카무카무
Camu Camu
📚 관련 논문 (24편)
1. Cell Rep Med. 2024 Aug 20;5(8):101682. doi: 10.1016/j.xcrm.2024.101682. Camu-camu decreases hepatic steatosis and liver injury markers in overweight, hypertriglyceridemic individuals: A randomized crossover trial. Agrinier AL(1), Morissette A(1), Daoust L(1), Gignac T(2), Marois J(3), Varin T
2. Arch Latinoam Nutr. 2015 Jun;65(2):119-27. Synergistic, additive and antagonistic effects of fruit mixtures on total antioxidant capacities and bioactive compounds in tropical fruit juices. Pereira AC, Wurlitzer NJ, Dionisio AP, Lacerda Soares MV, Rocha Bastos Mdo S, Elesbão Alves R, Monteneg
3. Crit Rev Food Sci Nutr. 2026;66(6):1140-1154. doi: 10.1080/10408398.2025.2540498. Epub 2025 Jul 31. Effect of consumption of Brazilian berries on intestinal health: a systematic review of in vivo studies. Carvalho Sette Abrantes L(1), Oliveira LA(1), Dias KA(1), Cupertino Fialho T(1), Vitóri
4. Rev Peru Med Exp Salud Publica. 2019 Oct-Dec;36(4):573-582. doi: 10.17843/rpmesp.2019.364.4270. Epub 2020 Jan 17. [Antimicrobial activity in vitro of Camu-Camu (Myrciaria Dubia) against oral microorganisms: a systematic review]. [Article in Spanish; Abstract available in Spanish from the publ
5. J Altern Complement Med. 2015 Jan;21(1):8-14. doi: 10.1089/acm.2014.0130. Epub 2014 Oct 2. Antioxidant and associated capacities of Camu camu (Myrciaria dubia): a systematic review. Langley PC(1), Pergolizzi JV Jr, Taylor R Jr, Ridgway C. Author information: (1)1 Maimon Research LLC , Tucson
1. BMJ Open. 2022 Jan 17;12(1):e053081. doi: 10.1136/bmjopen-2021-053081. Camu Camu effects on microbial translocation and systemic immune activation in ART-treated people living with HIV: protocol of the single-arm non-randomised Camu Camu prebiotic pilot study (CIHR/CTN PT032). Isnard S(1)(2)(3), Fombuena B(1)(2), Ouyang J(1)(2)(4), Royston L(1)(2)(3), Lin J(1)(2), Bu S(1)(2), Sheehan N(2), Lakatos PL(5), Bessissow T(5), Chomont N(6), Klein M(1)(2), Lebouché B(1)(2)(7)(8), Costiniuk CT(1)(2), Routy B(6), Marette A(9)(10), Routy JP(11)(2)(12); Camu Camu Study Group. Author information: (1)Research Institute of the McGill University Health Centre, McGill University Health Centre, Montreal, Quebec, Canada. (2)Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada. (3)Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, British Columbia, Canada. (4)Chongqing Public Health Medical Center, Chongqing, People's Republic of China. (5)Division of Gastroentrology, McGill University Health Centre, Montreal, Quebec, Canada. (6)Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada. (7)Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. (8)Department of Family Medicine, McGill University Health Centre, Montreal, Quebec, Canada. (9)Insitute of Nutrition and Functional food, Laval University, Quebec City, Quebec, Canada. (10)Department of Medicine, Faculty of Medicine, Cardiology Axis of the Quebec Heart and Lung Institute, Laval University, Quebec city, Quebec, Canada. (11)Research Institute of the McGill University Health Centre, McGill University Health Centre, Montreal, Quebec, Canada jean-pierre.routy@mcgill.ca. (12)Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada. INTRODUCTION: Despite the success of antiretroviral therapy (ART) in transforming HIV disease into a chronic infection, people living with HIV (PLWH) remain at risk for various non-AIDS inflammatory comorbidities. Risk of non-AIDS comorbidities is associated with gut dysbiosis, epithelial gut damage and subsequent microbial translocation, and increased activation of both circulating CD4+ and CD8+ T-cells. Therefore, in addition to ART, novel gut microbiota-modulating therapies could aid in reducing inflammation and immune activation, gut damage, and microbial translocation. Among various gut-modulation strategies under investigation, the Amazonian fruit Camu Camu (CC) presents itself as a prebiotic candidate based on its anti-inflammatory and antioxidant properties in animal models and tobacco smokers. METHOD AND ANALYSIS: A total of 22 PLWH on ART for more than 2 years, with a viral load <50 copies/mL, a CD4 +count >200 and a CD4+/CD8 +ratio <1 (suggesting increased inflammation and risk for non-AIDS comorbidities), will be recruited in a single arm, non-randomised, interventional pilot trial. We will assess tolerance and effect of supplementation with CC in ART-treated PLWH on reducing gut damage, microbial translocation, inflammation and HIV latent reservoir by various assays. ETHICS AND DISSEMINATION: The Canadian Institutes of Health Research (CIHR)/Canadian HIV Trials Network (CTN) pilot trial protocol CTNPT032 was approved by the Natural and Non-prescription Health Products Directorate of Health Canada and the research ethics board of the McGill university Health Centre committee (number 2020-5903). Results will be made available as free access through publications in peer-reviewed journals and through the CIHR/CTN website. TRIAL REGISTRATION NUMBER: NCT04058392. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bmjopen-2021-053081 PMCID: PMC8765027 PMID: 35039291 [Indexed for MEDLINE] Conflict of interest statement: Competing interests: J-PR has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb, Janssen, Argos Pharmaceuticals from InnaVirVax and has served on the Advisory Board of Theravectys. JBA has performed contract research and/or served on Advisory Boards for Gilead Sciences Canada, Merck Canada, Abbvie, ViiV Healthcare, Bristol Myers Squibb, Janssen and Argos Pharmaceuticals. NC has received research funding from EMD Serono and has served on the Advisory Board of Gilead Sciences Canada. SI is a post-doctoral fellow from the Fonds de recherche du Quebec en santé, and from the CIHR/CTN. BL is supported by a career award LE 250 from Quebec’s Ministry of Health for researchers in family medicine. BL has received consultancy fees and/or honoraria from Gilead, Merck, and ViiV, and research funds from Gilead, Merck, and ViiV, support to attend educational conferences from Viiv Healthcare and Gilead. LR is a postdoctoral fellow supported by the Swiss National Science Foundation.
2. CNS Drugs. 2019 Dec;33(12):1187-1199. doi: 10.1007/s40263-019-00674-8. An Update on Vitamin D and Disease Activity in Multiple Sclerosis. Smolders J(1)(2), Torkildsen Ø(3)(4), Camu W(5), Holmøy T(6)(7). Author information: (1)Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. (2)Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands. (3)Department of Neurology, Haukeland University Hospital, Bergen, Norway. (4)Institute for Clinical Medicine, University of Bergen, Bergen, Norway. (5)Centre de Référence SLA, CHU Gui de Chauliac et Univ Montpellier, Montpellier, France. (6)Department of Neurology, Akershus University Hospital, Box 1000, 1478, Lørenskog, Norway. trygve.holmoy@medisin.uio.no. (7)Institute of Clinical Medicine, University of Oslo, Oslo, Norway. trygve.holmoy@medisin.uio.no. Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism, yet have additional roles in immune and central nervous system cell homeostasis. Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing-remitting multiple sclerosis (RRMS), and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy. The results of the first large randomized clinical trials (RCTs), the SOLAR and CHOLINE studies, have now been published. The SOLAR study compared 14,000 IU of vitamin D3 (cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D3 100,000 IU every other week with placebo for 96 weeks in 129 randomized patients. All patients in both studies also used interferon-β-1a. None of the studies met their primary endpoints, which were no evidence of disease activity (NEDA-3) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks in CHOLINE. Both studies did, however, suggest modest effects on secondary endpoints. Thus, vitamin D reduced the number of new or enlarging lesions and new T2 lesions in SOLAR, and the annualized relapse rate and number of new T1 lesions, volume of hypointense T1 lesions, and disability progression in the 90 patients who completed 96 weeks' follow-up in CHOLINE. We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts. This contrasts the observation studies, where each 25 nmol/l increase in 25-hydroxyvitamin D levels were associated with 14-34% reduced relapse risk and 15-50% reduced risk of new lesions on magnetic resonnance imaging. This discrepancy may have several explanations, including confounding and reverse causality in the observational studies. The power calculations of the RCTs have been based on the observational studies, and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation. Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies, current evidence still support that people with MS should avoid vitamin D insufficiency, and preferentially aim for vitamin D levels around 100 nmol/L or somewhat higher. DOI: 10.1007/s40263-019-00674-8 PMCID: PMC6890630 PMID: 31686407 [Indexed for MEDLINE] Conflict of interest statement: Dr. Smolders received speaker and/or consultancy fees from Biogen, Merck, Novartis, and Sanofi-Genzyme. Dr Holmøy, Dr Torkildsen, and Dr Camu report no conflicts of interest that are directly relevant to this review.
3. J Cardiol. 2008 Oct;52(2):127-32. doi: 10.1016/j.jjcc.2008.06.004. Epub 2008 Jul 29. Tropical fruit camu-camu (Myrciaria dubia) has anti-oxidative and anti-inflammatory properties. Inoue T(1), Komoda H, Uchida T, Node K. Author information: (1)Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan. inouete@med.saga-u.ac.jp BACKGROUND: Oxidative stress as well as inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Although, various anti-oxidative dietary supplements have been evaluated for their ability to prevent atherosclerosis, no effective ones have been determined at present. "Camu-camu" (Myrciaria dubia) is an Amazonian fruit that offers high vitamin C content. However, its anti-oxidative property has not been evaluated in vivo in humans. METHODS: To assess the anti-oxidative and anti-inflammatory properties of camu-camu in humans, 20 male smoking volunteers, considered to have an accelerated oxidative stress state, were recruited and randomly assigned to take daily 70 ml of 100% camu-camu juice, corresponding to 1050 mg of vitamin C (camu-camu group; n=10) or 1050 mg of vitamin C tablets (vitamin C group; n=10) for 7 days. RESULTS: After 7 days, oxidative stress markers such as the levels of urinary 8-hydroxy-deoxyguanosine (P<0.05) and total reactive oxygen species (P<0.01) and inflammatory markers such as serum levels of high sensitivity C reactive protein (P<0.05), interleukin (IL)-6 (P<0.05), and IL-8 (P<0.01) decreased significantly in the camu-camu group, while there was no change in the vitamin C group. CONCLUSIONS: Our results suggest that camu-camu juice may have powerful anti-oxidative and anti-inflammatory properties, compared to vitamin C tablets containing equivalent vitamin C content. These effects may be due to the existence of unknown anti-oxidant substances besides vitamin C or unknown substances modulating in vivo vitamin C kinetics in camu-camu. DOI: 10.1016/j.jjcc.2008.06.004 PMID: 18922386 [Indexed for MEDLINE]
4. Anaesthesia. 2008 Oct;63(10):1105-23. doi: 10.1111/j.1365-2044.2008.05565.x. Epub 2008 Jul 10. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Fischer HB(1), Simanski CJ, Sharp C, Bonnet F, Camu F, Neugebauer EA, Rawal N, Joshi GP, Schug SA, Kehlet H; PROSPECT Working Group. Author information: (1)Department of Anaesthesia, Alexandra Hospital, Redditch, UK. barrie.fischer@worcsacute.nhs.uk Comment in Anaesthesia. 2009 Mar;64(3):332-3; author reply 333-4. doi: 10.1111/j.1365-2044.2009.05878_1.x. The PROSPECT Working Group, a collaboration of anaesthetists and surgeons, conducts systematic reviews of postoperative pain management for different surgical procedures (http://www.postoppain.org). Evidence-based consensus recommendations for the effective management of postoperative pain are then developed from these systematic reviews, incorporating clinical practice observations, and transferable evidence from other relevant procedures. We present the results of a systematic review of pain and other outcomes following analgesic, anaesthetic and surgical interventions for total knee arthroplasty (TKA). The evidence from this review supports the use of general anaesthesia combined with a femoral nerve block for surgery and postoperative analgesia, or alternatively spinal anaesthesia with local anaesthetic plus spinal morphine. The primary technique, together with cooling and compression techniques, should be supplemented with paracetamol and conventional non-steroidal anti-inflammatory drugs or COX-2-selective inhibitors, plus intravenous strong opioids (high-intensity pain) or weak opioids (moderate- to low-intensity pain). DOI: 10.1111/j.1365-2044.2008.05565.x PMID: 18627367 [Indexed for MEDLINE]
5. Reg Anesth Pain Med. 2004 Jul-Aug;29(4):312-6. Ropivacaine 3.75 mg/ml, 5 mg/ml, or 7.5 mg/ml for cervical plexus block during carotid endarterectomy. Umbrain VJ(1), van Gorp VL, Schmedding E, Debing EE, von Kemp K, van den Brande PM, Camu F. Author information: (1)Department of Anesthesiology (V.J.U., V.L.V.G., F.C.), Academisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium. Vincent.Umbrain@az.vub.ac.be OBJECTIVE: To examine the effect of 225 mg (7.5 mg/mL), 150 mg (5 mg/mL), and 112.5 mg (3.75 mg/mL) ropivacaine on quality of cervical plexus block during carotid endarterectomy. METHODS: Patients (n = 93) scheduled for carotid endarterectomy were randomized to receive a cervical plexus block with deep infiltration of 10 mL and superficial infiltration of 20-mL volumes of ropivacaine 7.5, 5.0, or 3.75 mg/mL. Pain, coughing, hemodynamic consequences of the block, postoperative visual analog scores, and pain satisfaction index were recorded. If necessary, anesthesia supplements with aliquots of 3 mL lidocaine 1% were given during surgery. RESULTS: Incidences of coughing and hoarseness were similar in all groups. More local anesthetic infiltrations were required in the ropivacaine 3.75-mg/mL and 5-mg/mL groups. Postoperatively, no intragroup differences were observed. A trend toward better pain satisfaction was observed in the ropivacaine 7.5-mg/mL group. CONCLUSION: The best quality of cervical plexus block associated with the smallest incidence of pain for patients undergoing carotid endarterectomy was obtained with 30 mL of 225 mg and 150 mg of ropivacaine, respectively. PMID: 15305249 [Indexed for MEDLINE]
6. Anesth Analg. 1999 Jan;88(1):134-40. doi: 10.1097/00000539-199901000-00025. The safety and effectiveness of remifentanil as an adjunct sedative for regional anesthesia. Lauwers M(1), Camu F, Breivik H, Hagelberg A, Rosen M, Sneyd R, Horn A, Noronha D, Shaikh S. Author information: (1)Department of Anesthesiology, Flemish Free University of Brussels Medical Center, Belgium. Comment in Anesth Analg. 1999 Aug;89(2):535. doi: 10.1097/00000539-199908000-00066. We assessed the sedative potential of continuous infusions of remifentanil with a validated composite alertness scale in 160 patients (ASA physical status I or II) undergoing hip replacement surgery with spinal block (n = 61) or hand surgery using brachial plexus block (n = 93). They were randomized to receive one of the following initial dose regimens in double-blinded fashion: placebo or 0.04, 0.07, or 0.1 microg x kg(-1) x min(-1) remifentanil subsequently titrated to effect. Additional midazolam IV was allowed for adequate sedation as required. The combined analysis of both surgery groups revealed a dose-related increase in achievement of sedation level > or =2 within 15 min of the start of the study drug infusion; all remifentanil dose comparisons with placebo reached significance (P < 0.001). The remifentanil 50% effective dose for a composite sedation level > or =2 within 15 min of the start of drug infusion was estimated as 0.043 microg x kg(-1) x min(-1) (95% confidence interval 0.01, 0.059). The requirement for midazolam decreased with increasing remifentanil dose compared with placebo (P < 0.001). The median time to return to alertness after the end of infusion was 10-12 min in the remifentanil groups and 5 min in the placebo group. Significant incidences of nausea, pruritus, sweating, and respiratory depression were reported during remifentanil infusions compared with placebo. The data suggest that remifentanil may be useful for supplementation of regional anesthesia, provided that ventilation is carefully monitored. IMPLICATIONS: In this dose-finding, placebo-controlled study, remifentanil infusions were used to provide sedation during spinal and brachial plexus regional anesthesia. The 50% effective dose for achievement of sedation was 0.043 microg x kg(-1) x min(-1). Return to alertness occurred after 10-12 min (median time). Remifentanil infusions can be used to supplement regional anesthesia, but this requires careful monitoring of ventilation. DOI: 10.1097/00000539-199901000-00025 PMID: 9895080 [Indexed for MEDLINE]
7. Lancet. 2025 May 24;405(10492):1837-1850. doi: 10.1016/S0140-6736(25)00262-4. Epub 2025 May 9. Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial. Bensimon G(1), Leigh PN(2), Tree T(3), Malaspina A(4), Payan CA(5), Pham HP(6), Klaassen P(7), Shaw PJ(8), Al Khleifat A(9), Amador MDM(10), Attarian S(11), Bell SM(8), Beltran S(12), Bernard E(13), Camu W(14), Corcia P(12), Corvol JC(15), Couratier P(16), Danel V(17), Debs R(18), Desnuelle C(19), Dimitriou A(20), Ealing J(21), Esselin F(14), Fleury MC(22), Gorrie GH(23), Grapperon AM(24), Hesters A(10), Juntas-Morales R(25), Kolev I(26), Lautrette G(16), Le Forestier N(10), McDermott CJ(8), Pageot N(27), Salachas F(10), Sharma N(28), Soriani MH(19), Sreedharan J(29), Svahn J(30), Verber N(31), Verschueren A(24), Yildiz O(32), Suehs CM(33), Saker-Delye S(34), Muller C(35), Masseguin C(35), Hajduchova H(36), Kirby J(31), Garlanda C(37), Locati M(38), Zetterberg H(39), Asselain B(40), Al-Chalabi A(29); MIROCALS Study Group. Author information: (1)Department of Clinical Pharmacology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Pharmacology, Paris Sorbonne University, Paris, France; Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Nîmes University Hospital, Nîmes, France. Electronic address: gbensimon.psl@gmail.com. (2)Department of Neuroscience, Brighton and Sussex Medical School, Falmer, Brighton, BN1 9PX, UK. (3)Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK. (4)Centre of Neuroscience and Trauma, Blizard Institute, Queen Mary University London, London, UK; UCL Queen Square MND Care and Research Centre, Institute of Neurology, University College London, London, UK. (5)Department of Clinical Pharmacology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Nîmes University Hospital, Nîmes, France. (6)Parean Biotechnologies, Saint-Malo, France. (7)WGK Clinical Services, London, UK. (8)Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; NIHR Sheffield Biomedical Research Centre, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. (9)Institute of Psychiatry, Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, King's College London, London, UK. (10)Centre de Référence Maladies Rares CRMR SLA Ile de France, Department of Neurology, DMU Neurosciences, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. (11)Centre de Référence Maladies Rares CRMR SLA, ERN-EURO NMD, CHU La Timone, APHM, Marseille, France; Aix-Marseille University, Marseille, France. (12)Centre de Référence Maladies Rares CRMR SLA CHRU Bretonneau, Tours, France. (13)Centre de Référence Maladies Rares CRMR CHU Lyon, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Université de Lyon, Lyon, France; Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, Lyon, France. (14)Centre de Référence Maladies Rares CRMR SLA CHU Montpellier, INM, Univ Montpellier, INSERM, Explorations neurologiques, Hôpital Gui de Chauliac, Montpellier, France. (15)Sorbonne Université, Assistance Publique Hôpitaux de Paris, Paris Brain Institute, Pitié-Salpêtrière Hospital, Paris, France. (16)Centre de Référence Maladies Rares CRMR SLA CHU Limoges, Hôpital Dupuytren, Limoges, France. (17)Centre de Référence Maladies Rares CRMR SLA CHU Lille, Lille, France. (18)Centre de Référence Maladies Rares CRMR SLA Ile de France, Department of Neurology, DMU Neurosciences, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Département de neurophysiologie clinique, Groupe Hospitalier Pitié Salpetrière, Paris, France. (19)Centre de Référence Maladies Rares CRMR SLA CHU de Nice, Service de Neurologie Hopital Pasteur 2, Nice, France. (20)Department of Neurology, King's College Hospital London, UK; Department of Neurology, Sismanogleio Hospital, Athens, Greece. (21)Manchester Centre for Clinical Neurosciences, Manchester, UK. (22)Centre de Resources et de Compétances CRC-SLA, CHU Hautepierre, Strasbourg, France. (23)Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. (24)Centre de Référence Maladies Rares CRMR SLA, ERN-EURO NMD, CHU La Timone, APHM, Marseille, France. (25)Centre de Référence Maladies Rares CRMR SLA CHU Montpellier, INM, Univ Montpellier, INSERM, Explorations neurologiques, Hôpital Gui de Chauliac, Montpellier, France; Neuromuscular Unit, department of Neurology, University Hospital of Vall d'Hebron, Barcelona, Spain. (26)Centre de Resources et de Compétances CRC-SLA Hospital-Saint Brieuc, Saint Brieuc, France; Service de Neurologie, Hôpital de Pontivy, Noyal-Pontivy, France. (27)Centre de Référence Maladies Rares CRMR SLA CHU Montpellier, INM, Univ Montpellier, INSERM, Explorations neurologiques, Hôpital Gui de Chauliac, Montpellier, France; Clinique Beau Soleil, Montpellier, France. (28)Department of Neurology, The National Hospital of Neurology and Neurosurgery, London, UK; BioCorteX, London, UK. (29)Department of Neurology, King's College Hospital London, UK. (30)Centre de Référence Maladies Rares CRMR CHU Lyon, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Université de Lyon, Lyon, France. (31)Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, Sheffield, UK. (32)Centre of Neuroscience and Trauma, Blizard Institute, Queen Mary University London, London, UK; UCL Queen Square MND Care and Research Centre, Institute of Neurology, University College London, London, UK; Hertfordshire Partnership University NHS Foundation Trust, Psychiatry, London, UK. (33)Departments of Medical Information and Respiratory Diseases, University of Montpellier, CHU Montpellier, Montpellier, France; Department of Research and Informatics, University Health, San Antonio, TX, USA. (34)DNA and Cell Bank, Genethon, Evry, France. (35)Delegation for Clinical Research and Innovation, Nîmes University Hospital, Nîmes, France. (36)ICON Clinical Research, Nanterre, France. (37)Department of Biomedical Sciences, Humanitas University, Milano, Italy; IRCCS Humanitas Research Hospital, Milano, Italy. (38)IRCCS Humanitas Research Hospital, Milano, Italy; Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Milano, Italy. (39)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. (40)Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, GINECO, Paris, France. BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS. METHODS: In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18-76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12-18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)-phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with ClinicalTrials.gov (NCT03039673) and is complete. FINDINGS: From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escorial criteria. At the cutoff date there was no loss to follow-up, and all 220 patients who were randomly allocated were documented as either deceased (90 [41%]) or alive (130 [59%]), so all participants were included in the ITT and safety populations. The primary endpoint unadjusted analysis showed a non-significant 19% decrease in risk of death with IL-2LD (hazard ratio 0·81 [95% CI 0·54-1·22], p=0·33), failing to demonstrate the expected two-fold decrease in risk of death. The analysis of the primary endpoint adjusted on prognostic covariates, all measured at time of random allocation, showed a significant decrease of the risk of death with IL-2LD (0·32 [0·14-0·73], p=0·007), with a significant treatment by CSF-pNFH interaction (1·0003 [1·0001-1·0005], p=0·001). IL-2LD was safe, and significantly increased Tregs and decreased plasma-CCL2 at all timepoints. Stratification on CSF-pNFH levels measured at random allocation showed that IL-2LD was associated with a significant 48% decrease in risk of death (0·52 [0·30-0·89], p=0·016) in the 70% of the population with low (750-3700 pg/mL) CSF-pNFH levels, while in the 21% with high levels (>3700 pg/mL), there was no significant difference (1·37 [0·68-2·75], p=0·38). INTERPRETATION: With this treatment schedule, IL-2LD resulted in a non-significant reduction in mortality in the primary unadjusted analysis. However, the difference between the results of unadjusted and adjusted analyses of the primary endpoint emphasises the importance of controlling for disease heterogeneity in ALS randomised controlled trials. The decrease in risk of death achieved by IL-2LD therapy in the trial population with low CSF-pNFH levels requires further investigation of the potential benefit of this therapy in ALS. FUNDING: European Commission H2020 Programme; French Health Ministry PHRC2014; and Motor Neurone Disease Association. Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/S0140-6736(25)00262-4 PMID: 40354799 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests All authors or their institutions received support for the present manuscript from the EU H2020 programme (number 633413) and from at least one of the following: the French Health Minister, the Motor Neurone Disease (MND) Association, the Association Française contre les Myopathies, the Association pour La Recherche sur SLA (ARSLA), MND Scotland, the My Name'5 Doddie Foundation, or the Alan Davidson Foundation. GB declares a license for MIROCALS data for regulatory purposes; and patent numbers WO2012123381A1, WO2021176044 A1, and WO2024121173A1. PNL declares patents (numbers WO2021176044 A1 and WO2024121173A1); and a license for MIROCALS data; and participation on a data, safety, and monitoring board for Novartis. TT, AM, ML, CG, and JK declare patents (numbers WO2021176044 A1 and WO2024121173A1); and a license for MIROCALS data. AM declares contracts from My Name'5 Doddie Foundation, Target ALS, NIHR UCL Biomedical Research Centre, LifeArc, Medical Research Council, NIH and Motor Neurone Disease Association; consulting fees from Pfizer, Novartis, LifeArc, Accure, Trace Neuroscience; and a licence to Biogen. AAK declares contracts with the Motor Neurone Disease Association (MNDA), National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, Amyotrophic Lateral Sclerosis (ALS) Association Milton Safenowitz Research Fellowship, Darby Rimmer MND Foundation, LifeArc, and the Dementia Consortium; equipment by NIHR Maudsley Biomedical Research Centre; and consulting fees from the UK National Endowment for Science, Technology and the Arts (NESTA). SA declares honoraria from Alexion, Argenx, Janssen, UCB, Roche, Sanofi, Pfizer, Biogen, Alnylam, AstraZeneca, Amicus, Novartis, and Laboratoire français du fractionnement et des biotechnologies. EB declares contracts with the ARSLA; consulting fees from Biogen; honoraria from Elsevier, Amylyx, Roche, Sanofi, and Effik; expert testimony for the Haute Autorité de Santé; support for attending meetings or travel from Effik and Zambon; and scientific committee membership for the ARSLA (non-financial interest). J-CC declares contracts with the Agence Nationale de la recherche (ANR), European Union Joint Programme - Neurodegenerative Disease Research (JPND), and Paris Brain Institute (ICM); consulting fees from Iregene, Alzprotect, Ferrer, Biogen, Servier, and UCB; support for attending meetings or travel from the International Movement Disorders Society; and participation on a data and safety monitoring board for Servier. PCou declares contracts with the ARSLA, ANR (PrevDemAls), ANR French German Cohort ALS (FCGals), and ANR (BMAALS); consulting fees from Zambon, Effik, Amylyx, Mitsubishi, and Biogen; lecture fees for Biogen, Zambon, and Mitsubishi; participation on advisory boards for Masitinib trial (ABScience) and MIROCALS; and position as chairman of the rare diseases network for ALS and other motorneuron diseases in France. JE is a co-opted trustee at MNDA. GHG declares contracts from My Name'5 Doddie Foundation. CJMD declares consulting fees from Amylyx; and participation on a data and safety monitoring board or advisory board for Verge and Novartis. NS declares a leadership role as the CEO and co-founder of BioCorteX. PJS declares contracts from US Department of Defense, Wolfson Foundation Equipment Award, My Name'5 Doddie Foundation, NIHR Sheffield Biomedical Research Centre, LifeArc, Medical Research Council, NIHR EXPERTS-ALS, and the Motor Neurone Disease Association; a license for MIROCALS data; and patents (numbers WO2021176044 A1 and WO2024121173A1). M-HS declares lecture fees from Zambon; support for attending meetings or travel from Effik-Italfarmaco; and membership of scientific advisory boards from Amylyx, Biogen, and Zambon. HZ declares contracts from the Swedish Research Council (#2023–00356; #2022–01018, and #2019–02397), the EU H2020 programme under grant agreement number 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the US Alzheimer Drug Discovery Foundation (ADDF; #201809–2016862), the AD Strategic Fund, and the Alzheimer's Association (#ADSF-21–831376-C, #ADSF-21–831381-C, #ADSF-21–831377-C, and #ADSF-24–1284328-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022–0270), the EU Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021–00694), the NIHR University College London (UCL) Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003); consulting fees from AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; lectures for Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD; membership of scientific advisory boards or roles as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; chair of the Alzheimer's Association Global Biomarker Standardization Consortium and chair of the IFCC WG-BND; and being co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme. AA-C declares contracts with the MRC, NIHR and Darby Rimmer Foundation; licence for MIROCALS data; consulting fees from Amylyx, Apellis, Biogen, Brainstorm, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, and Sanofi; and a patent (number WO2024121173A1). PCor declares honoraria from Amylyx, Biogen, Cytokinetics, Effik, Ferrer, Mitsubishi, Tanabe,QurALIs Vectory, and Zambon. CAMP, H-PP, PK, MDMA, SMB, SB, WC, VD, RD, CD, AD, FE, M-CF, A-MG, AH, RJ-M, IK, GL, NLF, NP, FS, JSr, JSv, NV, AV, OY, CMS, SSD, CMu, CMa, HH, and BA declare no competing interests.
8. JAMA. 2025 Apr 22;333(16):1413-1422. doi: 10.1001/jama.2025.1604. High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. Thouvenot E(1)(2), Laplaud D(3), Lebrun-Frenay C(4), Derache N(5), Le Page E(6), Maillart E(7), Froment-Tilikete C(8)(9), Castelnovo G(1), Casez O(10), Coustans M(11), Guennoc AM(12), Heinzlef O(13), Magy L(14), Nifle C(15), Ayrignac X(16), Fromont A(17), Gaillard N(18), Caucheteux N(19), Patry I(20), De Sèze J(21), Deschamps R(22), Clavelou P(23), Biotti D(24), Edan G(6), Camu W(25), Agherbi H(1), Renard D(1), Demattei C(26), Fabbro-Peray P(26), Mura T(26), Rival M(1)(2); D-Lay MS Investigators. Collaborators: Taithe F, Aufauvre D, Moreau T, Vaillant M, Outteryck O, Calais G, Hautecoeur P, Montcuquet A, Carra Dalliere C, Pittion-Vouyovitch S, Lancin Garcia C, Michel L, Faighel M, Schunck A, Wiertlewski S, Talmant V, Lejeune F, Delalande L, Couloume L, Cohen M, Wacongne A, Mas J, Maarouf A, Tourbah A, Deburghgraeve V, Kerbat A, Bourre B, Brassat D, Ciron J, Biberon J, Devy R, Yeung J, Gout O, Benoilid A, Collongues N, Louapre C, Ungureanu A, Papeix C, Dubessy Anne L, Galanaud D, Vukusic S, Durand-Dubief F. Author information: (1)CHU Nimes, Service de Neurologie, Univ Montpellier, Nimes, France. (2)Institut de Génomique Fonctionnelle, Univ Montpellier, CNRS, INSERM, Montpellier, France. (3)CHU Nantes, CRC-SEP, Nantes Université, CIC1413, Centre de Recherche en Transplantation et Immunologie Translationnelle, Inserm U1064, Nantes, France. (4)CHU Nice, Université cote d'Azur UR2CA-URRIS, Nice, France. (5)CHU Caen, CRC-SEP, Caen, France. (6)Clinical Neuroscience Centre, CIC_P1414 INSERM, Rennes University Hospital, Rennes, France. (7)Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Service de Neurologie, Paris, France. (8)Hospices Civils de Lyon, Service de neurocognition et neuro-ophtalmologie, Université Claude Bernard Lyon 1, Lyon, France. (9)Centre de Recherche en Neurosciences de Lyon, Equipe IMPACT, Lyon, France. (10)CHU Grenoble Alpes, Service de Neurologie, La Tronche, France. (11)CH De Cornouaille, Service de Neurologie, Quimper, France. (12)CHRU Tours, Service de Neurologie, Tours, France. (13)CHI Poissy Saint Germain, Service de Neurologie, Poissy, France. (14)CHU Dupuytren 1 , Service de Neurologie, Limoges, France. (15)CH Versailles - Hospital André Mignot, Service de Neurologie, Le Chesnay-Rocquencourt, France. (16)CHU Montpellier, Service de Neurologie, Montpellier, France. (17)CHU Dijon Bourgogne, Service de Neurologie, Dijon, France. (18)CH Perpignan, Service de Neurologie, Perpignan, France. (19)CHU Reims, Service de Neurologie, Reims, France. (20)CH Sud Francilien, Service de Neurologie, Corbeil-Essonnes, France. (21)Hôpital Civil, Service de Neurologie, Strasbourg, France. (22)Hôpital Fondation Adolphe De Rothschild, Service de Neurologie, Paris, France. (23)CHU Gabriel-Montpied, Service de Neurologie, Clermont-Ferrand, France. (24)CHU Toulouse, Service de Neurologie, Toulouse, France. (25)INM, UnivMontpellier, INSERM, Montpellier, France. (26)CHU Nimes, Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie (BESPIM), Univ Montpellier, Nimes, France. IMPORTANCE: Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting. OBJECTIVE: To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS. DESIGN, SETTING, AND PARTICIPANTS: The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited. INTERVENTION: Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months. MAIN OUTCOMES AND MEASURES: The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes. RESULTS: Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol. CONCLUSIONS AND RELEVANCE: Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01817166. DOI: 10.1001/jama.2025.1604 PMCID: PMC11894546 PMID: 40063041 [Indexed for MEDLINE] Conflict of interest statement: Conflict of Interest Disclosures: Dr Thouvenot reported receiving grants from Programme Hospitalier de Recherche Clinique (PHRC) (French Ministry of Health) and grants from Agence Nationale de la Recherche (French National Research Agency) during the conduct of the study and personal fees from Biogen, Merck, Novartis, Roche, and Sanofi and grants from Biogen, Novartis, France SEP (sclérose en plaques), and EDMUS Foundation outside the submitted work. Dr Laplaud reported receiving personal fees from Biogen, Novartis, Merck, Roche, and MSD outside the submitted work and grants from EDMUS Foundation and France SEP. Dr Derache reported receiving personal fees from Biogen, Janssen, Sanofi, Merck, and Novartis outside the submitted work. Dr Le Page reported receiving personal fees from Merck, Biogen Idec, Sanofi, Novartis, and Alexion outside the submitted work. Dr Maillart reported receiving personal fees from Biogen, Alexion, Janssen, Amgen, Novartis, Merck, Sandoz, Sanofi, and Roche and grants from Biogen outside the submitted work. Dr Casez reported receiving nonfinancial support from Biogen and personal fees from Merck, Novartis, Roche, and Janssen outside the submitted work. Dr Guennoc reported receiving personal fees from Merk Serono and grants from Biogen and ROCHE outside the submitted work. Dr Heinzlef reported receiving personal fees from Sanofi and Edimark and support for meeting organization from Merck, Biogen, Novartis outside the submitted work. Dr Magy reported receiving personal fees from Biogen, Novartis, Sanofi, and Merck outside the submitted work. Dr De Sèze reported receiving personal fees from Biogen, Roche, Novartis, Sanofi, Merck, Alexion, Amgen, and Sandoz outside the submitted work. Dr Camu reported receiving grants from French Ministry of Health during the conduct of the study. Dr Mura reported grants from PHRC during the conduct of the study. No other disclosures were reported.
9. Lancet Neurol. 2024 Nov;23(11):1133-1146. doi: 10.1016/S1474-4422(24)00373-9. Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial. Koch JC(1), Leha A(2), Bidner H(3), Cordts I(4), Dorst J(5), Günther R(6), Zeller D(7), Braun N(8), Metelmann M(9), Corcia P(10), De La Cruz E(11), Weydt P(12), Meyer T(13), Großkreutz J(14), Soriani MH(15), Attarian S(16), Weishaupt JH(17), Weyen U(18), Kuttler J(1), Zurek G(19), Rogers ML(20), Feneberg E(4), Deschauer M(4), Neuwirth C(8), Wuu J(21), Ludolph AC(22), Schmidt J(23), Remane Y(24), Camu W(11), Friede T(2), Benatar M(21), Weber M(8), Lingor P(25); ROCK-ALS Study group. Author information: (1)Department of Neurology, University Medical Center Göttingen, Göttingen, Germany. (2)Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany. (3)Münchner Studienzentrum, Technical University Munich, School of Medicine and Health, Munich, Germany. (4)Department of Neurology, Klinikum rechts der Isar, Technical University Munich, School of Medicine and Health, Munich, Germany. (5)Department of Neurology, Ulm University, Ulm, Germany. (6)Department of Neurology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; German Centre for Neurodegenerative Diseases, Site Dresden, Dresden, Germany. (7)Department of Neurology, University Hospital Würzburg, Würzburg, Germany. (8)Neuromuscular Diseases Unit/ALS Clinic, Cantonal Hospital St Gallen, St Gallen, Switzerland. (9)Department of Neurology, University Hospital Leipzig, Leipzig, Germany. (10)Centre de Référence Maladie Rare (CRMR) SLA et les Autres Maladies du Neurone Moteur (FILSLAN), Tours, France; Faculté de Médecine, INSERM U1253, "iBrain Imaging Brain and Neuropsychiatry" Université François-Rabelais de Tours, Tours, France. (11)ALS centre, CHU Gui de Chauliac, Univ Montpellier, INM, INSERM, Montpellier, France. (12)Department for Neuromuscular Disorders, University Hospital Bonn, Bonn, Germany; German Centre for Neurodegenerative Diseases, Site Bonn, Bonn, Germany. (13)Department of Neurology, Center for ALS and Other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. (14)Department of Neurology, Jena University Hospital, Jena, Germany; Precision Neurology of Neuromuscular and Motoneuron Diseases, University of Lübeck, Lübeck, Germany. (15)ALS Reference Centre, Pasteur 2 Hospital, CHU de Nice, Université Côte d'Azur, UMR2CA, Nice, France. (16)Neuromuscular Disease and ALS Reference Center, Timone University Hospital, Aix-Marseille University, CHU Timone, Marseille, France. (17)Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, Mannheim, Germany. (18)Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Bochum, Germany. (19)MVZ Medizinisches Labor Bremen GmbH, Bremen, Germany. (20)MND&NR Lab, FHMRI, College of Medicine and Public health, Flinders University, Bedford Park, Adelaide, SA, Australia. (21)Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. (22)Department of Neurology, Ulm University, Ulm, Germany; German Center for Neurodegenerative Diseases, Site Ulm, Ulm, Germany. (23)Department of Neurology, University Medical Center Göttingen, Göttingen, Germany; Department of Neurology and Pain Treatment, Neuromuscular Center, Center for Translational Medicine, Immanuel University Hospital Rüdersdorf, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Berlin, Germany; Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Berlin, Germany. (24)Central Pharmacy, Leipzig University Medical Center, Leipzig, Germany. (25)Department of Neurology, Klinikum rechts der Isar, Technical University Munich, School of Medicine and Health, Munich, Germany; German Center for Neurodegenerative Diseases, Site Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Electronic address: paul.lingor@tum.de. BACKGROUND: Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. METHODS: ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. FINDINGS: Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. INTERPRETATION: Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. FUNDING: Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases". Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/S1474-4422(24)00373-9 PMCID: PMC12741558 PMID: 39424560 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests JCK reports a grant from the Deutsche Gesellschaft für Muskelkranke and consulting fees from AbbVie, Biogen, Ipsen, Roche, and Zambon. RG reports grants from the Deutsche Gesellschaft für Muskelkranke, Initiative SMA, and Bundesministerium für Bildung und Forschung, as well as consulting fees from Biogen, Roche, ITF Pharma, and Zambon. DZ has received consulting fees from Novartis and Angelini Pharma and has served on an advisory board for Biogen. NB has received compensations from Mitsubishi Tanabe Pharma. PC serves on the editorial advisory boards of ALS and The Revue Neurologique; reports consultancy work or participation on advisory boards for Amylyx, Biogen, Cytokinetics, Ferrer, Mitsubishi Tanabe Pharma, VectorY, and Zambon; serves on the drug safety monitoring board for Quralis, and has received a research grant from Biogen. EDLC has received travel grants from Biogen and EFFIK. PW reports grants from the Boris Canessa Foundation and the Bundesministerium für Bildung and Forschung; and has received consulting fees from ITF Pharma, Zambon, Novartis, Biogen, and Roche. TM reports institutional grants from Cytokinetics, Ferrer, AL-S Pharma, Sanofi, Amylyx, Mitsubishi Tanabe, and Apellis Pharmaceuticals, as well as personal fees from Biogen, Amylyx, and ITF Pharma; and is co-founder and shareholder of the Ambulanzpartner Soziotechnologie APST. JG has received personal fees from UCB, Alexion, Amylyx, Roche, and Zambon; and is a member of advisory boards of the European Network to Cure ALS, Neuroimaging Society in amyotrophic Lateral Sclerosis, EU ALS coalition, and the World Federation of Neurology Motoneuron Disease group. M-HS received compensations for consulting from Amylyx, Zambon, EFFIK-Italfarmaco, and SOS Oxygene. M-LR reports grants from FightMND, MND Research Australia and the US National Institutes of Health. CN has received fees for non-related services for Biogen, Mitsubishi Tanabe, Roche, and Argenx. JW reports grants from the US National Institutes of Health. JS has received payments for participation on advisory boards, talks, travel, and research projects from Abcuro, Alnylam, Argenx, Biotest, CSL Behring, Grifols, Johnson & Johnson, Kezar, LFB, Lupin, Momenta, Novartis, Octapharma, and UCB, all unrelated to the present study. TF has received personal fees from Actimed, Bayer, Bristol Myers Squibb, Cardior, CSLBehring, Daiichi Sankyo, Galapagos, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, RECARDIO, Relaxera, Roche, Servier, Viatris, Vifor, Fresenius Kabi, PINK gegen Brustkrebs, Aslan, BionsenseWebster, Enanta, VICO Therapeutics, Pharmaceutical Product Development, and IQVIA, as well as institutional grants from Deutsche Forschungsgemeinschaft, Gemeinsamer Bundesausschuss, and the European Commission. MB reports grants from the US National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees for Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and uniQure; the University of Miami has licensed intellectual property to Biogen to support the design of the ATLAS trial (NCT04856982), for which MB is academic lead. PL reports grants from the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft; consulting fees from AbbVie, Amylyx, Bial, Desitin, ITF Pharma, Novartis, Stadapharm, Raya Therapeutic, Woolsey Pharmaceuticals, and Zambon; and is co-inventor on a patent for the use of fasudil in amyotrophic lateral sclerosis (EP 2825175 B1, US 9.980,972 B2). All other authors declare no competing interests.
10. Lancet Neurol. 2024 Jul;23(7):687-699. doi: 10.1016/S1474-4422(24)00134-0. Epub 2024 May 20. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Benatar M(1), Hansen T(2), Rom D(3), Geist MA(2), Blaettler T(2), Camu W(4), Kuzma-Kozakiewicz M(5), van den Berg LH(6), Morales RJ(7), Chio A(8), Andersen PM(9), Pradat PF(10), Lange D(11), Van Damme P(12), Mora G(13), Grudniak M(14), Elliott M(15), Petri S(16), Olney N(17), Ladha S(18), Goyal NA(19), Meyer T(20), Hanna MG(21), Quinn C(22), Genge A(23), Zinman L(24), Jabari D(25), Shoesmith C(26), Ludolph AC(27), Neuwirth C(28), Nations S(29), Shefner JM(18), Turner MR(30), Wuu J(31), Bennett R(2), Dang H(2), Sundgreen C(2); ORARIALS-01 trial team. Collaborators: Granit V, Steele J, Levy W, Paredes ME, Hernandez J, Bilsker M, Szacka K, Ronert A, Jablońska D, Łuczak AZ, Chaverri D, Janse van Mantgem MR, Bunte TM, Broere B, de Fockert A, Sanchez-Tejerina D, Landabaso C, Calvo A, Moglia C, Manera U, Canosa A, Vasta R, Salamone P, Fuda G, DeMarco G, Casale F, Me Forsberg K, Winroth I, Almgren Stenberg E, Holmgren M, Amador MDM, Lenglet T, Querin G, Coudoin S, Pavlakis P, Holzberg S, Sideri R, Marinou K, Czarnecki M, Ługiewicz R, Biel-Czarnecka M, Boczkowska M, Schotte C, Vynckier J, Van Daele S, Claeys T, Delmotte K, Swinnen B, Serrien A, D'Hondt A, Lamaire N, Debien E, Jones S, Vachon C, Grogan J, Solorzano G, Crowell A, Rakocevic G, Wagoner M, Alma O, Flavia W, Sonja K, Olivia SK, Camilla W, Anastasia S, Carola K, Chantal F, Adamo A, Turcotte N, Duncan J, Turner I, Elman L, Massie R, Berube M, Saunders N, Salmon K, Foucher J, Agessandro A, Shirley P, Jahan M, Phung L, Statland J, Jawdat O, Dimachkie M, Pasnoor M, Farmakidis C, Heim A, Lillig K, Lackey A, Weber M, Kurz M, Levine T. Author information: (1)Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: mbenatar@miami.edu. (2)Orphazyme, Copenhagen, Denmark. (3)Prosoft Clinical, Chesterbrook, PA, USA. (4)Department of Neurology University of Montpellier, CHU Montpellier, INM INSERM, Montpellier, France. (5)Department of Neurology, Medical University of Warsaw, Warsaw, Poland. (6)Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands. (7)Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain. (8)Rita Levi Montalcini Department of Neuroscience, University of Torino, Torino, Italy. (9)Department of Clinical Sciences, Neuroscience, Umeå University, Umeå, Sweden. (10)APHP, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France. (11)Department of Neurology, Hospital for Special Surgery, New York, NY, USA. (12)Department of Neurology, University Hospital Leuven, KU Leuven, Leuven, Belgium. (13)Istituti Clinici Scientifici Maugeri, IRCCS Milano, Milan, Italy. (14)Research and Development Department, Polish Stem Cell Bank, Warsaw, Poland. (15)University of Virginia Medical Center, Charlottesville, VA, USA. (16)Department of Neurology, Hannover Medical School, Hannover, Germany. (17)Providence Portland Medical Center, Providence Brain and Spine Institute, Portland, OR, USA. (18)Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA. (19)Department of Neurology, University of California Irvine, Irvine, CA, USA. (20)Department of Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. (21)University College London, National Hospital for Neurology and Neurosurgery, London, UK. (22)Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (23)Department of Neurology, Montreal Neurological Institute, Montreal, QC, Canada. (24)Sunnybrook Health Sciences Centre, Toronto, ON, Canada. (25)Department of Neurology, The University of Kansas Medical Center, Kansas City, KS, USA. (26)Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, ON, Canada. (27)Department of Neurology, University of Ulm, Ulm, Germany. (28)Neuromuscular Disease Unit/ALS Clinic, Kantonspital St Gallen, St Gallen, Switzerland. (29)University of Texas Southwestern, Dallas, TX, USA. (30)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (31)Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. Comment in Lancet Neurol. 2024 Jul;23(7):651-653. doi: 10.1016/S1474-4422(24)00223-0. 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. Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. DOI: 10.1016/S1474-4422(24)00134-0 PMID: 38782015 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests MB reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees from Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami licensed some of MB's research data to Biogen to aid in the design of the ATLAS trial; MB receives a royalty payment received by the University of Miami as part of this licensing agreement. DR received consulting fees from Orphazyme for biostatistical consulting services for the ORARIALS-01 protocol. LHvdB reports consulting fees from Amylyx, Biogen, Ferrer, Corcept, Orion, and Orphazyme, as well as payment for scientific advisory board activities from Takeda. AC reports grants from the Italian Ministry of Health, the Italian Ministry of University and Research, the European Commission, Biogen, and the ALS Association; as well as consulting fees from Mitsubishi Tanabe, Biogen, Roche, Sanofi, Denali Pharma, Cytokinetics, Eli Lilly, and Amylyx Pharmaceuticals; he has received a research grant from Biogen. PMA report grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Ulla-Carin Lindquist Foundation, NEURO, the Brain Foundation, and the European Commission; as well as consulting fees from Biogen, Avrion, Arrowhead, Regeneron, uniQure, Orphazyme, and Roche. P-FP reports meeting and travel support from Orphazyme. PVD reports grant from CSL Behring; speakers fees from Biogen and Amylyx; and participation in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, and VectorY. SP reports grants from Cytokinetics, Biogen, and Roche; consulting fees from Cytokinetics, Amylyx, Biogen, Roche, and Zambon; payment or honoraria from Biogen, Zambon, Roche, Amylyx, Italfarmaco, and Desitin; meeting and travel support from Biogen, Desitin, Zambon, Amylyx, Italfarmaco, PTC Therapeutics, and Ferrer; and participation in data safety monitoring boards or advisory boards for ORION Pharma, Amylyx, Biogen, Roche, and Zambon. SL reports consulting fees from Biogen and Amylyx; and participation in a data safety monitoring board (chair) for Neurosense Therapeutics. NAG reports grants from Abcuro, Amylyx, Alexion, Annelixis, Annexon, Brainstorm Cell Therapeutics, Calico, Cytokinetics, Fulcrum, Healey, Janssen, Kezar, Medicinova, MT Pharma, Octapharma, PTC, Sanofi, and Transposon; consulting fees from Abcuro, Alexion, Amylyx, Annexon, Argenx, Astrazeneca, CSL Behring, Fulcrum, Kezar, MT Pharma, Sanofi Genzyme, Sarepta, and UCB; and speakers fees from Argenx and CSL. CQ reports grants from Sanofi, Biogen, and Amylyx; consultant fees from Amylyx and Biogen; and honoraria from Seattle Science Foundation. AG reports consulting fees from Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics; support for attending meetings and travel from Amylyx, Mitsubishi Tanabe Pharma, QurAlis, Alexion, and ALS Pharmaceuticals; has a leadership role in ALS Canada; has stock or stock options in QurAlis; and has received equipment, materials, drugs, medical writing, gifts or other services from Amylyx. LZ reports grants from ALS Canada, Amylyx, Biogen, and Mitsubishi Tanabe Pharma; consulting fees from Amylyx, Cytokinetics, Mitsubishi Tanabe Pharma, Neurosense, and Biogen; and participation in a data safety monitoring board (chair) for Amylyx. CS reports speakers fees from Mitsubishi Tanabe Pharma Canada; participation in an advisory board for Biogen; and unpaid roles in Canadian ALS Research Consortium and Scientific Medical Advisory Board for ALS Canada. CN received compensation for consultant fees and training activities by Biogen, Roche, Genzyme, and Mitsubishi Tanabe. JMS reports grants from NINDS, ALS Association, AB Sciences, Acorda Therapeutics, Alector, Amylyx, Biogen, Cytokinetics Incorporated, Ionis, Mitsubishi Tanabe Pharma America, Quralis, PTC, Sanofi, Wave, and Myolex; consulting fees from Amylyx, Cytokinetics, Denali, GSK, Mitsubishi Tanabe Pharma America, Neurosense, Orthogonal, Pinteon, RRD, Acurastem, Revalasio, Apellis, Novartis, Sanofi, and Immunity Pharma; participation in data safety monitoring boards or advisory boards for Swanbio and Braingate; and stock or stock options in Aural Analytics. MRT reports salary support from the Motor Neurone Disease Association; royalties or licences from Oxford University Press, Oneworld, and Karger; speakers' honoraria from University of Miami; and participation in advisory board for Biogen and Novartis. JW reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association. TH, MAG, TB, RB, HD, and CS are previous employees of Orphazyme. MK-K reports research support from the JPND by the National Center for Research and Development, and from E-Rare by the National Science Center of Poland. MK-K also reports paid consulting fees from Amylyx, Ferrer, and Cytokinetics. All other authors declare no competing interests.
11. Ann N Y Acad Sci. 2024 Jun;1536(1):82-91. doi: 10.1111/nyas.15147. Epub 2024 May 21. Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis. Alarcan H(1)(2), Bruno C(3), Emond P(2)(4), Raoul C(5)(6), Vourc'h P(1)(2), Corcia P(2)(7), Camu W(5)(6), Veyrune JL(8), Garlanda C(9)(10), Locati M(10), Juntas-Morales R(11), Saker S(12), Suehs C(13), Masseguin C(14), Kirby J(15), Shaw P(15), Malaspina A(16), De Vos J(17), Al-Chalabi A(18), Leigh PN(19), Tree T(20), Bensimon G(#)(13), Blasco H(#)(1)(2). Author information: (1)Service de Biochimie et Biologie Moléculaire, CHRU Bretonneau, Tours, France. (2)UMR 1253 iBrain, Université de Tours, Inserm, Tours, France. (3)Service de Pharmacologie Médicale, CHRU Bretonneau, Tours, France. (4)Laboratoire de Médecine nucléaire in vitro, CHRU Bretonneau, Tours, France. (5)INM, University of Montpellier, INSERM, Montpellier, France. (6)ALS Reference Center, University of Montpellier, CHU Montpellier, Montpellier, France. (7)Service de Neurologie, CHRU Bretonneau, Tours, France. (8)Institute of Human Genetics, University of Montepllier, Montpellier, France. (9)Department of Biomedical Sciences, Humanitas University, Milan, Italy. (10)IRCCS Humanitas Research Hospital, Rozzano, Italy. (11)Neuromuscular Diseases Unit, European Reference Network on Rare Neuromuscular Diseases (ERN EURO-NMD), Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain. (12)Genethon, DNA and Cell bank, Evry, France. (13)Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique, Innovation et Méthodologie (BESPIM), Université de Nîmes, Nîmes, France. (14)Delegation for Clinical Research and Innovation, Nîmes University Hospital, Nîmes, France. (15)Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. (16)UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK. (17)Department of Cell and Tissue Engineering, University Montpellier, CHU Montpellier, Montpellier, France. (18)Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. (19)Brighton and Sussex Medical School, Brighton, UK. (20)Department of Computer Science, University of Sheffield, Sheffield, UK. (#)Contributed equally Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology. © 2024 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences. DOI: 10.1111/nyas.15147 PMID: 38771698 [Indexed for MEDLINE]
12. Trials. 2023 Dec 5;24(1):792. doi: 10.1186/s13063-023-07638-w. A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial. Lombardo FL(#)(1), Spila Alegiani S(#)(2), Mayer F(2), Cipriani M(3)(4), Lo Giudice M(5), Ludolph AC(6)(7), McDermott CJ(8), Corcia P(9)(10)(11)(12), Van Damme P(13)(14), Van den Berg LH(15), Hardiman O(16)(17), Nicolini G(18), Vanacore N(19), Dickie B(20), Albanese A(5), Puopolo M(4); TUDCA-ALS Study Group. Collaborators: Tornese P, Cocco A, Matteoli M, Lauranzano E, Malosio ML, Elia CA, Chiò A, Manera U, Moglia C, Calvo A, Salamone P, Fuda G, Colosimo C, Spera C, Ranchicchio PC, Stipa G, Frondizi D, Lunetta C, Sansone V, Tarlarini C, Gerardi F, Silani V, Doretti A, Colombo E, Demirtzidis G, Tedeschi G, Trojsi F, Passaniti C, Ballestrero S, Dorst J, Weiland U, Fromm A, Wiesenfarth M, Kandler K, Witzel S, Otto M, Schuster J, Meyer T, Maier A, Kettemann D, Petri S, Müschen L, Wohnrade C, Sarikidi A, Osmanovic A, Grosskreutz J, Rödiger A, Steinbach R, Ilse B, Smesny U, Untucht R, Günther R, Vidovic M, Shaw P, Collins A, Wollff H, Walsh T, Tuddenham L, Kazoka M, White D, Young S, Thompson B, Madarshahian D, Chhetri SK, Chaouch A, Young CA, Arndt H, Hanemann C, Lambert T, Beltran S, Couratier P, Esselin F, Camu W, De La Cruz E, Lemasson G, Masrori P, Maguire S, Fogarty L, Atoyebi T, Obáin NN. Author information: (1)National Centre for Disease Prevention and Health Promotion, Italian National Institute of Health, Rome, Italy. flavia.lombardo@iss.it. (2)National Center for Drug Research and Evaluation, Italian National Institute of Health, Rome, Italy. (3)Department of Statistical Sciences, Sapienza University of Rome, Rome, Italy. (4)Department of Neuroscience, Italian National Institute of Health, Rome, Italy. (5)Neurology Department, IRCCS Humanitas Research Hospital, Rozzano, Italy. (6)Neurology Department, University of Ulm, Ulm, Germany. (7)German Centre of Neurodegenerative Diseases, Site Ulm, Ulm, Germany. (8)Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK. (9)Centre de Référence Maladie Rare (CRMR) SLA Et Les Autres Maladies du Neurone Moteur (FILSLAN), Tours, France. (10)CHU Bretonneau, Tours, France. (11)Federation des CRMR-SLA Tours-Limoges, LITORALS, Tours, France. (12)Faculté de Médecine, INSERM U1253, "iBrain," Université François-Rabelais de Tours, Tours, France. (13)Neurology Department, University Hospitals Leuven, Louvain, Belgium. (14)Neuroscience Department, KU Leuven, Louvain, Belgium. (15)Department of Neurology, UMC Utrecht Brain Center, University Medical Centre Utrecht, Utrecht, Netherlands. (16)Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Dublin, Ireland. (17)Clinical Research Centre, Beaumont Hospital, Dublin, Ireland. (18)Medical Affairs, Bruschettini S.R.L, Genoa, Italy. (19)National Centre for Disease Prevention and Health Promotion, Italian National Institute of Health, Rome, Italy. (20)Motor Neurone Disease Association, Northampton, UK. (#)Contributed equally BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019. © 2023. The Author(s). DOI: 10.1186/s13063-023-07638-w PMCID: PMC10696667 PMID: 38053196 [Indexed for MEDLINE] Conflict of interest statement: Author AL declares participation in Advisory Boards of Roche Pharma AG, Biogen, Alector, and Amylyx. Author CJM reports consultancy with Biogen, Amylyx, and Cytokinetics. Author PV declares participation in Advisory Board meetings for Biogen, UCB, argenx, Cytokinetics, Ferrer, Muna Therapeutics, Augustine Therapeutics, Alector, Alexion, QurAlis, VectorY, and Amylyx (paid to institution) and grant from CSL Behring (E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders; paid to institution). Author OH declares participation in Advisory Boards for Accelsiors, Biogen Idec, Cytokinetics, NeuroSense Therapeutics, Neuropath Therapeutics, Novartis, Orion, Denali, and Wave Pharmaceuticals; role as principal investigator on the PRECISION ALS Project; Academic/Industry Collaboration funded by Science Foundation Ireland; Research collaboration with Biogen, Cytokinetics, and Ionis in delivering the IMPACT ALS survey and with Cytokinetics in delivering the REVEALS study of respiratory decline in ALS; editor-in-chief of ALS and the Frontotemporal Degeneration; editorial board member of the Journal of Neurology, Neurosurgery, and Psychiatry. Author GN declares that Bruschettini S.R.L is the pharmaceutical company providing the investigational medicinal product and industrial partner of the project, in which he is an employee as medical director. The remaining authors declare no competing interests.
13. Neurology. 2022 Aug 23;99(8):e762-e774. doi: 10.1212/WNL.0000000000200606. Epub 2022 Jun 6. Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies. Freedman MS(1), Pozzilli C(2), Havrdova EK(2), Lemle A(2), Burcklen M(2), Larbalestier A(2), Hennessy B(2), Sidorenko T(2), Vaclavkova A(2), Olsson T(2); Ponesimod Phase II Study Group. Collaborators: Leutmezer F, Tarnev I, Shotekov P, Krushkov H, Haralanov L, Tichá V, Zapletalová O, Rektor I, Vachova M, Kaňovský P, Skoda O, Kallela M, Kinnunen E, Erälinna JP, Sumelahti ML, Elovaara I, Camu W, Tumani H, Ruprecht K, Harms L, Sátori M, Valikovics A, Csányi A, Harcos P, Szakács Z, Jakab G, Achiron A, Flechter S, Zaffaroni M, Ghezzi A, Perini P, Gallo P, Luigi G, De Stefano N, Comi G, Van Munster C, Sanders E, van Dijl R, van Erven P, Kamienowski J, Kozubski W, Członkowska A, Zbrojkiewicz J, Corneliu Bulboaca A, Simi M, Stolyarov ID, Skoromets AA, Boyko A, Belova AN, Stuchevskaya FR, Yakupov EZ, Mishin GN, Poverennova IE, Magzhanov RV, Salina EA, Sholomov II, Dinčić E, Vojinović S, Miletić Drakulić S, Eichau S, Guillermo Izquierdo M, Eugenia V, Fernandez O, Sanchez F, García Merino JA, Svenningsson A, Lycke J, Gobbi C, O Kobys T, O Kareta SO, Dziak LA, Muratova TM, Silber E, Cottrell D, Hobart J, Zajicek J, Wendt J, Mattson D, Simnad V, Mehta L, Lynch S, Rowe V, Solomon A, Applebee A, Panitch H, Hamill R, Nicolas JA, Melanson M, Apperson M, Agius M, Keller BJ, Dunn J, Carnes K, Coyle P, Staunton S, Edwards K, Kisanuki Y, Racke MK, Boster A, Driver-Dunckley E, Carter J. Author information: (1)From the Multiple Sclerosis Research Unit, Department of Medicine, The University of Ottawa; The Ottawa Hospital Research Institute, Ontario, Canada (M.S.F.); Department of Human Neuroscience, Sapienza University of Rome, Italy (C.P.); Department of Neurology, First Medical Faculty, Charles University, Prague, Czech Republic (E.K.H.); Actelion Pharmaceuticals Ltd, Part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Allschwil, Switzerland (A. Lemle, M.B., A. Larbalestier, B.H., T.S., A.V.); and Karolinska Institute (T.O.), Stockholm, Sweden. mfreedman@toh.ca. (2)From the Multiple Sclerosis Research Unit, Department of Medicine, The University of Ottawa; The Ottawa Hospital Research Institute, Ontario, Canada (M.S.F.); Department of Human Neuroscience, Sapienza University of Rome, Italy (C.P.); Department of Neurology, First Medical Faculty, Charles University, Prague, Czech Republic (E.K.H.); Actelion Pharmaceuticals Ltd, Part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Allschwil, Switzerland (A. Lemle, M.B., A. Larbalestier, B.H., T.S., A.V.); and Karolinska Institute (T.O.), Stockholm, Sweden. OBJECTIVE: To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated. RESULTS: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%). CONCLUSION: The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free. TRIAL REGISTRATION INFORMATION: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study). Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000200606 PMCID: PMC9484728 PMID: 35667837 [Indexed for MEDLINE]
14. Neurol Neuroimmunol Neuroinflamm. 2022 Feb 21;9(3):e1148. doi: 10.1212/NXI.0000000000001148. Print 2022 May. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Vermersch P(1), Brieva-Ruiz L(2), Fox RJ(2), Paul F(2), Ramio-Torrenta L(2), Schwab M(2), Moussy A(2), Mansfield C(2), Hermine O(2), Maciejowski M(2); AB07002 Study Group. Collaborators: Hecham N, Deri NH, Djelilovic-Vranic J, Milanov I, Shotekov P, Blevins G, Girard J, Lapierre Y, Camu W, Castelnovo G, Clavelou P, Hautecoeur P, Marziniak M, Mayer C, Oschmann P, Reifschneider G, Schoell I, Tackenberg B, Bergh FT, Fakas N, Grigoriadis N, Kalochristianakis D, Mitsikostas D, Orologas A, Tavernarakis A, Thomaidis T, Kovacs K, Matyas K, Piros P, Satori M, Anand K, Shifrin A, Banaszkiewicz K, Bonek R, Chahwan M, Czernichowska-Kotiuszko M, Darda-Ledzion L, Debrowska-Wójcik J, Dziki M, Krzystanek E, Kulka M, Lisewski P, Ratajczak M, Szczudlik A, Szczygiel J, Tomaszewska M, Wójcik J, Zielonka D, Chiru M, Deme S, Manescu S, Nica SM, Popescu C, Szatmari S, Fedyanin A, Malkova N, Popov D, Volkova L, Vorobeva O, Brozman M, Cimprichova A, Cuchran P, Gurcik L, Krastev G, Lisá I, Nyeky M, Poljaková J, Turcani P, Frost A, Heckmann J, Agüera E, Coret F, Escartin A, Fernandez V, Callizo JA, Martin G, Martinez-Rodriguez JE, Gines MM, Munoz D, Olascoaga J, Prieto J, Ramo-Tello C, Belal S, Ben Ammou S, Frih-Ayed M, Gouider R, Mhiri C, Mrissa R, Cherkez A, Chmyr H, Chudovska L, Datskevych S, Dziak L, Galusha A, Khavunka M, Kobys T, Kozyolkin O, Lekomtseva Y, Litovchenko T, Moroz O, Moskovko G, Pashkovsky V, Sanotskyi Y, Shkrobot S, Braley T, Conway J, Hughes B, Katz A, Rizvi S, Singer R. Author information: (1)From the Univ. Lille (P.V.), UMR Inserm U1172, CHU Lille, FHU Precise, France; Neurology Department (L.B.-R.), Hospital Arnau de Vilanova de Lleida, Spain; Mellen Center for Multiple Sclerosis (R.J.F.), Neurological Institute, Cleveland Clinic, OH; Experimental and Clinical Research Center and NeuroCure Clinical Research Center (F.P.), Max Delbrueck Center for Molecular Medicine and Charité Universitaetsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Neurology Department (L.R.-T.), Dr Josep Trueta University Hospital, Girona; Neurodegeneration and Neuroinflammation Research Group (L.R.-T.), IDIBGI, Salt; Medical Science Department (L.R.-T.), University of Girona, Spain; Neurology Department (M.S.), Jena University Hospital, Germany; AB Science (A.M., C.M., O.H.), Paris, France; Imagine Institute (O.H.), INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France; and MA LEK AM Maciejowscy SC Centrum Terapii SM (M.M.), Katowice, Poland. patrick.vermersch@univ-lille.fr. (2)From the Univ. Lille (P.V.), UMR Inserm U1172, CHU Lille, FHU Precise, France; Neurology Department (L.B.-R.), Hospital Arnau de Vilanova de Lleida, Spain; Mellen Center for Multiple Sclerosis (R.J.F.), Neurological Institute, Cleveland Clinic, OH; Experimental and Clinical Research Center and NeuroCure Clinical Research Center (F.P.), Max Delbrueck Center for Molecular Medicine and Charité Universitaetsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Neurology Department (L.R.-T.), Dr Josep Trueta University Hospital, Girona; Neurodegeneration and Neuroinflammation Research Group (L.R.-T.), IDIBGI, Salt; Medical Science Department (L.R.-T.), University of Girona, Spain; Neurology Department (M.S.), Jena University Hospital, Germany; AB Science (A.M., C.M., O.H.), Paris, France; Imagine Institute (O.H.), INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France; and MA LEK AM Maciejowscy SC Centrum Terapii SM (M.M.), Katowice, Poland. BACKGROUND AND OBJECTIVES: Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active. METHODS: This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients. RESULTS: A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed. DISCUSSION: Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data. TRIAL REGISTRATION INFORMATION: The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years). Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/NXI.0000000000001148 PMCID: PMC9005047 PMID: 35190477 [Indexed for MEDLINE]
15. EBioMedicine. 2020 Sep;59:102844. doi: 10.1016/j.ebiom.2020.102844. Epub 2020 Jul 7. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. Camu W(1), Mickunas M(2), Veyrune JL(3), Payan C(4), Garlanda C(5), Locati M(6), Juntas-Morales R(1), Pageot N(1), Malaspina A(7), Andreasson U(8), Kirby J(9), Suehs C(10), Saker S(11), Masseguin C(12), De Vos J(3), Zetterberg H(13), Shaw PJ(9), Al-Chalabi A(14), Leigh PN(15), Tree T(16), Bensimon G(17). Author information: (1)Clinique du Motoneurone, CHU Gui de Chauliac, University of Montpellier, Montpellier, France. (2)Department Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK. (3)Department of Cell and Tisue Engineering, University of Montpellier, CHU Montpellier, Montpellier France. (4)Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes, France; Department of Pharmacology, AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, F-75013 Paris, France. (5)IRCCS Humanitas Clinical & Research Institute, Milan, Italy; Humanitas University, Pieve Emanuele, Milan, Italy. (6)IRCCS Humanitas Clinical & Research Institute, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University Milan, Milan Italy. (7)Neuroscience and Trauma Centre, Institute of Cell and Molecular Medicine, Department of Neuroimmunology, Barts and the London School of Medicine and Dentistry, London, UK. (8)Department of Psychiatry & Neurochemistry, University of Gothenburg, Mölndal, Sweden. (9)Sheffield Institute for Translational Neuroscience, Department of Neuroscience, University of Sheffield, Sheffield, UK. (10)Departments of Medical Information and Respiratory Diseases, University of Montpellier, CHU Montpellier, Montpellier, France. (11)DNA and Cell Bank, Genethon, Evry, France. (12)Delegation for Clinical Research and Innovation, Nîmes University Hospital, Nîmes, France. (13)Department of Psychiatry & Neurochemistry, University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK. (14)Institute of Psychiatry Psychology and Neuroscience, Department of Basic and Clinical Neuroscience, King's College London, London, UK; Department of Neurology, King's College Hospital, London, UK. (15)The Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton BN1 9RY, UK. (16)Department Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK. Electronic address: timothy.tree@kcl.ac.uk. (17)Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes, France; Department of Pharmacology, AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, F-75013 Paris, France; Department of Pharmacology, Sorbonne Université Médecine, F-75013 Paris, France. Electronic address: gbensimon.psl@gmail.com. BACKGROUND: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. METHODS: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. FINDINGS: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. INTERPRETATION: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. FUNDING: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA). Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.ebiom.2020.102844 PMCID: PMC7502670 PMID: 32651161 [Indexed for MEDLINE] Conflict of interest statement: Declaration of Competing Interest Drs. Camu, Mickunas, Payan, Juntas Morales, Pageot, Masseguin, Suehs, De Vos, Saker, Andreasson and Veyrune have nothing to disclose. Dr. Bensimon reports grants from French Health Ministry (PHRC-I), ARSLA and EU HORIZON 2020, during the conduct of the study; in addition, Dr. Bensimon has a patent (WO 2012123381 A1) with royalties paid to Assistance Publique Hopitaux de Paris (APHP), Institut National de la Sante et de la Recherche Medicale INSERM, and Sorbonne Universite. Drs. Bensimon, Tree, Leigh, Locati, Garlanda, Shaw, Kirby, Malaspina have a patent (B75649EPD40021) pending. Dr. Malaspina reports grants from EU HORIZON 2020, grants from MND Association UK, grants and other from Barts and the London Charity, and from UCB Pharma SPRL, during the conduct of the study; and from F. Hoffmann-La Roche outside the submitted work. Dr. Zetterberg reports personal fees from Samumed, Roche Diagnostics, Denali, CogRx and Wave, outside the submitted work. Dr. Kirby reports grants from The Nimes University Hospital Center (CHU Nimes) and grants from EU HORIZON 2020, during the conduct of the study. Dr. Shaw reports grants from EU HORIZON 2020, Sheffield component and MIROCALS (633413), outside the submitted work. Dr. Al-Chalabi reports involvement as Chief Investigator for LEVALS clinical trial and European CI for REFALS clinical trial for OrionPharma, as well as consultancy from Mitsubishi Tanabe Pharma, consultancy and involvement in debating panel for Cytokinetics Inc, consultancy from Chronos Therapeutics, GSK, Lilly, and from Biogen Idec, outside the submitted work.
16. Can J Surg. 2020 May 8;63(3):E250-E253. doi: 10.1503/cjs.010519. The relationship between postoperative opioid consumption and the incidence of hypoxemic events following total hip arthroplasty: a post hoc analysis. Essex MN(1), Camu F(1), Borgeat A(1), Salomon PA(1), Pan S(1), Cheung R(1). Author information: (1)From Pfizer Inc., New York, NY (Essex, Pan, Cheung); the Department of Anesthesiology, University of Brussels, Brussels, Belgium (Camu); the Department of Anaesthesiology, Balgrist University Hospital, Zurich, Switzerland (Borgeat); and Pfizer Inc., Mexico City, Mexico (Salomon). BACKGROUND: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events. METHODS: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events. RESULTS: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1). CONCLUSION: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events. Publisher: CONTEXTE: L’utilisation d’analgésiques opioïdes en période postopératoire peut provoquer une dépression respiratoire. Nous avons voulu déterminer si, après une arthroplastie totale de la hanche, une réduction de la consommation de morphine à 48 heures par l’administration de parécoxib (47,0 %), de propacétamol (35,1 %) ou d’une combinaison des deux (67,9 %) — avec ajustement selon un groupe placebo — se traduirait par une réduction du nombre d’épisodes d’hypoxémie. MÉTHODES: Nous avons effectué une analyse post hoc d’une étude randomisée de non-infériorité avec témoins sous placebo. Après une répartition aléatoire, chaque patient a reçu par intraveineuse du parécoxib (40 mg 2 fois par jour), du propacétamol (2 g 4 fois par jour), une combinaison de parécoxib et de propacétamol (40 mg 2 fois par jour + 2 g 4 fois par jour) ou un placebo. Tout au long de l’étude, la dose, la date et le moment de l’administration de morphine contrôlée par le patient ont été notés. Chez les patients qui ne recevaient pas d’oxygène d’appoint, la saturation périphérique en oxygène a été surveillée de manière continue pendant les 48 heures suivant l’opération. L’hypoxémie a été définie comme une saturation inférieure à 90 %. Le moment et les données d’oxymétrie ont été notés pour chaque épisode d’hypoxémie. Le coefficient de corrélation de Pearson a été utilisé pour évaluer la présence de corrélations entre la consommation cumulative de morphine durant les premières 48 heures et le nombre moyen d’épisodes d’hypoxémie. RÉSULTATS: Une proportion significativement plus faible de patients ayant reçu le traitement combiné de parécoxib et de propacétamol ont connu des épisodes d’hypoxémie, comparativement aux patients qui avaient reçu le placebo (2,8 % c. 13,2 %, p < 0,05), et le nombre moyen d'épisodes d'hypoxémie était significativement plus faible dans le groupe ayant reçu du parécoxib (0,12), du propacétamol (0,06) ou une combinaison de parécoxib et de propacétamol (0,03), par rapport au groupe placebo (0,36, p < 0,05 pour tous). Aucune corrélation n'a été observée entre la réduction de la quantité totale de morphine consommée à 48 heures et le nombre moyen d'épisodes d'hypoxémie pour tous les groupes (p > 0,1 pour tous). CONCLUSION: Après une arthroplastie totale de la hanche, une réduction de la consommation de morphine de plus de 70 % pourrait être nécessaire pour obtenir une réduction correspondante du nombre d’épisodes d’hypoxémie. © 2020 Joule Inc. or its licensors. DOI: 10.1503/cjs.010519 PMCID: PMC7828993 PMID: 32386476 [Indexed for MEDLINE] Conflict of interest statement: M. Essex, P. Salomon and S. Pan are employees of Pfizer and have stock or stock options with Pfizer. F. Camu has acted as consultant to pharmaceutical companies and health authorities, outside the submitted work. R. Cheung was an employee of Pfizer at the time of study conduct. No other competing interests were declared.
17. Neurol Neuroimmunol Neuroinflamm. 2019 Aug 6;6(5):e597. doi: 10.1212/NXI.0000000000000597. Print 2019 Sep. Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE). Camu W(1), Lehert P(2), Pierrot-Deseilligny C(2), Hautecoeur P(2), Besserve A(2), Jean Deleglise AS(2), Payet M(2), Thouvenot E(2), Souberbielle JC(2). Author information: (1)From CHU Gui de Chauliac (W.C.) and Institut de Génomique Fonctionnelle (E.T.), Université de Montpellier, France; Faculty of Economics (P.L.), UCL Mons, Louvain, Belgium; Faculty of Medicine (P.L.), the University of Melbourne, Australia; CHU Pitié Salpêtrière (C.P.-D.), Paris; GHICL St Vincent de Paul (P.H.), Lille; Merck (A.B., A.-S.J.-D., M.P.), Lyon; CHU Caremeau (E.T.), Nîmes; and CHU Necker (J.C.S.), Paris, France. w-camu@chu-montpellier.fr. (2)From CHU Gui de Chauliac (W.C.) and Institut de Génomique Fonctionnelle (E.T.), Université de Montpellier, France; Faculty of Economics (P.L.), UCL Mons, Louvain, Belgium; Faculty of Medicine (P.L.), the University of Melbourne, Australia; CHU Pitié Salpêtrière (C.P.-D.), Paris; GHICL St Vincent de Paul (P.H.), Lille; Merck (A.B., A.-S.J.-D., M.P.), Lyon; CHU Caremeau (E.T.), Nîmes; and CHU Necker (J.C.S.), Paris, France. Erratum in Neurol Neuroimmunol Neuroinflamm. 2019 Nov 15;7(1):e648. doi: 10.1212/NXI.0000000000000648. OBJECTIVE: To evaluate the safety and efficacy of cholecalciferol in patients with relapsing-remitting MS (RRMS). METHODS: In this double-blind, placebo-controlled parallel-group, 2-year study, 181 patients with RRMS were randomized 1:1. Key inclusion criteria were a low serum 25-hydroxy vitamin D (25OHD) concentration (<75 nmol/L), a treatment with interferon beta-1a 44 μg (SC 3 times per week) 4 months ± 2 months before randomization, and at least one documented relapse during the previous 2 years. Patients received high-dose oral cholecalciferol 100,000 IU or placebo every other week for 96 weeks. Primary outcome measure was the change in the annualized relapse rate (ARR) at 96 weeks. Secondary objectives included safety and tolerability of cholecalciferol and efficacy assessments (ARR, MRI parameters, and Expanded Disability Status Scale [EDSS]). RESULTS: The primary end point was not met. In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all efficacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026). The overall rate of adverse events was well balanced between groups. CONCLUSIONS: Although the primary end point was not met, these data suggest a potential treatment effect of cholecalciferol in patients with RRMS already treated with interferon beta-1a and low serum 25OHD concentration. Together with the good safety profile, these data support the exploration of cholecalciferol treatment in such patients with RRMS. CLINICALTRIALSGOV IDENTIFIER: NCT01198132. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and low serum 25OHD, cholecalciferol did not significantly affect ARRs. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/NXI.0000000000000597 PMCID: PMC6705622 PMID: 31454777 [Indexed for MEDLINE]
18. Amyotroph Lateral Scler Frontotemporal Degener. 2019;0(0):1-11. doi: 10.1080/21678421.2019.1612922. A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis. Shefner JM(1)(2), Cudkowicz ME(3), Hardiman O(4), Cockcroft BM(5), Lee JH(5), Malik FI(5), Meng L(5), Rudnicki SA(5), Wolff AA(5), Andrews JA(6); VITALITY-ALS Study Group. Collaborators: Van Damme P(7), Korngut L(8), Johnston W(9), O'Connell C(10), Grant I(11), Turnbull J(12), Shoesmith C(13), Zinman L(14), Botez S(15), Genge A(16), Dionne A(17), Couratier P(18), Attarian S(19), Pouget J(19), Camu W(20), Desnuelle C(21), Salachas F(22), Corcia P(23), Meyer T(24), Petri S(25), Ludolph A(26), Hardiman O(27), Calvo A(28), Lunetta C(29), Silani V(30), van den Berg L(31), de Carvalho M(32), Mora Pardina J(33), Young C(34), Al-Chalabi A(35), Radunovic A(36), Hanemann C(37), Shefner JM(38), Ladha S(39), Goyal N(40), Ravits J(41), Lewis R(42), Joyce N(43), Oskarsson B(43), Katz JS(44), So Y(45), Cockroft BM(46), Lee JH(46), Malik FI(46), Meng L(46), Rudnicki SA(46), Wolff AA(46), Quan D(47), Felice K(48), Bayat E(49), Boylan K(50), Benatar MG(51), Vu T(52), Glass J(53), Sufit R(54), Bodkin C(55), Swenson A(56), Statland J(57), Maragakis N(58), Cudkowicz ME(59), Berry J(59), Brown R(60), Salameh J(60), Goutman S(61), Newman DS(62), Guliani G(63), Maiser S(63), Pestronk A(64), Hayat G(65), Pattee G(66), Cohen J(67), Brooks B(68), Bedlack R(69), Andrews JA(70), Caress J(71), Mitsumoto H(72), Lange D(73), Bradshaw D(74), Kolb SJ(75), Karam C(76), Khoury J(76), Goslin K(77), Simmons Z(78), McCluskey L(79), Heiman-Patterson T(80), Donofrio P(81), Heitzman D(82), Harati Y(83), Jackson C(84), Phillips L(85), Weiss M(86), Nance C(87), Sultan S(87), Barkhaus P(88). Author information: (1)Barrow Neurological Institute, Phoenix, Arizona. (2)Department of Neurology, University of Arizona, Phoenix, AZ, USA. (3)Department of Neurology, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, USA. (4)Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland. (5)Cytokinetics, Inc., South San Francisco, California, USA. (6)The Neurological Institute, Columbia University, New York, NY, USA. (7)Universitair Ziekenhuis Leuven, Leuven. (8)Heritage Medical Research Clinic, Calgary, Alberta. (9)Kaye Edmonton Clinic, Edmonton, Alberta. (10)River Valley Health - Stan Cassidy Foundation, Stan Cassidy Fredericton, New Brunswick. (11)QEII Health Sciences Centre, Halifax, Nova Scotia. (12)McMaster University, Hamilton, Ontario. (13)London Health Sciences Centre, London, Ontario. (14)Sunnybrook Health Sciences Centre, Toronto, Ontario. (15)CHUM Hospital Notre-Dame, Montreal, Quebec. (16)Montreal Neurological Institute and Hospital, Montreal, Quebec. (17)CHU de Québec, Hôpital de l'Enfant-Jésus, Québec City, Quebec. (18)CHU - Hôpital Dupuytren, Limoges. (19)CHU - Hôpital de la Timone, Marseilles. (20)Hôpital de Chauliac, Montpellier. (21)CHU de Nice - Hopital de l'Archet 1, Nice. (22)Hôpital La Pitié Salpétrière, Paris. (23)Centre SLA de Tours, Tours. (24)Charite - Campus Virchow-Klinikum (CVK), Berlin. (25)Medizinische Hochschule Hannover, Hannover. (26)Universitätsklinikum Ulm, Ulm. (27)Trinity Biomedical Sciences Institute, Trinity College, Dublin. (28)Ospedale Molinette, AOU Cittàdella Salute e della Scienza di Torino, Torino. (29)Ospedale Niguarda Ca' Granda, AO, Milan. (30)Ospedale S. Luca, Istituto Auxologico Italiano-IRCCS Istituto, Milan. (31)Universitair Medisch Centrum Utrecht, locatie Academisch Zie, Utrecht. (32)H. Santa Maria, Centro Hospitalar de Lisboa Norte, Lisbon. (33)H. San Rafael, Madrid. (34)Walton Centre for Neurology and Neurosurgery, Liverpool. (35)King's College Hospital, London. (36)Barts and the London MND Centre, London. (37)Plymouth Hospitals NHS Trust, Plymouth. (38)Barrow Neurological Institute, Phoenix, AZ. (39)St. Joseph's Hospital and Medical Center, Phoenix, AZ. (40)University of California Irvine, Irvine, CA. (41)University of California San Diego Altman Clinical and Translational Research Institute, La Jolla, CA. (42)Cedars-Sinai Medical Center, Los Angeles, CA. (43)University of California Davis Medical Center, Sacramento, CA. (44)California Pacific Medical Center, San Francisco, CA. (45)Stanford Neuroscience Health Center, Stanford, CA. (46)Cytokinetics, Inc., South San Francisco, CA. (47)University of Colorado Hospital - Anschutz Outpatient Pavilion, Aurora, CO. (48)Hospital for Special Care, New Britain, CT. (49)George Washington University, Washington, DC. (50)Mayo Clinic Jacksonville, Jacksonville, FL. (51)University of Miami UHealth Professional Arts Center, Miami, FL. (52)University of South Florida, Tampa, FL. (53)Emory University School of Medicine, Atlanta, GA. (54)Northwestern University - Feinberg School of Medicine, Chicago, IL. (55)Indiana University, Indianapolis, IN. (56)University of Iowa Hospitals & Clinics, Iowa City, IA. (57)University of Kansas Medical Center, Kansas City, KS. (58)Johns Hopkins Medicine - Transverse Myelitis Center, Baltimore, MD. (59)Massachusetts General Hospital, Boston, MA. (60)UMass Memorial Medical Center - University Campus, Worcester, MA. (61)University of Michigan, Ann Arbor, MI. (62)Henry Ford Hospital, Detroit, MI. (63)Hennepin County Medical Center, Twin Cities ALS Research Consortium, Minneapolis, MN. (64)Washington University, St. Louis, MO. (65)Saint Louis University, St. Louis, MO. (66)Neurology Associates, P.C., Lincoln, NE. (67)Dartmouth Hitchcock Medical Center, Lebanon, NH. (68)Carolinas Neuromuscular/ALS MDA Center, Charlotte, NC. (69)Duke University Medical Center, Durham, NC. (70)The Neurological Institute Columbia University, New York, NY. (71)Wake Forest University Baptist Medical Center, Winston-Salem, NC. (72)Columbia University Medical Center, New York, NY. (73)Weill Medical College of Cornell University, New York, NY. (74)State University of New York (SUNY), Syracuse, NY. (75)Ohio State University Medical Center, Columbus, OH. (76)Oregon Health & Science University, Portland, OR. (77)Providence Brain and Spine Institute ALS Center, Portland, OR. (78)Penn State Milton S. Hershey Medical Center, Hershey, PA. (79)Pennsylvania Hospital, Philadelphia, PA. (80)Temple University School of Medicine, Philadelphia, PA. (81)Vanderbilt University Medical Center, Nashville, TN. (82)Texas Neurology, Dallas, TX. (83)Baylor College of Medicine, Houston, TX. (84)University of Texas Health Science Center San Antonio, San Antonio, TX. (85)University of Virginia, Charlottesville, VA. (86)University of Washington, Seattle, WA. (87)West Virginia University, Morgantown, WV. (88)Medical College of Wisconsin Milwaukee, WI. Erratum in Amyotroph Lateral Scler Frontotemporal Degener. 2019 Nov;20(7-8):630. doi: 10.1080/21678421.2019.1639381. OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. RESULTS: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. CONCLUSIONS: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898). DOI: 10.1080/21678421.2019.1612922 PMID: 31081694 [Indexed for MEDLINE]
19. Eur Respir J. 2019 Feb 14;53(2):1801749. doi: 10.1183/13993003.01749-2018. Print 2019 Feb. Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures. Guimarães-Costa R(1)(2), Similowski T(3)(4)(2), Rivals I(4)(5), Morélot-Panzini C(3)(4), Nierat MC(4), Bui MT(6), Akbar D(7), Straus C(4)(8), Romero NB(6), Michel PP(7), Menegaux F(9), Salachas F(1), Gonzalez-Bermejo J(4)(10)(11), Bruneteau G(1)(1)(12)(11); RespiStimALS team; contributors to the RespiStimALS study were:. Collaborators: Del Mar Amador M, Antoine JC, Arne-Bes MC, Attali V, Beauvais K, Brunaud-Danel V, Bruneteau G, Camdessanche JP, Camu W, Carluer L, Cassereau J, Chapart M, Chenuel B, Chereau N, Cintas P, Clavelou P, Corcia P, Cornette A, Couratier P, Court-Fortune I, Cuvelier A, Delclaux C, Desnuelle C, Di Maria S, Fargeot C, Fauroux B, Finet-Monnier A, Celine Fleury M, Gaillat C, Georges M, Giroud M, Gonzalez-Bermejo J, Greil A, Guerrier M, Nicolas G, Guy N, Hannequin D, Juillien V, Juntas-Morales R, Kessler R, Kolev Y, Lagarde J, Lautrette G, Le Cam P, LeForestier N, Lemasson G, Lenglet T, Magro P, Mallart A, Martinaud O, Meininger V, Menegaux F, Meslier N, Moirot P, Morelot-Panzini C, Nadjar Y, Niel-Duriez M, Nierat MC, Noullet S, Pageot N, Perez T, Perrin C, Pillet O, Pittion S, Pouget J, Pradat PF, Prigent H, Rabec C, Ricard JD, Romero N, Royer C, Salachas F, Schaup B, Sedkaoui K, Similowski T, Soriani MH, Straus C, Tanguy ML, Tranchant C, Vandenberghe N, Vershueren A, Viader F, Wienalek-Bachelet AC. Author information: (1)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Département de Neurologie, Centre référent SLA, Paris, France. (2)Joint first authors. (3)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie, Médecine Intensive et Réanimation, Département R3S, Paris, France. (4)Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France. (5)Equipe de Statistique Appliquée, ESPCI Paris, PSL Research University and Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France. (6)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Unité de Morphologie Neuromusculaire, Institut de Myologie, Paris, France. (7)CELIS Cell Culture Core Facility, Institut du Cerveau et de la Moelle Épinière, ICM, INSERM U1127, CNRS UMR 7225, Sorbonne Université, Paris, France. (8)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service des Explorations de la Fonction Respiratoire, de l'Exercice et de la Dyspnée, Département R3S, Paris, France. (9)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Département de Chirurgie Générale et Endocrinologique, Paris, France. (10)AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Unité Fonctionnelle SSR Respiratoire, Service de Pneumologie, Médecine Intensive et Réanimation Département R3S, Paris, France. (11)Joint last authors. (12)Institut du Cerveau et de la Moelle Épinière, ICM, INSERM U1127, CNRS UMR 7225, Sorbonne Université, Paris, France. Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function. Copyright ©ERS 2019. DOI: 10.1183/13993003.01749-2018 PMID: 30523161 [Indexed for MEDLINE] Conflict of interest statement: Conflict of interest: R. Guimarães-Costa has nothing to disclose. Conflict of interest: T. Similowski reports personal fees from AstraZeneca, Boerhinger Ingelheim France, GSK Lungpacer Inc., TEVA, Chiesi, Pierre Fabre and Invacare, and personal fees and non-financial support from Novartis, outside the submitted work. In addition, he received honoraria from Synapse Biomedical to translate the DPS/NeurRx4 user manual from English into French in 2007 and, from 2012 to 2016, Synapse Biomedical contributed to a fundraiser organised by T. Similowski to promote respiratory research. T. Similowski is also engaged in scientific collaborations with two other companies manufacturing phrenic stimulation devices. With Lungpacer Inc (Canada) he acts as a paid consultant and investigator in clinical trials, while with Atrotech-Neuroresp (France) he acts as a probono consultant (no fees or other support). Conflict of interest: I. Rivals has nothing to disclose. Conflict of interest: C. Morélot-Panzini has nothing to disclose. Conflict of interest: M-C. Nierat has nothing to disclose Conflict of interest: M.T. Bui has nothing to disclose. Conflict of interest: D. Akbar has nothing to disclose. Conflict of interest: C. Straus has nothing to disclose. Conflict of interest: N.B. Romero has nothing to disclose. Conflict of interest: P.P. Michel has nothing to disclose. Conflict of interest: F. Menegaux has nothing to disclose. Conflict of interest: F. Salachas has nothing to disclose. Conflict of interest: J. Gonzalez-Bermejo has nothing to disclose. Conflict of interest: G. Bruneteau has nothing to disclose.
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