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.
Trial registration The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.
- Multiple Sclerosis
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Laquinimod, a novel oral immunomodulator, is under study for treatment of multiple sclerosis (MS).1–4 The safety, tolerability and efficacy of once-daily 0.6 mg laquinimod was studied in the ALLEGRO (Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis)1 and BRAVO (Benefit-Risk Assessment of AVonex and LaquinimOd)4 trials, both 24-month, phase III, randomised, placebo-controlled studies in patients with relapsing-remitting (RR) MS. In ALLEGRO, laquinimod significantly reduced relapse rate and the cumulative number of gadolinium-enhancing (GdE) lesions and new T2 lesions compared with placebo. Additionally, laquinimod showed significant effects on reducing disability and brain atrophy progression.1 Because brain atrophy reflects the most destructive aspects of MS5 and correlates with disability progression,6–9 we hypothesised that laquinimod may exert, in addition to its anti-inflammatory effects, an effect on irreversible brain damage.
MS has long been thought to be primarily a white matter (WM) disease of the central nervous system. Increasing evidence suggests grey matter (GM) is also affected in MS early in the disease.10 Remarkably, damage to whole GM and to selected GM structures, including the thalamus, correlates better with disability progression than WM injury.11–13
Preplanned exploratory substudies of ALLEGRO using various MRI techniques were conducted to investigate drug effects on diffuse disease-related abnormalities, irreversible tissue damage and metabolic abnormalities that could contribute to the observed clinical benefits of laquinimod for delaying disability progression in ALLEGRO. The MRI markers included changes in WM, GM and thalamic volumes; evolution of active lesions into permanent black holes (PBH)14; extent of tissue disruption in normal appearing brain tissue (NABT), WM, GM and T2 lesions, assessed by magnetisation transfer (MT) MRI15; and changes in N-acetylaspartate/creatinine (NAA/Cr) levels, measured by proton MR spectroscopy (1H-MRS).16–18
Patient inclusion and exclusion criteria, randomisation procedures, endpoints and procedures for assessing safety, tolerability and efficacy of laquinimod versus placebo in the ALLEGRO study are described elsewhere.1 Briefly, eligible patients had a diagnosis of relapsing-remitting MS (RRMS)19 and had experienced one or more relapses in the previous 12 months, two or more relapses in the previous 24 months or at least one relapse between 12 and 24 months prior to screening and had at least one GdE lesion in the 12 months before screening. Participants were 18–55 years and had Expanded Disability Status Scale scores between 0 and 5.5.
Patients provided written informed consent before participating in any study procedure and were asked to re-sign an informed consent form following a relapse. The study protocol was approved by all local institutional review boards. The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.
The ALLEGRO trial was conducted at 139 sites in 24 countries. RRMS patients were randomised 1 : 1 to receive a once-daily oral laquinimod 0.6 mg dose or matching placebo. Per protocol, all patients underwent MRI scans at 0, 12 and 24 months (or last observation). A subgroup of patients (laquinimod n=149, placebo n=157), the ‘frequent MRI’ cohort, participated in an ancillary substudy of ALLEGRO at 58 sites and had MRI scans taken at 3 and 6 months also. The Neuroimaging Research Unit in Milan, Italy served as the MRI analysis centre (MRI-AC).
MRI endpoints included per cent change in WM, GM and thalamic volume from baseline to months 12 and 24 and between months 12 and 24. Also measured was the cumulative number of new T1 hypointense lesions at month 24.
Data from the subgroup of patients in the frequent MRI cohort were evaluated to determine the numbers and proportions of PBH at months 12 and 24 that evolved from active lesions (ie, GdE lesions and/or new T2 lesions) detected at different study time points.
In the MT MRI substudy (performed at 10 sites), average MT ratio (MTR) changes from baseline of NABT, WM, GM and T2 lesions at 12 and 24 months and between months 12 and 24 were evaluated. The 1H-MRS substudy (performed at 6 sites) assessed the change from baseline to month 24 in NAA/Cr levels in WM. Patient participation in the different MRI substudies was based on centre capabilities and patients’ willingness.
Each patient was studied using the same scanner and MRI sequences during the study. The main MRI acquisition protocol is described in detail elsewhere1 and included dual-echo sequences for quantification of T2-hyperintense lesions, high resolution precontrast 3D T1-weighted sequences for estimation of atrophy, and postcontrast T1-weighted images (obtained 5 min after injection of 0.1 mmol/kg Gd) for the identification of GdE lesions.
For analysis of WM and GM volumes, 3D T1-weighted images were segmented with SPM8 (http://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Intracranial volume (ICV) was calculated as the sum of WM, GM and cerebrospinal fluid (CSF) obtained with this segmentation procedure. To verify that the presence of lesions did not influence the segmentation, T1 hypointense lesions were refilled on baseline scans.20 The correlations between GM/WM volumes calculated after lesion refilling with those obtained without refilling were then estimated. The correlation was highly significant (Pearson r=0.97 for GM and 0.99 for WM, p<0.001). The thalamus was segmented on the same images using FIRST (http://www.fmrib.ox.ac.uk/fsl/first). Baseline WM, GM and thalamic volumes were divided by ICV to correct for head size. Longitudinal changes in WM, GM and thalamic volumes were calculated as the percentage change versus baseline.
The evolution of active lesions into PBH was assessed as previously described.14 ,21 New lesions were defined as a GdE lesion and/or a new T2 lesion arising from an area of previously normal-appearing WM. PBH were defined as lesions with signal intensity between that of GM and CSF on postcontrast T1-weighted images.
MT MRI and 1H-MRS scans were acquired before Gd administration, using 1.5 Tesla scanners only. For MT MRI, proton density-weighted gradient-echo MRI scans (TR=1400–2000 ms, TE=12–15 ms, FA=40°, slice thickness=3 mm, 44 contiguous axial slices, frequency offset in the range between 1000 and 1500 Hz) were acquired with and without a MT saturation pulse at baseline, month 12 and month 24. MTR was calculated in each voxel as the percentage change between images with (Ms) and without (M0) the MT pulse, which were previously coregistered halfway (MTR=[M0-Ms]*100/M0). MTR images were then coregistered to the dual-echo scans and histograms of NABT, WM and GM were produced. The average MTR values were calculated for each histogram and for T2 lesions.
1H-MRS data were obtained from a volume of interest, located in the WM centred in the body of the corpus callosum (5 mm left-right×70 mm anterior-posterior×15 mm cranio-caudal) using a 90°-180°-180° (PRESS) volume selective sequence (TR=2000 ms, TE=272 ms). MR images showing the voxel placement superimposed on the intersecting slices were sent to the MRI-AC to verify correct positioning of the voxel and to assess the quality of the spectrum. Metabolite quantification was performed using the LCmodel.22
Efficacy analyses included all patients with at least one valid postbaseline scheduled MRI measurement. Outcomes were assessed using all evaluable scans and all endpoints were analysed at a significance level of 5%. See online supplement for a detailed description of statistical analyses.
A total of 1106 RRMS patients were randomised to treatment; their disease and demographic characteristics at baseline are reported elsewhere.1 Of them, 939 patients (laquinimod n=478, placebo n=461) had at least one valid postbaseline scheduled MRI scan. Figure 1 shows patient disposition for all efficacy assessments. Baseline characteristics in the efficacy population were comparable with those of all patients in ALLEGRO, and there were no significant differences between the laquinimod and placebo treatment groups in demographic or MS disease characteristics at baseline (data not shown). In the frequent cohort, 124 patients (laquinimod n=55, placebo n=69) had active lesions at baseline or during the study and were included in the PBH analyses. The MT MRI substudy included 92 patients. Of these, 75 patients (laquinimod n=38, placebo n=37) had evaluable scans at baseline and month 12, and 63 (laquinimod n=31, placebo n=32) at baseline and month 24. The 1H-MRS analysis included 28 patients and 27 of them (laquinimod n=12, placebo n=15) had baseline and month 24 evaluable scans.
Baseline MRI measures by treatment group for patients in the brain volume analyses and in the PBH, MT MRI and 1H-MRS substudies are shown in E-tables 1 and 2. There was a statistically significant imbalance in GM volume between the laquinimod and placebo groups at baseline (0.40 [0.04] vs 0.41 [0.04], respectively, p=0.0441). There was no other statistically significant difference in any baseline MRI measure between patients in the laquinimod and placebo cohorts.
WM, GM and thalamic volumes
Median per cent changes in WM and GM from baseline to month 12 were lower for patients treated with laquinimod compared with placebo patients (p=0.004 for both), and differences at month 24 were statistically significant for WM, while approached statistical significance for GM (p=0.035 and p=0.078) (table 1). Differences in median per cent changes in WM and GM between months 12 and 24 were not statistically significant between the laquinimod and placebo groups (p=0.857 and p=0.664).
The per cent changes in thalamic volume from baseline to month 12 and 24 were lower for patients treated with laquinimod compared with placebo patients (p=0.005, p=0.003, respectively) (table 1).
Subgroup analysis of per cent changes in thalamic volume from baseline to months 12 and 24 was performed by presence of T2 thalamic lesions at baseline. Overall 485 patients had T2 thalamic lesions at baseline, whereas only 452 were included in the subgroup analysis (20 patients from the placebo arm and 13 from the laquinimod arm did not have scans at month 12 or 24). These analyses showed a significant treatment effect for laquinimod over placebo only for the subgroup of patients that had T2 thalamic lesions at baseline, while there was no significant effect for the subgroup of patients that did not have T2 thalamic lesions at baseline (data not shown). Additionally, significant negative correlation was found between thalamic volume change and T2 thalamic lesion volume change from baseline to month 24 (Pearson r=−0.184, p<0.001).
New T1 hypointense lesions
The mean (±SD) cumulative number of new T1 hypointense lesions at months 12 and 24 in the laquinimod group (1.61±3.16) was lower than in the placebo group (2.23±3.88), risk ratio=0.733, 95% CI 0.593 to 0.905 (p=0.004).
Lesion evolution to PBH
The mean numbers of PBH at months 12 and 24 that evolved from active lesions at different study time points were significantly lower in the laquinimod compared with the placebo group (p<0.05 for all comparisons, risk ratios ranged from 0.42 to 0.51) (table 2).
The mean number of PBH that developed from only GdE lesions detected while on treatment was lower with laquinimod versus placebo at month 12 (from GdE lesions detected at months 3 and 6, risk ratio=0.45, p=0.022) and at month 24 (from GdE lesions at months 3, 6, and 12, risk ratio=0.44, p=0.005). A similar trend was apparent for the mean numbers of PBH at months 12 and 24 that evolved from new T2 lesions in laquinimod versus placebo comparisons (p=0.030 and p=0.009, respectively). There was no difference between placebo and laquinimod at 12 and 24 months in the number of PBH evolved from GdE lesions present at baseline. However, if all GdE lesions were included in the analysis (those detected at baseline and while on treatment), the mean number of PBH at month 24 was lower with laquinimod versus placebo (risk ratio=0.45, p=0.001).
The proportions of active, GdE and new T2 lesions that evolved into PBH were lower, albeit not statistically significantly, with laquinimod than with placebo for all assessments (table 3).
The proportion of all active lesions to evolve into PBH at month 24 was 23% with laquinimod versus 28% with placebo (p=0.260). The proportion of all GdE lesions evolving into PBH at month 24 was 21% with laquinimod versus 29% with placebo (p=0.117). The proportion of all new T2 lesions evolving into PBH at month 24 was 23% with laquinimod versus 26% with placebo (p=0.572).
Least square (LS) mean changes in MTR values with placebo showed decreases from baseline to months 12 and 24 and between months 12 and 24 for all assessments. MTR values in the laquinimod group increased from baseline to months 12 and 24 for all MTR outcomes and slightly decreased from month 12 to month 24 for all assessments except for T2 lesion, which slightly increased (table 4).
Significant differences between treatment arms in LS mean change in MTR values favoured laquinimod at months 12 and 24 for NABT (p=0.013 and p=0.015, respectively), WM (p=0.013 and p=0.011) and GM (p=0.014 and p=0.034). Changes in LS mean MTR of T2 lesions did not differ significantly between laquinimod and placebo patients at any time point. No significant treatment differences were found for any MTR measures between month 12 and month 24.
The adjusted mean change in NAA/Cr value from baseline to month 24 was an increase of 0.047 for laquinimod patients and a decrease of 0.176 for placebo patients, representing a treatment difference of 0.22 (95% CI −0.11 to 0.56; p=0.179).
In the phase III ALLEGRO and BRAVO studies, oral laquinimod significantly reduced the risk of confirmed disability progression by 33% to 36% compared with placebo in RRMS patients.1 ,4 To understand better the mechanisms associated with this finding, we evaluated several putative MR markers of brain tissue damage.22 Results of these exploratory studies support the concept that laquinimod may have an effect on brain damage and supports the clinical disability results obtained in the ALLEGRO pivotal study.1 Compared with placebo, patients treated with laquinimod showed decreased rates of WM, GM and thalamic atrophy; developed fewer PBH; and tended to accumulate less damage to the NABT, WM and GM.
Brain volume loss has been correlated with the progression of disability in MS.7–9 The ALLEGRO and BRAVO studies showed that laquinimod decreases the rate of whole brain atrophy compared with placebo.1 ,4 To evaluate whether this effect is diffuse or limited to a specific brain compartment, we assessed tissue loss in the WM and GM separately. Our results indicate that reduced atrophy with laquinimod occurs in WM and GM and this is mostly driven by a drug's effect during the first year of treatment. Although the efficacy of laquinimod on GdE lesion formation is known to be modest,1 ,4 ‘pseudoatrophy’ (loss of water without loss of tissue secondary to the resolution of focal and diffuse inflammatory oedema) is likely to have been more severe in laquinimod-treated patients than in those receiving placebo. Given the fact that ‘pseudoatrophy’ occurs early after treatment initiation, we believe that the reported first year effect sizes of laquinimod on atrophy measures are underestimated, which suggests an even greater ability of the drug to prevent tissue loss soon after administration. The reason why such an effect was lost during the second year of treatment is unclear. It could be argued that laquinimod's effect on reducing brain tissue damage is short term, although one might also speculate that the dose used was not enough to maintain over time the ability of laquinimod to control mechanisms leading to irreversible tissue loss. That laquinimod is able to prevent GM loss (which at baseline was more pronounced in treated vs placebo patients) is important since it has been shown that GM atrophy is present since the earliest stages of MS, may be more marked than WM atrophy, is more strongly associated with clinical disability and tends to worsen over time.11 ,23 ,24
Since several studies have suggested that the quantification of thalamic atrophy might be more clinically relevant than estimating volume changes of the entire brain GM,11 ,23 ,24 we also measured volume modifications of this structure in isolation. Thalamic volume loss was significantly reduced in laquinimod-treated compared with placebo-treated patients at 12 and 24 months. Notably, when the presence of thalamic lesions was considered in the analysis, the effect of treatment on thalamic atrophy was significant only for patients with thalamic lesions at study entry, suggesting that the effect of laquinimod in preventing progression of thalamic atrophy may be driven, at least partially, by its anti-inflammatory activity.2 ,3
In natural history studies, it has been shown that over 6–12 months about 30% to 40% of active MS lesions evolve into PBH,18 which correspond to areas of severe and irreversible tissue damage.25 The analysis of PBH evolution in the frequent MRI cohort showed that the number of PBH that developed from active lesions was significantly lower in patients treated with laquinimod compared with those receiving placebo at months 12 and 24. This finding, which agrees with the observation in the whole cohort that laquinimod-treated patients had fewer new T1 hypointense lesions on scans obtained at month 24 than placebo-treated patients, was driven by an effect on GdE and new T2 lesions. Of note, such an effect was not seen on the number of GdE lesions present on baseline scans; this suggests that laquinimod might not prevent intrinsic tissue loss in lesions formed before its administration. The proportion of new T2 and GdE lesions evolving to PBH at month 24 was lower but not significantly different in laquinimod-treated patients versus those receiving placebo. The number of PBH is a measure of the overall extent of irreversible tissue damage, whereas the proportion of PBH provides insight into the developmental fate of existing active GdE and T2 lesions. Therefore, the more pronounced effect exerted by laquinimod on PBH number versus proportion suggests that laquinimod efficacy in reducing lesion evolution to PBH is likely secondary to mechanisms that occur before lesion formation.
MTR values in MS lesions and in normal-appearing WM correlate with the percentage of residual axons and the degree of demyelination, may reflect remyelination26 and are predictive of future disability.9 ,11 ,12 ,15 ,27 Our MT MRI findings showed that laquinimod treatment reduces or stabilises damage occurring in brain tissues. Mean MTR values at 12 and 24 months were significantly higher in NABT, WM and GM with laquinimod compared with placebo treatment.
NAA/Cr levels are indicative of axonal and neuronal integrity17 ,28; NAA/Cr typically decreases by approximately 5% per year in untreated RRMS patients17 ,28 and is correlated with the severity of disability and cognitive impairment.9 ,16 ,29 ,30 Albeit statistical significance was not reached, the mean NAA/Cr levels in WM increased from baseline to month 24 in laquinimod-treated patients, but decreased in placebo-treated patients. This finding should prompt further studies in larger patient populations.
Together, results of these assessments made using a variety of MRI approaches indicate oral laquinimod is likely to exert a neuroprotective effect resulting in a reduced amount of irreversible brain tissue damage, which in turn might explain the observed ability of the drug to slow down disability accumulation in RRMS patients.
We thank the Independent Data Monitoring Committee, members of the MRI Analysis Center and the Principal Investigators for each country previously listed in Comi et al; Yossi Gilgun, PhD and Nora Tarcic, PhD of the Teva Innovative Research and Development Clinical Team (Netanya, Israel) who participated in the development and monitoring of the study; Nissim Sasson, M.A. of the Teva Statistical Data Management Team (Netanya, Israel) who managed the statistical analyses; and Pippa Loupe, PhD of Medical Affairs, Teva Pharmaceuticals (Kansas City, MO), James D. Bergstrom, PhD of Mountain Stream Communications, LLC (Hillsborough, NJ) and Sheila Truten, B.S. of Medical Communication Company (Wynnewood, PA), who participated in the writing and editing of this article. Teva Pharmaceutical Industries and the Study Steering Committee were jointly involved in study design, analysis and writing the report. The authors had full access to all data and final responsibility for manuscript submission.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
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- Data supplement 1 - Online appendix
Collaborators ALLEGRO study group members: Members of the MRI analysis centre—Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Ospedale San Raffaele, Milan, Italy: M Filippi (Chair), MA Rocca, M Absinta, G Longoni, S. Galantucci, E Pagani, L. Dall'Occhio, P. Misci, M. Petrolini, S. Sala, and R. Vuotto. Steering committee—G Comi (Chair), A Boyko, M Filippi, D Jeffery, L Kappos, and×Montalban. Independent Data Monitoring Committee—H McFarland (Chair), K Bauer, N Galay. Principal Investigators—Austria: J Weber, C Franta, C Lampi. Bulgaria: P Shotekov, S Bozhinov, N Deleva, L Haralanov, S Ivanova Hristova, I Petrov, I Milanov. Canada: M Kremenchutzky, H Rabinovitch, C Ayotte, F GrandMaison, A Lamontagne, R Leckey, L Lee. Czech Republic: P Hradilek, P Kanovsky. Estonia: K Gross-Paju, P Taba. France: P Vermersch, L Rumbach, P Clavelou, C Confavreux, J Pelletier, G Edan. Georgia: R Shakarishvili, A Tsiskaridze. Germany: E Becker, A Chan, J Eggers, J Haas, C Heesen, F Heidenreich, J. Koehler, H W Koelmel, R Linker, P Oschmann, S Rauer, M Maschke, M Mueller, G Reifschneider, B Wildemann, A Steinbrecher, H Tumani, U Ziebold, T Ziemssen. Hungary: J Kanya, G Jakab, A Valikovics, L Bartos. Israel: D Karussis, H Rawashdeh, A Karni, J Chapman. Italy: G Comi, D Caputo, D Centonze, S Cottone, A Ghezzi, D Maimone, E Montanari, K Plewnia, E Scarpini. Latvia: M Metra. Lithuania: D Rastenyte, S Sceponaviciute. Netherlands: B De Jong, S Frequin, L Visser, C. Zwanikken. Poland: K Selmaj, B. Blaszczyk, A Wajgt, R Nowak, E Jasinska, W Brola, M Sobkowiak-Osinska, J Kapustecki, J Zaborski. Romania: CA Panea, M Simu, AC Bulboaca, RI Balasa, N Carciumaru. Russia: A Boyko, A Skoromets, I Stolyarov, S Perfilyev, M Odinak, O Amelina, N Malkova, A Gustov, L Volkova, A Shutov. Serbia: J Drulovic, S Vojinovic. Spain: Montalban, R Arroyo, A Saiz Hinarejos, L Brieva, L Ramio, J Meca Lallana, MdC Amigo Jorrin, JM Prieto, D Munoz Gracia, Y Aladro, F Coret, A Escartin, E Diez Tejedor. Sweden: J Hillert, T Olddon, C Martin. Turkey: E Idiman. UK: B Sharrack, G Giovannoni, C Young. Ukraine: T Nehrych, S Moskovko, T Kobys, AIpatov, K Loganovskyi. USA: N AbouZeid, D Jeffery, B Dihenia, A Carpenter, S Flitman, S Gazda, A Goodman, B Green, A Gupta, J Herbert, B Hughes, A Jacobs, B Khatri, S Lynch, T Miller, C Markowitz, R Murray, G Pardo, G Parry, G Gottschalk, H Rossman, S Scaberry, F Thomas, A Turel, G Anderson,CTwyman, D Wynn.
Contributors MF, DJ, LK, XM, ANB and GC were the members of the steering committee. MF, MAR and EP were involved in the analysis of MRI data. All authors reviewed the study report and contributed to the manuscript preparation.
Funding Provided by Teva Pharmaceutical Industries.
Competing interests MF serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Genmab A/S; has received funding for travel from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono and Teva Pharmaceutical Industries Ltd.; serves as a consultant to Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono, Novartis, Pepgen Corporation and Teva Pharmaceutical Industries Ltd.; serves on speakers’ bureaus for Bayer Schering Pharma, Biogen Idec, Genmab A/S, Merck Serono and Teva Pharmaceutical Industries Ltd.; receives research support from Bayer Schering Pharma, Biogen Idec, Genmab A/S, Novartis, Merck Serono, Teva Pharmaceutical Industries Ltd., Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health and CurePSP. MAR received speakers honoraria from Biogen Idec and Serono Symposia International Foundation and receives research support from the Italian Ministry of Health. EP has nothing to disclose. NDS serves on scientific advisory boards for Merck Serono and Novartis, has received funding for travel from Teva Pharmaceutical Industries Ltd., Merck Serono and Novartis and has received speaker honoraria from Teva Pharmaceutical Industries Ltd., BioMS Medical, Biogen Idec, Bayer Schering Pharma and Merck Serono. DJ has received honoraria for speaking and consulting from Bayer, Biogen, Teva, Serono, Pfizer, Glaxo, Novartis, Acorda, Genzyme and Questcor and has received research support from Bayer, Biogen, Teva, Serono, Pfizer and Novartis. LK has received financial support for research activities from Abbott, Actelion, Advancell, Allozyne, Barofold, Bayer, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, CLC Behring, Elan, GeBeuro SA, Genzyme, Glaxo-SmithKline, Johnson and Johnson, Lilly, Merck Serono, Mitsubishi Pharma, Novartis, Novonordisk, Octapharma, Petimmune, Sanofi-Aventis, Roche, Teva, UCB, Xenoport and Wyeth. He also received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member for clinical trials or participated in clinical trial advisory boards in the past, with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. XM has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member for clinical trials or participated in trial advisory boards in the past, with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall. ANB has nothing to disclose. GC has received consulting fees for participating on advisory boards from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Actelion and honorarium for speaking activities for Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi, Genzyme, Merck Serono, Bayer, Biogen, Serono Symposia International Foundation.
Patient consent Obtained.
Ethics approval Local Institutional Review Boards of the centres participating in the ALLEGRO trial; centres are listed in the supplementary file.
Provenance and peer review Not commissioned; externally peer reviewed.