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