MIROCALS: Modifying Immune Response and OutComes in ALS

Sponsor

Centre Hospitalier Universitaire de Nīmes (Other)

Overall Status

Completed

CT.gov ID

NCT03039673

Collaborator

(none)

304

Enrollment

Locations

Arms

49.1

Actual Duration (Months)

17.9

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Riluzole Drug: IL-2 Drug: 5% glucose water solution	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

304 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official 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

Actual Study Start Date :

Jun 19, 2017

Actual Primary Completion Date :

Jul 22, 2021

Actual Study Completion Date :

Jul 22, 2021

Arms and Interventions

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.

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

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.

Outcome Measures

Primary Outcome Measures

Time to death from date of randomization to date of death [Month 21]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

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