E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 (for Germany only):
- 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.
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in Lymphocyte subset parameters as
measured by flow cytometry |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1) Change from baseline in biased T cell clonal repertoire based T
cell receptor (TCR) spectratyping
2) Change from baseline in serum cytokine as measured by
multicytokine array tool
3) Change from baseline in Mitogen/TCR-specific T cell proliferation
as measured by flow cytometry |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Main study period is followed by an extension period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Reference population of untreated healthy subjects |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is not the LPLV considering that an extension period is proposed to the patients after the main study period |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |