Clinical trial NCT01863888: Effect of Teriflunomide on Immune Cell Subsets in the Blood of Patients With Multiple Sclerosis
Official title: Exploratory Open Label Study to Investigate the Effect of Teriflunomide on Immune Cell Subsets in the Blood of Patients With Relapsing Forms of Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2013-05-29
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To measure the effect of Teriflunomide on lymphocytes subsets in patients with relapsing forms of multiple sclerosis as compared with baseline values and those of a reference population of untreated healthy subjects.

Secondary Objectives:

To assess if Teriflunomide treatment results in biased T cell clonal diversity. To assess the effect of Teriflunomide on the function of peripheral blood mononuclear cells (proliferation and cytokine production in situ).

To assess the circulating cytokines profile in the serum of Relapsing Multiple Sclerosis (RMS) patients during a 24-week treatment versus baseline and healthy controls.

To assess the reversibility of all parameter changes in patients who discontinue treatment after accelerated elimination procedure with cholestyramine or activated charcoal.

Detailed description: The duration of the study for patients is 32 weeks which includes 4 weeks for screening, 24 weeks for treatment and 4 weeks for follow-up. An extension of the study is proposed until Teriflunomide is commercially available in the country where patient lives.

The duration of the study for healthy volunteers is 25 weeks which includes only one week for screening.

Eligibility criteria: Inclusion criteria:

Patients (male and female) with relapsing forms of multiple sclerosis meeting McDonald criteria for MS at the screening visit and having either one of the following treatment status:

* Naïve to disease modifying (DM) treatment or no DM treatment for more than 2 years
* Or currently (not more than 3 months interruption) on MS therapy with IFN β-1 or Glatiramer acetate and a period of at least 2 weeks without IFN β-1 or Glatiramer acetate before switching to teriflunomide.

Male and female patients, between 18 and 56 years of age, exclusive.

Healthy volunteers:

Male and female subjects, between 18 and 56 years of age, exclusive. Body weight between 50.0 and 95.0 kg, inclusive, if male; and between 40.0 and 85.0 kg, inclusive, if female, body mass index between 18.0 and 30.0 kg/m2, inclusive.

Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).

Normal vital signs after 10 minutes resting in supine position:

* 95 mmHg \< systolic blood pressure (SBP) \<140 mmHg
* 45 mmHg \< diastolic blood pressure (DBP) \<90 mmHg
* 40 bpm \< heart rate (HR) \<100 bpm Normal standard 12-lead electrocardiogram (ECG) after 10 minutes resting in supine position; 120 ms \< PR \<220 ms, QRS \<120 ms, QTc ≤ 430 ms if male, ≤ 450 ms if female.

Laboratory parameters within the normal range (or defined screening threshold for the Investigator site), unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; however liver function parameter(s) should not exceed the upper laboratory norm.

Exclusion criteria:

Did not consent to HIV testing (the specifics of informed consent process for the HIV testing should be done in accordance with local guidelines).

A relapse within 30 days prior to screening. Clinically relevant cardiovascular, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the patient at risk by participating in the study.

Patients with a congenital or acquired severe immunodeficiency, a history of cancer (except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis), lymphoproliferative disease, or any patient who has received lymphoid irradiation.

Human immunodeficiency virus (HIV) positive patients. Known history of active tuberculosis not adequately treated or positive QuantiFERON TB Gold test.

Hypoproteinemia (eg, in case of severe liver disease or nephrotic syndrome) with serum albumin \<3.0 g/dL.

Moderate to severe impairment of renal function, as shown by serum creatinine \>133 μmol/L (or \>1.5 mg/dL).

Patients with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia.

Acute or chronic infection. Liver function impairment or persisting elevations \>1.5ULN (confirmed by retest) of serum glutamic pyruvic transaminase/ alanine aminotransferase (SGPT/ALT), serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST), or direct bilirubin greater than 1.5-fold the upper limit of normal.

Use of adrenocorticotrophic hormone (ACTH) or systemic corticosteroids for 2 weeks prior to screening.

Prior or concomitant use of cytokine therapy or intravenous immunoglobulins in the 3 months prior to screening.

Prior use of alemtuzumab or cladribine. Prior use (within 1 year) of fingolimod (Gylenia®). Prior use (within 2 years) of mitoxantrone, natalizumab (Tysabri®), or immunosuppressant agents (i.e. azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate).

Prior treatment with teriflunomide, and prior or concomitant use of leflunomide (ARAVA®) or hypersensitivity to any of the other ingredients or excipients of the investigational product.

Prior use of any investigational drug in the 6 months preceding screening. Pregnant or breast-feeding women. Women of childbearing potential not utilizing effective contraceptive method and /or women of childbearing potential who are unwilling to or unable to be tested for pregnancy.

Known history of hypersensitivity to teriflunomide or leflunomide. Persisting elevations (confirmed by retest) of serum amylase or lipase greater than 2-fold the upper limit of normal.

Known history of chronic pancreatic disease or pancreatitis.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Change from baseline in Lymphocyte subset parameters as measured by flow cytometry
timeFrame: At 12 weeks and 24 weeks
Secondary outcomes:
measure: Change from baseline in biased T cell clonal repertoire based T cell receptor (TCR) spectratyping
timeFrame: At 12 weeks and 24 weeks
measure: Change from baseline in serum cytokine as measured by multicytokine array tool
timeFrame: At 12 weeks and 24 weeks
measure: Change from baseline in Mitogen/TCR-specific T cell proliferation as measured by flow cytometry
timeFrame: At 12 weeks and 24 weeks
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Investigational Site Number 056001
city: Overpelt
country: Belgium
facility: Investigational Site Number 056002
city: Sijsele-Damme
country: Belgium
facility: Investigational Site Number 056003
city: Bad Mergentheim
country: Germany
facility: Investigational Site Number 276-003
city: Hannover
country: Germany
facility: Investigational Site Number 276-004
city: Marburg
country: Germany
facility: Investigational Site Number 276-005
city: Mönchengladbach
country: Germany
facility: Investigational Site Number 276-007
city: Münster
country: Germany
facility: Investigational Site Number 276-001
city: Ulm
country: Germany
facility: Investigational Site Number 276-002
city: Sittard-Geleen
country: Netherlands
facility: Investigational Site Number 528001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: