ...; Hernandez, Jessi ...; Bilsker, Martin; Szacka, Katarzyn ...; Ronert, Adam; Jablońska, Dorot ...; Łuczak, Alina Zu ...; Chaverri, Delia; Janse van Mantge ...; Bunte, Tommy M; Broere, Bianca; de Fockert, Aria ...; Sanchez-Tejerina ...; Landabaso, Carme ...; Calvo, Andrea; Moglia, Cristina; Manera, Umberto; Canosa, Antonio; Vasta, Rosario; Salamone, Paolin ...; Fuda, Giuseppe; DeMarco, Giovann ...; Casale, Federico; ME Forsberg, Kar ...; Winroth, Ivar; Almgren Stenberg ...; Holmgren, Monica; Amador, Maria de ...; Lenglet, Timothe ...; Querin, Giorgia; Coudoin, Sylvie; Pavlakis, Pantel ...; Holzberg, Shara; Sideri, Riccardo; Marinou, Kalliop ...; Czarnecki, Macie ...; Ługiewicz, Renat ...; Biel-Czarnecka, ...; Boczkowska, Marc ...; Schotte, Carolin ...; 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, Guill ...; Crowell, Allison; Rakocevic, Goran; Wagoner, Mary; Alma, Osmanovic; Flavia, Wiehler; Sonja, Körner; Olivia, Schreibe ...; Camilla, Wohnrad ...; Anastasia, Sarik ...; Carola, Kassebau ...; Chantal, Fischer; Adamo, Ashley; Turcotte, Nicole; Duncan, Jessie; Turner, Ivone; Elman, Lauren; Massie, Rami; Berube, Maxime; Saunders, Natali ...; Salmon, Kristian ...; Foucher, Juliett ...; Agessandro, Abra ...; Shirley, Pham; Jahan, Mookshah; Phung, Liane; Statland, Jeffre ...; Jawdat, Omar; Dimachkie, Mazen; Pasnoor, Mamatha; Farmakidis, Cons ...; Heim, Andrew; Lillig, Katie; Lackey, Alyssa; Weber, Markus; Kurz, Martina; Levine, Todd; visa färre...

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