MIROCALS: Modifying Immune Response and OutComes in ALS (MIROCALS)

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

MIROCALS is a phase II study of ld-IL-2 as a therapeutic agent for ALS. A randomized (1:1), placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2 safety and clinical efficacy on survival and functional decline in newly diagnosed ALS patients treated for 18 months. Randomization will be stratified according to (i) country (n = 2 levels: UK, France) and (ii) site of onset (n= 2 levels: bulbar vs limb onset).

The primary objective to evaluate the clinical efficacy and safety of the experimental drug (ld IL-2) over an 18 months period in order to establish the proof of concept (PoC) that modifying immune responses through the enhancement of regulatory T cells modifies the rate of ALS disease progression.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Riluzole; Drug: IL-2; Drug: 5% glucose water solution

Detailed Description

The secondary objectives of MIROCALS are:

To validate a new phase-II study design to improve the efficiency of drug development in ALS with early determination of drug response using established biomarkers (BMs).

The aims of this new trial design are:

(i) To shorten future trials duration in ALS using an early drug responding surrogate marker of disease activity; (ii) To establish the proof of mechanism (PoM) of the tested drugs; (iii) To identify drug responder status.

Additional exploratory objectives are:

(i) Deep immune & inflammatory phenotyping (ii) Brain biomarkers (iii) Genomics and Transcriptomics

• Study Type: Interventional
• Enrollment (Actual): 304
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037
    • CHRU de Lille - Hôpital Roger Salengro
  • Limoges, France, 87042
    • CHU de Limoges - Hôpital Dupuytren
  • Lyon, France, 69677
    • HCL - Hôpital Neurologique P. Wertheimer
  • Marseille, France, 13385
    • APHM - Hopital de la Timone
  • Montpellier Cedex 5, France, 34295
    • CHRU de Montpellier - Hôpital Gui de Chauliac
  • Nice, France, 06002
    • CHU de Nice - Hopital Pasteur
  • Paris Cedex 13, France, 75651
    • APHP - Groupe Hospitalier Pitié-Salpetrière
  • Saint Brieuc, France, 22027
    • Centre Hospitalier de Saint Brieuc - Hôpital Yves Le Foll
  • Strasbourg, France, 67098
    • CHU de Strasbourg - Hôpital de Hautepierre
  • Tours, France, 37044
    • CHRU de Tours - Hôpital Bretonneau
• United Kingdom
  • Brighton, United Kingdom, BN1 9RY
    • Trafford Centre for Biomedical Research
  • Glasgow, United Kingdom, G514TF
    • Institute of Neurological Sciences, Queen Elizabeth University Hospital
  • London, United Kingdom, E1 4NS
    • North-East London and Essex MND Regional Care Centre
  • London, United Kingdom, SE5 8AF
    • King's MND Care and Research Centre
  • London, United Kingdom, WC1N 3BG
    • Centre for Neuromuscular Diseases - National Hospital of Neurology
  • Manchester, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust, Neurology Dept
  • Sheffield, United Kingdom, S10 2JF
    • Sheffield Care and Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main Inclusion criteria

• Patient is 18 years old and less than 76 years old
• Possible, Probable, Probable laboratory-supported or Definite ALS as defined by El Escorial Revised ALS diagnostic criteria
• Disease duration <= 24 months
• Slow Vital capacity >= 70% of normal
• No prior or present riluzole treatment
• Lumbar punctures accepted by patient and done

Main Exclusion criteria

• Other neurodegenerative disease that could explain signs or symptoms
• Contra indication for lumbar puncture (history of allergy to xylocaine, presence of contra-indicated treatment, or coagulation test abnormality, clinically significant coagulopathy or thrombocytopenia)
• Non authorized treatment
• Other disease or disorders that could preclude functional assessment, or life-threatening disorders
• Any documented, active, past or present, auto-immune disorders except asymptomatic Hashimoto thyroiditis
• Using assisted ventilation
• Feeding through gastrostomy or nasogastric tube
• Women of child-bearing potential or sexually active man without contraception
• Pregnant or breast feeding woman
• Any clinically significant laboratory abnormality (excepting cholesterol, triglyceride, glucose, CK, ferritin)
• History of documented symptomatic and treated asthma within the past 5 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low dose interleukin-2; Patients randomized to this arm will receive subcutaneous injections of low-dose interleukin-2 in addition to oral Riluzole treatment. Intervention: Riluzole Intervention: IL-2	Drug: Riluzole; All patients will be treated with Riluzole for a period of three months prior to final inclusion and randomization. Riluzole treatment will continue throughout the 18 months of follow-up planned for in this protocol. Riluzole treatment is part of routine care for patients with ALS.; Drug: IL-2; The dose of IL-2 to be used in this study will be 2.0 million IU/day. Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period. In case of intolerance, a flexible dose-reduction schedule is available.; Other Names: low dose interleukin-2; ultra low dose interleukin-2
Placebo Comparator: Placebo; Patients randomized to this arm will receive subcutaneious placebo injections (5% glucose water solution) in addition to oral Riluzole treatment. Intervention: Riluzole Intervention: 5% glucose water solution	Drug: Riluzole; All patients will be treated with Riluzole for a period of three months prior to final inclusion and randomization. Riluzole treatment will continue throughout the 18 months of follow-up planned for in this protocol. Riluzole treatment is part of routine care for patients with ALS.; Drug: 5% glucose water solution; The placebo consists of 5% glucose water solution, which is the matrix with which low-dose IL-2 injections are prepared in the experimental arm. Placebo injections are prepared in exactly the same manner as IL-2 injections, just without the IL-2. Each treatment course will last 5 days (i.e. 1 sub-cutaneous injection per day for 5 consecutive days). The 5-day course will be repeated every 4-weeks over an 18-month treatment period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death from date of randomization to date of death	Time to death from date of randomization to date of death as documented in death certificates, or date of last documented news for patients lost to follow-up, or 640 days for patients who survive more than 640 days (censoring at 640 days). Death certificates are collected by the centre's principal investigator from the City Hall of the patients' home or birth place.	Month 21

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Principal Investigator: Nigel Leigh, MD, PhD, Brighton and Sussex Medical School; Study Director: Gilbert Bensimon, MD, PhD, Centre Hospitalier Universitaire de Nîmes

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): July 22, 2021
• Study Completion (Actual): July 22, 2021

Study Registration Dates

• First Submitted: January 31, 2017
• First Submitted That Met QC Criteria: January 31, 2017
• First Posted (Estimate): February 1, 2017

Study Record Updates

• Last Update Posted (Actual): April 11, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: interleukin-2; low-dose interleukin-2
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Neuroprotective Agents; Protective Agents; Anticonvulsants; Interleukin-2; Riluzole
• Other Study ID Numbers: H2020/PHRC-N/2014/GB-01; No 633413 (Other Grant/Funding Number: EU Horizon 2020 research and innovation programme); PHRC-N, 14-0077, 2014 (Other Grant/Funding Number: the French Ministry of Health); Leigh/Jul15/971-797 (Other Grant/Funding Number: MND Association grant)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No