Long-term Effect of Fingolimod on Circulating Immunocompetent Mononuclear Cells in Patients With Multiple Sclerosis (Biobank II)
Verified February 2014 by Heinrich-Heine University, Duesseldorf
Information provided by (Responsible Party):
Heinrich-Heine University, Duesseldorf
First received: December 19, 2012
Last updated: February 27, 2014
Last verified: February 2014
The purpose of this study is to explore immunomodulatory and immunosuppressive mechanisms of action of fingolimod in patients with Relapsing remitting multiple Sclerosis to collect data on biomarkers after initiation of fingolimod treatment.
Relapsing Remitting Multiple Sclerosis
||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
||The Long-term Effect of Fingolimod on Circulating Immunocompetent Mononuclear Cells in Patients With Multiple Sclerosis
Primary Outcome Measures:
- Reduction of CD4+ and CD8+ naïve T cells (CCR7+ CD45RA+) and central memory T cells (CCR7+CD45RA-), and an elevation of effector memory T cells (CCR7- CD45RA-) by examining the blood [ Time Frame: Day 0, Day 28, Day 84, Day 168, Day 336, Day 504, Day 672 after treatment ] [ Designated as safety issue: No ]
The primary endpoints are the reduction of CD4+ and CD8+ naïve T cells (CCR7+ CD45RA+) and central memory T cells (CCR7+CD45RA-), and an elevation of effector memory T cells (CCR7- CD45RA-)in the blood, and to study the effect of Fingolimod on Th17 cells by studying their signature cytokines (IL-17, IL-21, IL-22) as well as signature transcription factors (ROR-gamma-t, ROR-alpha, STAT3, Runx1) in peripheral venous blood over 2 years versus baseline.
Secondary Outcome Measures:
- To investigate changes from baseline in B Lymphocytes, monocytes and NK cells in the blood after treatment with fingolimod [ Time Frame: Day 0, Day 28, Day 84, Day 168, Day 336, Day 504, Day 672 after treatment ] [ Designated as safety issue: No ]
To investigate changes from baseline in B Lymphocytes, monocytes and NK cells in the blood after treatment with fingolimod. This will be assessed by studying surface markers by FACS analysis for B lymphocytes (CD19, CD20, CD69), monocytes (CD14), NK cells (CD56).
Other Outcome Measures:
- Change of the biomarkers BDNF, NGF, CNTF and LIF in the blood during treatment with fingolimod [ Time Frame: Day 0, Day 28, Day 84, Day 168, Day 336, Day 504, Day 672 after treatment ] [ Designated as safety issue: No ]
The exploratory endpoints are the change from baseline in the biomarkers BDNF, NGF, CNTF and LIF in the blood. The changes in mRNA expression and serum protein levels will be analysed in peripheral blood as a result of fingolimod treatment.
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||January 2016 (Final data collection date for primary outcome measure)
Other Name: Gilenya
After treatment with fingolimod the blood of the patients will be collected at different time points to examine the changes of T cells, B cells and biomarkers.
|Ages Eligible for Study:
||18 Years to 65 Years
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Written informed consent from patients capable of giving or withholding full informed consent must be obtained before any assessment is performed in this trial.
- Male or female subjects aged 18-65 years.
- Subjects with relapsing remitting forms of MS defined by 2010 revised McDonald criteria (see Appendix).
- Patients with high disease activity despite treatment with a disease modifying therapy (≥ 1 relapse in the previous year, ≥ 9 hyperintense T2 lesions or ≥1 Gd-enhancing lesion or "non-responding" which could be defined as unchanged or increased relapse rate or ongoing severe relapses compared to previous year) or patients with rapidly evolving severe RRMS (e.g. ≥ 2 relapses with disease progression in one year and ≥ 1 Gd-enhancing lesion or with a significant increase in T2 lesions compared to a recent MRI).
- Patients with Expanded Disability Status Scale (EDSS) score of 0-6.5 (see Appendix).
- Sufficient ability to read, write, communicate and understand
- Patients with a manifestation of MS other than relapsing remitting MS.
- Patients with a history of chronic disease of the immune system other than MS, which requires systemic immunosuppressive treatment, or a known immunodeficiency syndrome.
- History or presence of malignancy (other than localized basal cell carcinoma of the skin and carcinoma in situ of the cervix) in the last 5 years
- Diabetic patients with moderate or severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and uncontrolled diabetic patients with HbA1c > 7%.
- Diagnosis of macular edema during Baseline Visit (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at the ophthalmic baseline visit).
- Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS, Hepatitis B, Hepatitis C infection or to have positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests.
- Negative for varicella-zoster virus IgG antibodies at Baseline.
- Have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 1 month prior to baseline.
- Patients who have received total lymphoid irradiation or bone marrow transplantation.
- Patients who expect to be treated with any disease modifying drugs (DMD) during the study (i.e. IFN-β, glatiramer acetate); however no washout is needed for DMDs prior to baseline.
Patients who have been treated with:
• Systemically applied corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to baseline;
• Immunosuppressive medications such as azathioprine or methotrexate within 3 months prior to baseline;
• Immunoglobulins and/or monoclonal antibodies (including natalizumab) within 3 months prior to baseline;
- Cladribine at any time.
- Cyclophosphamide and mitoxantrone within 6 months prior to start of fingolimod
- Patients with any medically unstable condition, as assessed by the primary treating physician at each site.
Patients with any of the following cardiovascular conditions and/or findings in the baseline ECG-recordings:
• history of cardiac arrest
• congestive heart failure
• cerebrovascular disease
• history of myocardial infarction
• history of symptomatic bradycardia or recurrent syncope
• known ischemic heart disease
• severe untreated sleep apnea
• uncontrolled hypertension
• known history of angina pectoris due to coronary spasm or history of Raynaud's phenomenon;
• cardiac failure at time of Baseline (Class III, according to New York Heart Association Classification) or any severe cardiac disease as determined by the investigator;
• history or presence of a Mobitz 2 second degree AV block or a third degree AV block or an increased QTc interval >450 ms in males and >470 ms in females corrected using Bazett´s formula;
• Patients with sick sinus syndrome or sino-atrial heart block
- Patients receiving Class Ia (ajmaline, disopyramide, procainamide, quinidine) and III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibutilide, azimilide, dofetilide).
- Patients concurrently treated with heart-rate-lowering drugs as beta blockers, or heart-rate lowering calcium channel blockers (verapamil, diltiazem or ivabradine) or patients receiving digoxin, anticholinesterasic agents or pilocarpine
- resting pulse rate <45 bpm prior to baseline;
- bradycardia measured by continuous ambulatory ECG of <40 bpm at any hour (mean) or of<30 bpm at any time (beat to beat)
Patients with any of the following pulmonary conditions • Pulmonary fibrosis
• Active tuberculosis
- Patients with severe hepatic dysfunction (Child-Pugh-Class C)
Patients with any of the abnormal laboratory values:
• white blood cell (WBC) count <3,500/mm3 or lymphocyte count <800/mm3
Patients with any of the following neurologic/psychiatric disorders:
- history of substance abuse (drug or alcohol) in the past five years or any other factor (i.e.serious psychiatric condition) that may interfere with the subject's ability to cooperate and comply with the study procedures;
- progressive neurological disorder, other than MS, which may affect participation in the study
- Participation in any clinical research study evaluating another investigational drug or therapy within 4 weeks prior to baseline
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5mIU/ml) Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to baseline. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
21. History of hypersensitivity to the active substance or to any other of the excipients of fingolimod.
22. Prior enrolment in a trial with fingolimod. Patients who failed to be enrolled in another clinical trial with fingolimod, i.e. screening failures, may be enrolled.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01755871
Heinrich-Heine University, Duesseldorf
||Bernd Kieseier, Prof.
||Heinrich Heine Universität Düsseldorf
No publications provided
||Heinrich-Heine University, Duesseldorf
History of Changes
|Other Study ID Numbers:
|Study First Received:
||December 19, 2012
||February 27, 2014
||Germany: Federal Institute for Drugs and Medical Devices
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on July 22, 2014
Multiple Sclerosis, Relapsing-Remitting
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Immune System Diseases
Physiological Effects of Drugs