Gavin Giovannoni1, Volker Knappertz2, Joshua R Steinerman2, Aaron P Tansy2, Thomas Li2, Stephen Krieger2, Antonio Uccelli2, Bernard M J Uitdehaag2, Xavier Montalban2, Hans-Peter Hartung2, Maria Pia Sormani2, Bruce A C Cree2, Fred Lublin2, Frederik Barkhof2. 1. From Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK (G.G.); Teva Pharmaceuticals R&D, Teva Pharmaceutical Industries, Great Valley, Pennsylvania, USA and Department of Neurology, Medical Faculty, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (V.K.); Teva Pharmaceutical Industries, Malvern, Pennsylvania, USA (J. S.); Teva Pharmaceutical Industries, Malvern, Pennsylvania, USA (A. T.); Teva Pharmaceutical Industries, Great Valley, Pennsylvania, USA (T. L.); Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA (S.K.); Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research, University of Genoa, and Ospedale Policlinico San Martino-IRCCS, Genoa, Italy (A.U.); Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, MS Center Amsterdam, Amsterdam, The Netherlands (B.M.J.U.); Division of Neurology, University of Toronto/MS Centre St Michael's Hospital, Toronto, Canada (X.M.); Neurology-Neuroimmunology Department & Neurorehabilitation Unit, Multiple Sclerosis Centre of Catalonia, Barcelona, Spain (X.M.); Department of Neurology, Hospital Universitari de la Vall d'Hebron, Barcelona, Spain (X.M.); Department of Neurology, Medical Faculty, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany (H.H.); Department of Health Sciences, University of Genoa, Genoa, Italy (M. P. S.); Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA (B.A.C.C.); Saunders Family Professor of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA (F.L.); Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, and UCL Institutes of Neurology and Healthcare Engineering, London, UK (F.B.) g.giovannoni@qmul.ac.uk. 2. From Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK (G.G.); Teva Pharmaceuticals R&D, Teva Pharmaceutical Industries, Great Valley, Pennsylvania, USA and Department of Neurology, Medical Faculty, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany (V.K.); Teva Pharmaceutical Industries, Malvern, Pennsylvania, USA (J. S.); Teva Pharmaceutical Industries, Malvern, Pennsylvania, USA (A. T.); Teva Pharmaceutical Industries, Great Valley, Pennsylvania, USA (T. L.); Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA (S.K.); Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research, University of Genoa, and Ospedale Policlinico San Martino-IRCCS, Genoa, Italy (A.U.); Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, MS Center Amsterdam, Amsterdam, The Netherlands (B.M.J.U.); Division of Neurology, University of Toronto/MS Centre St Michael's Hospital, Toronto, Canada (X.M.); Neurology-Neuroimmunology Department & Neurorehabilitation Unit, Multiple Sclerosis Centre of Catalonia, Barcelona, Spain (X.M.); Department of Neurology, Hospital Universitari de la Vall d'Hebron, Barcelona, Spain (X.M.); Department of Neurology, Medical Faculty, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany (H.H.); Department of Health Sciences, University of Genoa, Genoa, Italy (M. P. S.); Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA (B.A.C.C.); Saunders Family Professor of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA (F.L.); Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands, and UCL Institutes of Neurology and Healthcare Engineering, London, UK (F.B.).
Abstract
OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events. RESULTS:374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS:Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.
RCT Entities:
OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events. RESULTS: 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS:Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.
Authors: Kimberley Allen-Philbey; Stefania De Trane; Zhifeng Mao; Cesar Álvarez-González; Joela Mathews; Amy MacDougall; Andrea Stennett; Xia Zhou; Ozlem Yildiz; Ashok Adams; Lucia Bianchi; Camilla Blain; Christine Chapman; Karen Chung; Cris S Constantinescu; Catherine Dalton; Rachel A Farrell; Leonora Fisniku; Helen Ford; Bruno Gran; Jeremy Hobart; Zhaleh Khaleeli; Miriam Mattoscio; Sue Pavitt; Owen Pearson; Luca Peruzzotti-Jametti; Antonio Scalfari; Basil Sharrack; Eli Silber; Emma C Tallantyre; Stewart Webb; Benjamin P Turner; Monica Marta; Sharmilee Gnanapavan; Gunnar Juliusson; Gavin Giovannoni; David Baker; Klaus Schmierer Journal: Ther Adv Neurol Disord Date: 2021-11-25 Impact factor: 6.570
Authors: Vivien Li; Baptiste Leurent; Frederik Barkhof; Marie Braisher; Fay Cafferty; Olga Ciccarelli; Arman Eshaghi; Emma Gray; Jennifer M Nicholas; Mahesh Parmar; Guy Peryer; Jenny Robertson; Nigel Stallard; James Wason; Jeremy Chataway Journal: Neurology Date: 2022-03-23 Impact factor: 11.800