@article{discovery10106477,
            year = {2020},
           month = {July},
         journal = {EBioMedicine},
           title = {Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial},
            note = {This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
ARTICLE IN PRESS
JID: EBIOM [m5G;July 23, 2020;9:54]
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        abstract = {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 {\ensuremath{<}}�75 years, disease duration {\ensuremath{<}}�5 years, riluzole treatment {\ensuremath{>}}�3 months, and a slow vital capacity {$\ge$}�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�{\ensuremath{<}}�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�{\ensuremath{<}}�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).},
          author = {Camu, W and Mickunas, M and Veyrune, J-L and Payan, C and Garlanda, C and Locati, M and Juntas-Morales, R and Pageot, N and Malaspina, A and Andreasson, U and Kirby, J and Suehs, C and Saker, S and Masseguin, C and De Vos, J and Zetterberg, H and Shaw, PJ and Al-Chalabi, A and Leigh, PN and Tree, T and Bensimon, G},
             url = {https://doi.org/10.1016/j.ebiom.2020.102844},
        keywords = {Amyotrophic lateral sclerosis, Biomarkers, Low dose interleukin-2, Neuro-inflammation, Randomised clinical trial, Regulatory T cells}
}