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

Amyotrophic Lateral Sclerosis Clinical Trial

— IMODALS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02059759
• Other study ID #: LOCAL/2014/WC-01
• Secondary ID: 2014-001327-71
• Status: Completed
• Phase: Phase 2
• First received: February 7, 2014
• Last updated: May 30, 2016
• Start date: September 2015
• Est. completion date: May 2016

Study information

• Verified date: May 2016
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéFrance: Committee for the Protection of Personnes
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: May 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

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).
• 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).
• 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).

Locations

Country	Name	City	State
France	CHRU de Montpellier - Hôpital Gui de Chauliac	Montpellier

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Age (years)		Baseline	No
Other	Sex (male/female)		Baseline	No
Other	Body mass index (kg/m^2)		Baseline	No
Other	Disease duration from date of first symptoms (fatigue, weakness)		Baseline	No
Other	The patient's current Riluzole posology		Baseline to week 25	No
Other	The patient's currentposology for other concomitant treatments		Baseline to week 25	No
Other	Description of concomitant treatments, if any		Throughout study, up to 25 weeks	No
Other	Routine serology results dating to within the last 30 days: HIV-1 (positive/negative ?)		Baseline	No
Other	Routine serology results dating to within the last 30 days: Epstein Barr Virus (positive/negative ?)		Baseline	No
Other	Routine serology results dating to within the last 30 days: cytomegalovirus (positive/negative ?)		Baseline	No
Primary	CD4+ CD25+ CD127- FoxP3+(Treg) cells: change in percentage of total lymphocytes	Treg refers to regulatory T cells	Day 8	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 1	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 8	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 29	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 57	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Day 64	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Week 13	Yes
Secondary	Presence/absence of abnormal vital signs	(based on a systematic check of vital signs: pulse, blood pressure, oxymetry, temperature)	Week 25	Yes
Secondary	MedDRA classification of all adverse events throughout the study	MedDRA refers to "Medical Dictionary for Regulatory Activities"	Week 25	Yes
Secondary	Thyroid function: blood T4		Baseline (day 0 to day -15)	Yes
Secondary	Thyroid function: blood T4		Week 13	Yes
Secondary	Thyroid function: blood TSH		Baseline (day 0 to day -15)	Yes
Secondary	Thyroid function: blood TSH		Week 13	Yes
Secondary	Presence/absence of clinically significant abnormality on a lung x-ray		Baseline (day 0 to day -15)	Yes
Secondary	Presence/absence of clinically significant abnormality on a lung x-ray		Week 13	Yes
Secondary	Presence/absence of clinically significant abnormality on an electrocardiogram		Baseline (day 0 to day -15)	Yes
Secondary	Presence/absence of clinically significant abnormality on an electrocardiogram		Week 13	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	Vital capacity (% of normal)	This is a measure of respiratory function.	Baseline (day 0 to day -15)	Yes
Secondary	Vital capacity (% of normal)	This is a measure of respiratory function.	Day 1	Yes
Secondary	Vital capacity (% of normal)	This is a measure of respiratory function.	Week 13	Yes
Secondary	Vital capacity (% of normal)	This is a measure of respiratory function.	Week 25	Yes
Secondary	The ALSFRS Questionnaire		Day 1	No
Secondary	The ALSFRS Questionnaire		Day 29	No
Secondary	The ALSFRS Questionnaire		Day 57	No
Secondary	The ALSFRS Questionnaire		Week 13	No
Secondary	The ALSFRS Questionnaire		Week 25	No
Secondary	Tregs (absolute number and % CF4+ cells)		Day 1	No
Secondary	Tregs (absolute number and % CF4+ cells)		Day 8	No
Secondary	Tregs (absolute number and % CF4+ cells)		Day 57	No
Secondary	Tregs (absolute number and % CF4+ cells)		Day 64	No
Secondary	Tregs (absolute number and % CF4+ cells)		Week 13	No
Secondary	Tregs (absolute number and % CF4+ cells)		Week 25	No
Secondary	Total lymphocyte number		Day 1	No
Secondary	Total lymphocyte number		Day 8	No
Secondary	Total lymphocyte number		Day 57	No
Secondary	Total lymphocyte number		Day 64	No
Secondary	Total lymphocyte number		Week 13	No
Secondary	Total lymphocyte number		Week 25	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 1	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 8	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 57	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Day 64	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		Week 13	No
Secondary	CD56+(NK), CD19+(B), CD3+, CD4+, CD8+ cell populations: numbers and percentages of total lymphocytes		week 25	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 1	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 8	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 57	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Day 64	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Week 13	No
Secondary	effector T cells: number and % of CD4 cells	This is measured as CD4+ lymphocytes minus regulatory T cells	Week 25	No
Secondary	Phosphorylated neurofilament heavy protein (pNfH) levels in serum		day 1	No
Secondary	Light chain neurofilament levels in serum		Day 1	No
Secondary	Light chain neurofilament levels in serum		Week 13	No