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

Sponsor

Centre Hospitalier Universitaire de Nīmes (Other)

Overall Status

Completed

CT.gov ID

NCT02059759

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

4.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Placebo Drug: 1.0 MIU IL-2 per day Drug: 2.0 MIU IL-2 per day	Phase 2

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:

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

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2015

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

May 1, 2016

Arms and Interventions

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: Aldesleukine Proleukin
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: Aldesleukine Proleukin

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

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

Other Names:

Aldesleukine

Proleukin

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

Other Names:

Aldesleukine

Proleukin

Outcome Measures

Primary Outcome Measures

CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes [Day 8]
Treg refers to regulatory T cells

Secondary Outcome Measures

Presence/absence of specific, pre-defined adverse events. [Day 1]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 2]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 3]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 4]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 5]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 6]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 7]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 8]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 29]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 30]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 31]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 32]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 33]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 34]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 35]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 36]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 57]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 58]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 59]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 60]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 61]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 62]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 63]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of specific, pre-defined adverse events. [Day 64]
The pre-defined events include: injection site reaction, flu like syndrome, fatigue, gastro-intestinal signs, allergic signs.
Presence/absence of abnormal vital signs [Day 1]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Day 8]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Day 29]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Day 57]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Day 64]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Week 13]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of abnormal vital signs [Week 25]
(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
MedDRA classification of all adverse events throughout the study [Week 25]
MedDRA refers to "Medical Dictionary for Regulatory Activities"
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 [Day 1]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Day 8]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Day 29]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Day 57]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Day 64]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Week 13]
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)
Presence/absence of a clinically significant abnormality among routine laboratory tests [Week 25]
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)
Vital capacity (% of normal) [Baseline (day 0 to day -15)]
This is a measure of respiratory function.
Vital capacity (% of normal) [Day 1]
This is a measure of respiratory function.
Vital capacity (% of normal) [Week 13]
This is a measure of respiratory function.
Vital capacity (% of normal) [Week 25]
This is a measure of respiratory function.
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 [Day 1]
This is measured as CD4+ lymphocytes minus regulatory T cells
effector T cells: number and % of CD4 cells [Day 8]
This is measured as CD4+ lymphocytes minus regulatory T cells
effector T cells: number and % of CD4 cells [Day 57]
This is measured as CD4+ lymphocytes minus regulatory T cells
effector T cells: number and % of CD4 cells [Day 64]
This is measured as CD4+ lymphocytes minus regulatory T cells
effector T cells: number and % of CD4 cells [Week 13]
This is measured as CD4+ lymphocytes minus regulatory T cells
effector T cells: number and % of CD4 cells [Week 25]
This is measured as CD4+ lymphocytes minus regulatory T cells
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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)