title: Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.
abstract: BACKGROUND
  Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far.
  
  
  OBJECTIVE
  To compare CPM to methylprednisolone (MP) in SPMS.
  
  
  METHODS
  Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
  
  
  RESULTS
  Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
  
  
  CONCLUSIONS
  Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00241254.
authors.affiliation: Service de Neurologie et INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, France.|INSERM U 1215, Université de Bordeaux, Bordeaux, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brochet
authors.affiliation: Service de Neurologie et INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, France.
authors.forename: Mathilde S A
authors.initials: MS
authors.lastname: Deloire
authors.affiliation: Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique, Pôle de Santé Publique, CHU de Bordeaux, Bordeaux France.
authors.forename: Paul
authors.initials: P
authors.lastname: Perez
authors.affiliation: Service de Neurologie et INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, France.
authors.forename: Timothé
authors.initials: T
authors.lastname: Loock
authors.affiliation: Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique, Pôle de Santé Publique, CHU de Bordeaux, Bordeaux France.
authors.forename: Louise
authors.initials: L
authors.lastname: Baschet
authors.affiliation: Service de Neurologie, CHU de Nancy, Nancy, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Debouverie
authors.affiliation: Service de Neurologie, CHU de Nancy, Nancy, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Pittion
authors.affiliation: Service de Neurologie et INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Ouallet
authors.affiliation: Service de Neurologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Clavelou
authors.affiliation: Service de Neurologie et CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: de Sèze
authors.affiliation: Service de Neurologie et CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Collongues
authors.affiliation: Univ. Lille, CHU Lille, LIRIC-INSERM U995, FHU Imminent, Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.affiliation: Univ. Lille, CHU Lille, LIRIC-INSERM U995, FHU Imminent, Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Zéphir
authors.affiliation: Service de Neurologie, CHU de Nîmes, Nîmes, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Castelnovo
authors.affiliation: Service de Neurologie, CHU de Montpellier, Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.affiliation: Service de Neurologie, CHU de Nice, Nice, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lebrun
authors.affiliation: Service de Neurologie, CHU de Nice, Nice, France.
authors.forename: Mikael
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Service de Neurologie et INSERM-CHU CIC-P 0005, CHU de Bordeaux, Bordeaux, France.|INSERM U 1215, Université de Bordeaux, Bordeaux, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ruet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use*; D006233:Persons with Disabilities; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005602:France; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy*; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008775:Methylprednisolone