MIROCALS: Modifying Immune Response and OutComes in ALS

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.

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

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