Amyotrophic Lateral Sclerosis
Conditions
Keywords
low-dose interleukin 2
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.
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.
Interventions
DRUGPlacebo
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).
DRUG1.0 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).
DRUG2.0 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).
Sponsors
Centre Hospitalier Universitaire de Nīmes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes | Day 8 | Treg refers to regulatory T cells |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Thyroid function: blood T4 | Baseline (day 0 to day -15) | — |
| Presence/absence of clinically significant abnormality on an electrocardiogram | Baseline (day 0 to day -15) | — |
| 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) |
| Vital capacity (% of normal) | Baseline (day 0 to day -15) | This is a measure of respiratory function. |
| The ALSFRS Questionnaire | Day 1 | — |
| Tregs (absolute number and % CF4+ cells) | Day 1 | — |
| Total lymphocyte number | Day 1 | — |
| CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes | Day 1 | — |
| effector T cells: number and % of CD4 cells | Day 1 | 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 | — |
| 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 abnormal vital signs | Day 1 | (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 TSH | Baseline (day 0 to day -15) | — |
| Presence/absence of clinically significant abnormality on a lung x-ray | Baseline (day 0 to day -15) | — |
Other
| Measure | Time frame |
|---|---|
| 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 |
| Sex (male/female) | Baseline |
| Age (years) | Baseline |
Countries
France
Outcome results
None listed