Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2 (IMODALS)

The primary objective is to evaluate in ALS patients the regulatory T cell early response to two low-doses of IL-2 at 1 and 2 MIU per day after one course of 5 consecutive days comparatively to placebo.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: 1.0 MIU IL-2 per day; Drug: 2.0 MIU IL-2 per day

Detailed Description

This is a phase II study on ld-IL-2 as a therapeutic agent for ALS which aims at defining the activity and safety of a range a doses for subsequent use of the best dose in a phase II/III trial. For ethical reasons, ld-IL-2 must be tested as an add-on therapy to riluzole hence all patients will need to be treated with riluzole for at least three months prior to entry. A randomized (1:1:1), placebo-controlled, double-blind, parallel group trial will be carried out to assess ld-IL-2 activity on regulatory T cells and immuno-inflammatory markers in ALS patients treated for 3 months (5 days every four weeks repeated three times).

The secondary objectives of this study are:

A. To evaluate maintenance of Tcell response after three repeated 5-day courses at one course every four weeks for 12 weeks.

B. To evaluate the safety of ld-IL-2 therapy in an ALS population, with an overall follow-up of 6 months (up to 15 weeks after last administration); C. To evaluate functional changes throughout the study; D. To evaluate changes in other pre-defined blood cytology parameters, and a blood biomarker for axonal damage.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34295
    • CHRU de Montpellier - Hôpital Gui de Chauliac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The patient has been correctly informed
• The patient must have given his/her informed and signed consent.
• The patient must be insured or beneficiary of a health insurance plan.
• The patient is at least 18 years old and less than 75 years old
• Probable, or laboratory-supported probable or definite ALS as defined by El Escorial Revised ALS diagnostic criteria (according to Airlie House Conference 1988)
• Stable on riluzole treatment for more than 3 months with liver function test results < 2ULN
• Disease duration ≤ 5 years
• Vital capacity ≥ 70% of normal
• Ability to swallow without the requirement for nasogastric or PEG feeding
• Agreement for patient to use an adequate method of contraception throughout the study and for 2 weeks after post study visit
• The patient is available and willing to participate in seven study visits occurring at the CHU within the next six months

Exclusion Criteria:

• The patient is participating in another interventional study
• Within the past three months, the patient has participated in another interventional
• The patient is in an exclusion period determined by a previous study
• The patient is under judicial protection
• The patient is an adult under guardianship
• The patient refuses to sign the consent
• It is impossible to correctly inform the patient
• Other life threatening disease
• Presence of contra-indicated concomitant treatments or with potential neuroprotective benefit (see section 11.2 of the protocol)
• Presence of tracheostomy or non-invasive ventilation
• Use of Percutaneous endoscopic gastrostomy (PEG) or nasogastric tube
• Presence of clinical infection (treated or untreated)
• Positive serology for CMV, EBV (confirmed by viral load), or HIV
• Vaccination within 8 weeks prior to first experimental dosing
• Other disease precluding functional assessments
• Cancer within the past 5 years (except stable non-metastatic basal cell skin carcinoma or in situ carcinoma of the cervix)
• Severe cardiac or pulmonary disease
• Documented auto-immune disorders except asymptomatic Hashimoto thyroiditis
• Women of child bearing age without contraception or pregnant or breast feeding
• Any clinically significant laboratory abnormality (excepting cholesterol, triglyceride and glucose)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: Placebo	Drug: Placebo; Patients in this arm will receive sub-cutaneous injections of placebo (same vehicle as for experimental arms, and same volume) for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).
Experimental: 1.0 IL-2; Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: 1.0 MIU IL-2 per day	Drug: 1.0 MIU IL-2 per day; Patients in this arm will receive sub-cutaneous injections corresponding to 1.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).; Other Names: Proleukin; Aldesleukine
Experimental: 2.0 IL-2; Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months). Intervention: 2.0 MIU IL-2 per day	Drug: 2.0 MIU IL-2 per day; Patients in this arm will receive sub-cutaneous injections corresponding to 2.0 MIU of IL-2 per injection for 5 consecutive days at the beginning of three consecutive months (a total of 15 injections, 5 per month for 3 months).; Other Names: Proleukin; Aldesleukine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes	Treg refers to regulatory T cells	Day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 1
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 2
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 3
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 4
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 5
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 6
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 7
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 8
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 29
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 30
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 31
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 32
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 33
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 34
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 35
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 36
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 57
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 58
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 59
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 60
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 61
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 62
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 63
Presence/absence of specific, pre-defined adverse events.	The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.	Day 64
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 1
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 8
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 29
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 57
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 64
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Week 13
Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Week 25
MedDRA classification of all adverse events throughout the study	MedDRA refers to "Medical Dictionary for Regulatory Activities"	Week 25
Thyroid function: blood T4		Baseline (day 0 to day -15)
Thyroid function: blood T4		Week 13
Thyroid function: blood TSH		Baseline (day 0 to day -15)
Thyroid function: blood TSH		Week 13
Presence/absence of clinically significant abnormality on a lung x-ray		Baseline (day 0 to day -15)
Presence/absence of clinically significant abnormality on a lung x-ray		Week 13
Presence/absence of clinically significant abnormality on an electrocardiogram		Baseline (day 0 to day -15)
Presence/absence of clinically significant abnormality on an electrocardiogram		Week 13
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration ); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Day 1
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Day 8
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Day 29
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Day 57
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Day 64
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Week 13
Presence/absence of a clinically significant abnormality among routine laboratory tests	The routine blood tests considered are: haemogram (hemoglobin, hematocrit, red blood cell count, white blood cell count, leukocyte formula, platelets, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration); blood biochemistry (ionogram, urea, creatinine, glucose, C reactive protein, procalcitonin, protein, albumin); liver function panel (aspartate transaminase, alanine transaminase, gamma-glutamyl transpeptidase, bilirubin); iron metabolism (iron, ferritin, transferrin)	Week 25
Vital capacity (% of normal)	This is a measure of respiratory function.	Baseline (day 0 to day -15)
Vital capacity (% of normal)	This is a measure of respiratory function.	Day 1
Vital capacity (% of normal)	This is a measure of respiratory function.	Week 13
Vital capacity (% of normal)	This is a measure of respiratory function.	Week 25
The ALSFRS Questionnaire		Day 1
The ALSFRS Questionnaire		Day 29
The ALSFRS Questionnaire		Day 57
The ALSFRS Questionnaire		Week 13
The ALSFRS Questionnaire		Week 25
Tregs (absolute number and % CF4+ cells)		Day 1
Tregs (absolute number and % CF4+ cells)		Day 8
Tregs (absolute number and % CF4+ cells)		Day 57
Tregs (absolute number and % CF4+ cells)		Day 64
Tregs (absolute number and % CF4+ cells)		Week 13
Tregs (absolute number and % CF4+ cells)		Week 25
Total lymphocyte number		Day 1
Total lymphocyte number		Day 8
Total lymphocyte number		Day 57
Total lymphocyte number		Day 64
Total lymphocyte number		Week 13
Total lymphocyte number		Week 25
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 1
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 8
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 57
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 64
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Week 13
CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		week 25
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 1
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 8
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 57
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 64
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Week 13
effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Week 25
Phosphorylated neurofilament heavy protein (pNfH) levels in serum		day 1
Light chain neurofilament levels in serum		Day 1
Light chain neurofilament levels in serum		Week 13

Other Outcome Measures

Outcome Measure	Time Frame
Age (years)	Baseline
Sex (male/female)	Baseline
Body mass index (kg/m^2)	Baseline
Disease duration from date of first symptoms (fatigue, weakness)	Baseline
The patient's current Riluzole posology	Baseline to week 25
The patient's currentposology for other concomitant treatments	Baseline to week 25
Description of concomitant treatments, if any	Throughout study, up to 25 weeks
Routine serology results dating to within the last 30 days: HIV-1 (positive/negative ?)	Baseline
Routine serology results dating to within the last 30 days: Epstein Barr Virus (positive/negative ?)	Baseline
Routine serology results dating to within the last 30 days: cytomegalovirus (positive/negative ?)	Baseline

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Study Director: Raul Juntas-Morales, MD, CHRU de Montpellier

Publications and helpful links

General Publications

• Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine. 2020 Sep;59:102844. doi: 10.1016/j.ebiom.2020.102844. Epub 2020 Jul 7.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: February 7, 2014
• First Submitted That Met QC Criteria: February 7, 2014
• First Posted (Estimate): February 11, 2014

Study Record Updates

• Last Update Posted (Estimate): June 1, 2016
• Last Update Submitted That Met QC Criteria: May 30, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: 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; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Aldesleukin; Interleukin-2
• Other Study ID Numbers: LOCAL/2014/WC-01; 2014-001327-71 (EudraCT Number)