eprintid: 10106477 rev_number: 26 eprint_status: archive userid: 608 dir: disk0/10/10/64/77 datestamp: 2020-08-04 15:49:31 lastmod: 2021-09-26 23:20:03 status_changed: 2020-08-04 15:49:31 type: article metadata_visibility: show creators_name: Camu, W creators_name: Mickunas, M creators_name: Veyrune, J-L creators_name: Payan, C creators_name: Garlanda, C creators_name: Locati, M creators_name: Juntas-Morales, R creators_name: Pageot, N creators_name: Malaspina, A creators_name: Andreasson, U creators_name: Kirby, J creators_name: Suehs, C creators_name: Saker, S creators_name: Masseguin, C creators_name: De Vos, J creators_name: Zetterberg, H creators_name: Shaw, PJ creators_name: Al-Chalabi, A creators_name: Leigh, PN creators_name: Tree, T creators_name: Bensimon, G title: Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial ispublished: inpress divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: Amyotrophic lateral sclerosis, Biomarkers, Low dose interleukin-2, Neuro-inflammation, Randomised clinical trial, Regulatory T cells 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] Please cite 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 < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 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 < 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 < 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). date: 2020-07-07 date_type: published official_url: https://doi.org/10.1016/j.ebiom.2020.102844 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1799171 doi: 10.1016/j.ebiom.2020.102844 pii: S2352-3964(20)30219-X lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Stacey, Thomas actors_id: TSSTA20 actors_role: owner full_text_status: public publication: EBioMedicine article_number: 102844 event_location: Netherlands citation: Camu, W; Mickunas, M; Veyrune, J-L; Payan, C; Garlanda, C; Locati, M; Juntas-Morales, R; ... Bensimon, G; + view all <#> Camu, W; Mickunas, M; Veyrune, J-L; Payan, C; Garlanda, C; Locati, M; Juntas-Morales, R; Pageot, N; Malaspina, A; Andreasson, U; Kirby, J; Suehs, C; Saker, S; Masseguin, C; De Vos, J; Zetterberg, H; Shaw, PJ; Al-Chalabi, A; Leigh, PN; Tree, T; Bensimon, G; - view fewer <#> (2020) Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine , Article 102844. 10.1016/j.ebiom.2020.102844 <https://doi.org/10.1016/j.ebiom.2020.102844>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10106477/7/1-s2.0-S235239642030219X-main.pdf