title: Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage.
abstract: OBJECTIVE
  In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.
  
  
  METHODS
  1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.
  
  
  RESULTS
  Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179).
  
  
  CONCLUSIONS
  Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients.
  
  
  BACKGROUND
  The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rocca
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pagani
authors.affiliation: Quantitative Neuroimaging Laboratory, Department of Neurology, Neurosurgery & Behavioral Sciences, University of Siena, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: Cornerstone Health Care, North Carolina, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.affiliation: Clinical Neuroimmunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Clinical Neuroimmunology, Vall d'Hebron University Hospital and University of Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Department of Neurology and Neurosurgery, Russian State Medical University and Moscow MS Center, Moscow, Russia.
authors.forename: Alexei N
authors.initials: AN
authors.lastname: Boyko
authors.affiliation: Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000097:blood; D001921:Brain / Q000473:pathology*; D003404:Creatinine / Q000097:blood; D004185:Disability Evaluation; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D013788:Thalamus / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015363:Quinolones; D001224:Aspartic Acid; C476223:laquinimod; C000179:N-acetylaspartate; D003404:Creatinine
keywords: MRI; Multiple Sclerosis