Clinical trial NCT02059759: Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2
Official title: Immuno-modulation in Amyotrophic Lateral Sclerosis- a Phase II Study of Safety and Activity of Low Dose Interleukin-2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: low-dose interleukin 2
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
First posted: 2014-02-11
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes
timeFrame: Day 8
Secondary outcomes:
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 1
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 2
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 3
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 4
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 5
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 6
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 7
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 8
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 29
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 30
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 31
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 32
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 33
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 34
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 35
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 36
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 57
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 58
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 59
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 60
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 61
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 62
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 63
measure: Presence/absence of specific, pre-defined adverse events.
timeFrame: Day 64
measure: Presence/absence of abnormal vital signs
timeFrame: Day 1
measure: Presence/absence of abnormal vital signs
timeFrame: Day 8
measure: Presence/absence of abnormal vital signs
timeFrame: Day 29
measure: Presence/absence of abnormal vital signs
timeFrame: Day 57
measure: Presence/absence of abnormal vital signs
timeFrame: Day 64
measure: Presence/absence of abnormal vital signs
timeFrame: Week 13
measure: Presence/absence of abnormal vital signs
timeFrame: Week 25
measure: MedDRA classification of all adverse events throughout the study
timeFrame: Week 25
measure: Thyroid function: blood T4
timeFrame: Baseline (day 0 to day -15)
measure: Thyroid function: blood T4
timeFrame: Week 13
measure: Thyroid function: blood TSH
timeFrame: Baseline (day 0 to day -15)
measure: Thyroid function: blood TSH
timeFrame: Week 13
measure: Presence/absence of clinically significant abnormality on a lung x-ray
timeFrame: Baseline (day 0 to day -15)
measure: Presence/absence of clinically significant abnormality on a lung x-ray
timeFrame: Week 13
measure: Presence/absence of clinically significant abnormality on an electrocardiogram
timeFrame: Baseline (day 0 to day -15)
measure: Presence/absence of clinically significant abnormality on an electrocardiogram
timeFrame: Week 13
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Day 1
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Day 8
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Day 29
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Day 57
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Day 64
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Week 13
measure: Presence/absence of a clinically significant abnormality among routine laboratory tests
timeFrame: Week 25
measure: Vital capacity (% of normal)
timeFrame: Baseline (day 0 to day -15)
measure: Vital capacity (% of normal)
timeFrame: Day 1
measure: Vital capacity (% of normal)
timeFrame: Week 13
measure: Vital capacity (% of normal)
timeFrame: Week 25
measure: The ALSFRS Questionnaire
timeFrame: Day 1
measure: The ALSFRS Questionnaire
timeFrame: Day 29
measure: The ALSFRS Questionnaire
timeFrame: Day 57
measure: The ALSFRS Questionnaire
timeFrame: Week 13
measure: The ALSFRS Questionnaire
timeFrame: Week 25
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Day 1
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Day 8
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Day 57
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Day 64
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Week 13
measure: Tregs (absolute number and % CF4+ cells)
timeFrame: Week 25
measure: Total lymphocyte number
timeFrame: Day 1
measure: Total lymphocyte number
timeFrame: Day 8
measure: Total lymphocyte number
timeFrame: Day 57
measure: Total lymphocyte number
timeFrame: Day 64
measure: Total lymphocyte number
timeFrame: Week 13
measure: Total lymphocyte number
timeFrame: Week 25
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: Day 1
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: Day 8
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: Day 57
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: Day 64
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: Week 13
measure: CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes
timeFrame: week 25
measure: effector T cells: number and % of CD4 cells
timeFrame: Day 1
measure: effector T cells: number and % of CD4 cells
timeFrame: Day 8
measure: effector T cells: number and % of CD4 cells
timeFrame: Day 57
measure: effector T cells: number and % of CD4 cells
timeFrame: Day 64
measure: effector T cells: number and % of CD4 cells
timeFrame: Week 13
measure: effector T cells: number and % of CD4 cells
timeFrame: Week 25
measure: Phosphorylated neurofilament heavy protein (pNfH) levels in serum
timeFrame: day 1
measure: Light chain neurofilament levels in serum
timeFrame: Day 1
measure: Light chain neurofilament levels in serum
timeFrame: Week 13
Other outcomes:
measure: Age (years)
timeFrame: Baseline
measure: Sex (male/female)
timeFrame: Baseline
measure: Body mass index (kg/m^2)
timeFrame: Baseline
measure: Disease duration from date of first symptoms (fatigue, weakness)
timeFrame: Baseline
measure: The patient's current Riluzole posology
timeFrame: Baseline to week 25
measure: The patient's currentposology for other concomitant treatments
timeFrame: Baseline to week 25
measure: Description of concomitant treatments, if any
timeFrame: Throughout study, up to 25 weeks
measure: Routine serology results dating to within the last 30 days: HIV-1 (positive/negative ?)
timeFrame: Baseline
measure: Routine serology results dating to within the last 30 days: Epstein Barr Virus (positive/negative ?)
timeFrame: Baseline
measure: Routine serology results dating to within the last 30 days: cytomegalovirus (positive/negative ?)
timeFrame: Baseline
Locations:
city: Montpellier
country: France
facility: CHRU de Montpellier - Hôpital Gui de Chauliac
Study officials:
affiliation: CHRU de Montpellier
name: Raul Juntas-Morales, MD
role: STUDY_DIRECTOR
References:
citation: 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.