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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: 1.0 MIU IL-2 per day
* Drug: 2.0 MIU IL-2 per day


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* 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).<br>|
| Experimental: 1.0 IL-2<br>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<br>* 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).<br>* Other names: Proleukin;|
| Experimental: 2.0 IL-2<br>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<br>* 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).<br>* Other names: Proleukin;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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low-dose interleukin 2