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Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502670/ https://www.ncbi.nlm.nih.gov/pubmed/32651161 http://dx.doi.org/10.1016/j.ebiom.2020.102844 |
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author | Camu, William Mickunas, Marius Veyrune, Jean-Luc Payan, Christine Garlanda, Cecilia Locati, Massimo Juntas-Morales, Raul Pageot, Nicolas Malaspina, Andrea Andreasson, Ulf Kirby, Janine Suehs, Carey Saker, Safa Masseguin, Christophe De Vos, John Zetterberg, Henrik Shaw, Pamela J Al-Chalabi, Ammar Leigh, P Nigel Tree, Timothy Bensimon, Gilbert |
author_facet | Camu, William Mickunas, Marius Veyrune, Jean-Luc Payan, Christine Garlanda, Cecilia Locati, Massimo Juntas-Morales, Raul Pageot, Nicolas Malaspina, Andrea Andreasson, Ulf Kirby, Janine Suehs, Carey Saker, Safa Masseguin, Christophe De Vos, John Zetterberg, Henrik Shaw, Pamela J Al-Chalabi, Ammar Leigh, P Nigel Tree, Timothy Bensimon, Gilbert |
author_sort | Camu, William |
collection | PubMed |
description | 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). |
format | Online Article Text |
id | pubmed-7502670 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-75026702020-09-28 Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial Camu, William Mickunas, Marius Veyrune, Jean-Luc Payan, Christine Garlanda, Cecilia Locati, Massimo Juntas-Morales, Raul Pageot, Nicolas Malaspina, Andrea Andreasson, Ulf Kirby, Janine Suehs, Carey Saker, Safa Masseguin, Christophe De Vos, John Zetterberg, Henrik Shaw, Pamela J Al-Chalabi, Ammar Leigh, P Nigel Tree, Timothy Bensimon, Gilbert EBioMedicine Research Paper 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). Elsevier 2020-07-07 /pmc/articles/PMC7502670/ /pubmed/32651161 http://dx.doi.org/10.1016/j.ebiom.2020.102844 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Camu, William Mickunas, Marius Veyrune, Jean-Luc Payan, Christine Garlanda, Cecilia Locati, Massimo Juntas-Morales, Raul Pageot, Nicolas Malaspina, Andrea Andreasson, Ulf Kirby, Janine Suehs, Carey Saker, Safa Masseguin, Christophe De Vos, John Zetterberg, Henrik Shaw, Pamela J Al-Chalabi, Ammar Leigh, P Nigel Tree, Timothy Bensimon, Gilbert Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title | Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title_full | Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title_fullStr | Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title_full_unstemmed | Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title_short | Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial |
title_sort | repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (imodals): a phase 2a randomised, double-blind, placebo-controlled trial |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502670/ https://www.ncbi.nlm.nih.gov/pubmed/32651161 http://dx.doi.org/10.1016/j.ebiom.2020.102844 |
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