MIROCALS_H2020/PHRC-N/2014/GB-01_ID-IL-2_Neuro-Inflammation in ALS Pts

• Research type

  Research Study

• Full title

  Efficacy and safety of low-dose IL-2 (ld-IL-2) as a Treg enhancer for controlling neuro-inflammation in newly diagnosed Amyotrophic Lateral Sclerosis (ALS) patients: A randomized, double-blind, placebo- controlled, phase-II Proof of Concept/ Proof of Mechanism Clinical Trial

• IRAS ID

  207544

• Contact name

  Peter Nigel Leigh

• Contact email

  P.Leigh@bsms.ac.uk

• Sponsor organisation

  CHU DE NIMES

• Eudract number

  2015-005347-14

• Clinicaltrials.gov Identifier

  PHRC-National 2014 grant, N°14-0077, 2014; The Motor Neurone Disease Association grant, N° 971-797

• Duration of Study in the UK

  2 years, 11 months, 30 days

• Research summary

  Summary of Research

  Amyotrophic Lateral Sclerosis (ALS) is a devastating, disabling and rare disease which progressively breaks down and damages the nerve cells in the brain and spine. It affects approx 50,000 people in the EU at any time and approx 10,000 deaths each year. Some interventions are provided to manage the symptoms of this disease, but care is largely supportive and palliative. The cost to society and to individuals is significant; much of it is health care costs. There is a pressing need to find disease-modifying therapies that will slow disease progression, increase survival and better quality of life.
  Riluzole is still the only agent shown to modify survival in ALS but its affects are modest. This tells us that modifying disease progression is a realistic goal in ALS.

  Research has shown neuroinflammation significantly contributes to neuronal damage. It is thought if this neuroinflammation can be modified this targeted therapy would be very effective in ALS patients. Previous therapeutic attempts targeted the suppression of all immuno-inflammatory cells, but the risks of toxicity outweighed the benefits of drug effect.
  Targeting specific regulatory T-cells called Tregs has shown to reduce neuroinflammation more safely and effectively and low dose IL-2 (ld-IL2) acts through these Tregs.
  This study is a randomised, double-blind, placebo-controlled, parallel group, stratified study (country (UK vs France) and site of disease onset (limb vs bulbar)). Bulbar region is lower part of the skull. It investigates the efficacy & safety of low-dose IL2 therapy for 18 months as an add-on therapy with riluzole, and compares the efficacy and safety to riluzole plus placebo in recently diagnosed ALS patients.
  The study will take place in 5 Hospitals in England (and 5 Hospitals in France) and will run for 36 months. They hope to recuit 72 patients in the UK from October 2016 (216 patients in total across France and UK).

  Summary of Results

  Financial Support
  MIROCALS was made possible through grants from European Union H2020 Programme in 2015 with co-funding from The Motor Neurone Disease Association of England, Wales and Northern Ireland (MNDA: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3Du001.QwnS5iG-2B4nwcunWxC03fkKs72ntpp9oJew9D8ll3tY8MB4rdMrNVyCqru75O9VpAvmKg_a04dWCHmDh7gi4hRuvmsd-2FMEDkPNm6D0IRdq0o1v81fHw-2B4nazeKEhMVRoGPAq15Oy4uFYb78ihD6qX3TmXd5a4UojwOMpsS5R2YdR73Xo4hi6mJs8PSXivmltOtf7JU7wbofE5N0Ro73OgO0-2BjF5ycEYm8V6oILC6dzXL0Q5w2Vcko4IWv9AzdwOAs9a7GGp0XNToA1LEUtBNoJHRGkrA-3D-3D&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C0f1828544f5d4ccde4a908dc3f6215f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638454937706498751%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=C76ba%2Blbf7y42SDeG%2FfOyWsjMy457FptK%2Ff5TPciaJg%3D&reserved=0 and the Programme Hospitalier pour La Recherche Clinique (PHRC) of the French Health Ministry.

  Other contributors included MyName’5Doddie Foundation, MND Scotland, The French ALS Association (ARSLA) and The Moulton Foundation.

  The Lead Investigators have no Conflicts of Interest to declare.

  The Team.
  The MIROCALS Consortium (see https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3Du001.QwnS5iG-2B4nwcunWxC03fkKs72ntpp9oJew9D8ll3tY-2BFxvL6c37T2-2Fay8QKnHTJGHYuL-2BtTnmBj0v-2B0zID5VZBATCD1JHSzJcbGsLNa0miY-3DDDKC_a04dWCHmDh7gi4hRuvmsd-2FMEDkPNm6D0IRdq0o1v81fHw-2B4nazeKEhMVRoGPAq15s3yGMe2AsRmrIJwsOoNBe6gmKxb9YQIOXewOwLHdFRz8EHhCjUflLU6Pn5WLrPGYnHbVqfNC-2Bi1jTkEA-2Fc2pAD1MhXqM0oC0yUpEMCMOd6J2BmawkelWgmgmu5iwj4ADGN-2FTlqDNZ2UpFBdMDaxL2Q-3D-3D&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C0f1828544f5d4ccde4a908dc3f6215f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638454937706508667%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=oxtBiVugz593OKT6tb5K0clIJI%2BIseiELugHfwjV4S0%3D&reserved=0 ) includes clinical and laboratory research teams in UK, France, Sweden, and Italy. MIROCALS was led by Dr Gilbert Bensimon (lead investigator, study coordinator, and trial methodologist, University Hospital of Nimes and Sorbonne University Paris, France) and Professor P Nigel Leigh (co-coordinator and Principal Investigator, Brighton and Sussex Medical School, UK; see also https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3Du001.QwnS5iG-2B4nwcunWxC03fkOwzk1-2FYLATo5ok2wp7rzJ4Ssu4b-2FEX0fZivdlPVBtV6FqHOqkIsRutb2wwIQ2FfStPxyvpe0GiD3BSjQHEQbzyGY4YeeAtUk2-2Bngska2YsQ30d0aPP4qL2EFKo2idjkgw-3D-3Dtfmt_a04dWCHmDh7gi4hRuvmsd-2FMEDkPNm6D0IRdq0o1v81fHw-2B4nazeKEhMVRoGPAq15TmWJy9wp9-2FqEX3rgncWP8ccHWxBAFLHWrX9yJvpgpUubzuX6BS79ufl5-2FjMmtwwYDtjn2GED3BDXKC8SDS9UerGybthegKrhxwau2tAzf3B9tLIb0iiHCQmdXl7k8ljrO6XWoJ-2BYfUHHeky3YzUr0A-3D-3D&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C0f1828544f5d4ccde4a908dc3f6215f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638454937706516123%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=RUk6ad6n1NcbKmigH2w0QeEIDQIv7EJm%2Bqhm8A%2FZCSo%3D&reserved=0

  Participants were recruited into the trial in 7 clinical centres in UK and 10 in France. Recruitment began in July 2017 and the last patient visit was in July 2022. The trial data is currently being analysed but the initial findings have been communicated at several scientific meetings form December 2022 onwards. The full and definitive communication of the key results is expected mid-2024.

  Involvement of People Living with and/or Affected by MND/ALS.
  The MNDA was closely involved as representing people living with and affected by MND/ALS and provided sustained input throughout the study, in addition to providing substantial co-funding with the European Union H2020 award, and funding from the French Health Ministry via the PHRC.

  In Europe, only one treatment (riluzole) is approved for MND/ALS. Riluzole only slows the progression of the disease a small amount. MND/ALS remains a devastating disorder and the majority of people with MND/ALS die within 3-5 years of developing symptoms. There is thus an urgent need for more effective treatments aimed at further slowing disease progression.

  With this in mind, we developed MIROCALS as a phase 2 (early phase) trial to test the idea that interleukin-2 (IL2), a molecule that is important in regulating our immune system, might slow down the progression of MND/ALS. IL2 increases the numbers and effectiveness of immune cells known as Regulatory T cells (Tregs) which have been shown to reduce inflammation (‘neuroinflammation’) and thus protect motor nerve cells in the brain and spinal cord in laboratory models of MND/ALS. Importantly, better survival in MND/ALS has been linked to having higher numbers of Tregs in the blood.

  We first carried out a smaller clinical trial (‘IMODALS’: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3Du001.QwnS5iG-2B4nwcunWxC03fkI9RwPwUHy2AvrW05KvbQznY5MY-2BKgGLOu4ESvsMUI5Ojv1hpbRIUjpjFlirNJJ8nNLwLOFWT3MQe-2BqaVlmFfTBTe3P-2FHQQ4Rm9AV7Fo9Tor1C7l_a04dWCHmDh7gi4hRuvmsd-2FMEDkPNm6D0IRdq0o1v81fHw-2B4nazeKEhMVRoGPAq15J15VlCFL3KYFoZAfV4DzZGbUd-2Fv5QHdJsJG3tQ8rHuAVAHIocKUptGyKIcs8GQCFaObQUbUneiP485Qt0oYm7n3zQM6g2huX-2FQVsC5a7JamhYNcyUsLjDGJi75jAet6eudwJVIBEBcbJfbfOEaQCIQ-3D-3D&data=05%7C02%7Clondoncentral.rec%40hra.nhs.uk%7C0f1828544f5d4ccde4a908dc3f6215f9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638454937706522820%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=iDw5KuiL1vA6K5ZkDl39Xj6ClKtvDrVrPtHi47jrLC4%3D&reserved=0 in 36 people with MND/ALS. This study wqs designed only to assess the safety and cellular and molecular responses to IL2. It showed that, when injected under the skin daily for 5 days every 28 days, low dose IL2 powerfully increased the numbers of circulating Tregs, and improved their efficiency in controlling potentially harmful immune responses. IL2 at this dose was safe and well tolerated by these individuals. (At much higher doses IL2 has many unpleasant side effects and would be dangerous to use in MND/ALS). However, IMODALS was not designed to detect an effect of IL2 on the progression of the disease, so the next step was to design a larger study which could detect improvement in survival and activities of daily life in this disorder.

  We therefore designed the MIROCALS study to provide at least preliminary evidence of a clinically useful effect of low dose IL2 in MND/ALS.

  The study was funded in 2015 and began recruiting participants in mid-2017, with the last trial visit in July 2022. The COVID pandemic inevitably had a big impact on the study but we were able to complete the trial without losing any information on the key measures of effectiveness, namely survival, and daily activities assessed by a standard questionnaire known as the ALS Functional Rating Scale-revised (ALSFRS-R).

  We recruited 220 trial participants in France and UK.. All participants received riluzole as the standard NICE-approved treatment, but because we wished to recruit people with MND/ALS as early as possible after diagnosis, we specified that they must not have started on riluzole prior to entering the trial. After a 3 month 'run-in' to start on riluzole, participants were randomly allocated to receive the placebo (110 participants) or IL2 (110 participants). The treatment period was 18 months after which we followed all participants to check survival at 21 months. Neither the clinical staff nor the participants knew which treatment they were on until all the trial data had been checked and 'locked' on the trial database (i.e., the study was 'double-blind').

  Built into the design of the study were biomarker (i.e., cellular or molecular indicators of the state of the disease and/or of response to treatment) studies in blood and cerebrospinal fluid (CSF). The biomarkers we chose included cells (Tregs and other blood cell types) and molecules (e.g., CSF phosphorylated neurofilament heavy chain protein-CSF pNFH) that can provide insights into differences between MND/ALS participants who may have a greater or lesser chance of responding to IL2, and which may change in response to the trial treatment.

  Analysis of the data is ongoing, and The MIROCALS team will soon publish the results of the study, but it will be for Regulatory Agencies to decide whether further trials are needed to confirm these findings.

• REC name

  London - Central Research Ethics Committee

• REC reference

  16/LO/1004

• Date of REC Opinion

  25 Aug 2016

• REC opinion

  Further Information Favourable Opinion