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

Phase 2

Completed

• Conditions: Amyotrophic Lateral Sclerosis
• Interventions: Drug: Placebo; Drug: 1.0 MIU IL-2 per day; Drug: 2.0 MIU IL-2 per day

• Registration Number: NCT02059759
• Lead Sponsor: Centre Hospitalier Universitaire de Nīmes

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.

Study Timeline

• Study First Submitted: 2014-02-07
• Study First Submitted QC: 2014-02-07
• Study First Posted: 2014-02-11
• Study Start: 2015-09
• Primary Completion: 2015-12
• Status Verified: 2016-05
• Study Completion: 2016-05
• Last Update Submitted: 2016-05-30
• Last Update Posted: 2016-06-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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
1.0 IL-2	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). Intervention: 1.0 MIU IL-2 per day
2.0 IL-2	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). Intervention: 2.0 MIU IL-2 per day

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Presence/absence of abnormal vital signs	Week 25	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)
Presence/absence of clinically significant abnormality on an electrocardiogram	Week 13
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)	Week 25	This is a measure of respiratory function.
The ALSFRS Questionnaire	Week 25
Tregs (absolute number and % CF4+ cells)	Week 25
Total lymphocyte number	Week 25
Phosphorylated neurofilament heavy protein (pNfH) levels in serum	day 1
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	Week 25	This is measured as CD4+ lymphocytes minus regulatory T cells
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.
Light chain neurofilament levels in serum	Week 13
MedDRA classification of all adverse events throughout the study	Week 25	MedDRA refers to "Medical Dictionary for Regulatory Activities"
Thyroid function: blood T4	Week 13
Thyroid function: blood TSH	Week 13
Presence/absence of clinically significant abnormality on a lung x-ray	Week 13

Trial Locations

Locations (1)

CHRU de Montpellier - Hôpital Gui de Chauliac; 🇫🇷 Montpellier, France