Relapsing-Remitting Multiple SclerosisNCT01790269
Monitoring Natural Killer Cells in Multiple Sclerosis Patients Treated With Fingolimod
An observational study of Relapsing-Remitting Multiple Sclerosis, run by Charite University, Berlin, Germany at 1 site in Germany.
Trial summary
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on fingolimod treated kidney transplant patients showed that NK cells were not influenced in any of the treatment groups. Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Relapsing-Remitting Multiple Sclerosis
- How many people
- 21 participants
- Where
- 1 siteGermany
- Study dates
- Sep 2013to Aug 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Study population: Definite diagnosis of Relapsing-Remitting Multiple Sclerosis according to the 2010 revised McDonald criteria (Polman et al., 2011)
Who may be able to join
- Definite diagnosis of RRMS according to the 2010 revised McDonald criteria (Polman et al., 2011)
- 18 to 64 years old
- Indication for on-label treatment with fingolimod (Gilenya®) ac-cording to the current approval
- EDSS score ≤ 6,0
- Neurological stable with no evidence of relapse or corticosteroid treatment within 30 days prior to screening
- Ability to provide written informed consent
- Highly effective contraception (Pearl Index < 1), reliable abstinence from any heterosexual relationships, or sterilization of the only partner in women of childbearing potential
- Negative pregnancy test (HCG rapid test in the urine) at screening and baseline in women of childbearing potential
Who cannot join
- Patients with MS manifestations other than RRMS
- Patients with known contraindications to Gilenya® according to the current "Fachinformation", in particular
- Immunodeficiency syndrome
- Increased risk of opportunistic infections
- Severe active or chronic active infections (hepatitis, tuberculosis)
- History or presence of malignancy (other than localized basal or squamous cell carcinoma of the skin). Severe liver dysfunction (Child Pugh C)
Show all 23Show fewer
- Hypersensitivity against active or any other compound of study medication
- 2nd degree Mobitz Type II or higher degree AV block, Sick-sinus syndrome, or Sinuatrial heart block, Significant QT prolongation (QTc>470 msec (female) or >450 msec (males))
- History of symptomatic bradycardia or recurrent syncope, known ischaemic heart disease, cerebrovascular disease, history of myocardial infarction, hypokalaemia, congestive heart failure, history of cardiac arrest, uncontrolled hypertension, or severe sleep apnea. Patients with clinically significant liver, kidney or bone marrow dysfunction, defined by the following laboratory values at the time of screening:
- HB <8.5 g / dl
- WBC <2.5 / nl
- platelets <100/nl
- creatinine clearance by Cockroft-Gault formula: Cl <110ml/min (men) and Cl <95ml/min (women), from age of 30 limit drops 10ml/min per decade
- AST / ALT> 3.5 times higher than the upper reference value
- bilirubin > 2.0 mg / dl
- Patients without a history of varicella or without vaccination against varicella zoster virus (VZV) and VZV negative antibody serology
- Pregnancy or lactation
- Participation in another interventional clinical trial within the last 3 months prior to baseline or during the study period
- Treatment with Natalizumab within the last 3 months prior to baseline, treatment with mitoxantrone, azathioprine or any other immunosuppressive drugs except prednisolone within the last 6 months prior to baseline.
- Patients receiving antiarrythmics class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) or beta blockers. Patients receiving heart rate lowering calcium channel blockers (e.g. verapamil, diltiazem or ivabradine) or other sub-stances which may decrease heart rate (e.g. digoxin, anticholinesteratic agents or pilocarpine).
- Medical, psychiatric or other conditions that limit the patient' s ability to understand the patient's information, to give informed consent or to follow the study protocol
- Lack of consent to the storage and analysis of pseudonymous data in the context of the clinical trial
- Prisoners or patients that are housed in an judicial institution
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Monitoring Natural Killer Cells in Multiple Sclerosis Patients Treated With Fingolimod: a Monocentric, Prospective, One Year, Baseline-to-treatment, Open-label Single Group Pilot Trial
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on fingolimod treated kidney transplant patients showed that NK cells were not influenced in any of the treatment groups. However, more recent reports indicate an increased frequency of NK cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative reduction of immature CD56bright NK cells in fingolimod-treated MS patients. It has been demonstrated that the expression of NK cell relevant sphingosine 1-phosphate (S1P) receptors seems to increase during NK cell maturation. Thus, different NK cell sub-types may response differently to S1P-receptor agonist such as fingolimod.
Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the effects of fingolimod on NK cell maturation/differentiation.
Read the detailed description
In the past decade, it has become evident that natural killer (NK) cells are more than simply killers and seem to be involved in the regulation of autoimmune conditions such as Multiple Sclerosis (MS). Yet, the complexity of NK cell activation and maturation is only now being understood. Several recent publications have reported on markers characterizing different stages of human NK cell maturation/ differentiation, including CD27, CD62L, CD94 and CD57. In our more recent study, the investigators demonstrated that the chemokine receptor CX3CR1 represents an additional marker for NK cells, which in conjunction with other novel markers, serves to delineate the sequential stages of human NK cell differentiation. CX3CR1 has been suggested to be essential for the protective effects of NK cells in the animal model of MS. In this context, the investigators previously reported on the correlation of the frequency of circulating CX3CR1-positive NK cells with disease activity in patients with MS. Moreover, our unpublished data indicates an association of genetic variation in NK cell-related genes and response to IFN-beta treatment. Thus, it appears that NK cells (or at least certain NK cell fractions) may be not only protective in MS but also mediators of therapeutic benefits.
Fingolimod (GILENYA®) is a modulator of the sphingosine 1-phosphate receptor (S1P-receptors) indicated for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical relapses. Gilenya® is licensed in Germany since April 2011 as an escalation therapy for patients with highly active RRMS.
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on fingolimod treated kidney transplant patients showed that NK cells were not influenced in any of the treatment groups. However, more recent reports indicate an increased frequency of NK cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative reduction of immature CD56bright NK cells in fingolimod-treated MS patients. However, this latter study exclusively compared frequencies of NK cells in untreated MS patients and patients treated with fingolimod, while longitudinal intraindividual data during treatment was not presented.
Moreover, these two studies have not considered the potential diverse effects of fingolimod on different NK cells subpopulations. It has been demonstrated that the expression of NK cell relevant sphingosine 1-phosphate (S1P) receptors seems to increase during NK cell maturation. Thus, different NK cell sub-types may response differently to S1P-receptor agonist such as fingolimod.
Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the effects of fingolimod on NK cell maturation/differentiation.
- Conditions
- Relapsing-Remitting Multiple Sclerosis
- Keywords
- Relapsing-Remitting Multiple Sclerosis, NK cells, Fingolimod
- Medical subject headings
- Multiple Sclerosis, Relapsing-Remitting
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| fingolimod treated patients | Indication for on-label treatment with fingolimod (Gilenya®) according to the current approval |
What is being measured
The primary outcome is the main question the study is designed to answer.
Status of NK cell maturation
Status of NK cell maturation, defined as the ratio immature NK cells / total NK cells (percentage), before fingolimod treatment vs. after 12 months of treatment (V4). The maturation status is determined by the expression of certain cell surface markers which can be evaluated by flow cytometry.
Measured: Baseline to (12 months) treatment
Secondary outcomes (5)
NK cell frequency
NK cell frequency at all time points (determined by flow cytometry)
Measured: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
Percentage immature NK cells/total NK cells
Percentage immature NK cells/total NK cells at all time points
Measured: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell activation
NK cell activation (expression of certain cell surface markers determined by flow cytometry) at all time points
Measured: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell maturation and activation
NK cell maturation and activation in relation to clinically detectable therapeutic effect (determined a) by annual relapse rate over study period vs. annualized relapse rate in the preceding two years; and b) by the development of disability (determined by Expanded Disability Status Scale (EDSS) during treatment with fingolimod)
Measured: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell cytotoxicity and the cytokine production
NK cell cytotoxicity and the cytokine production (IL-15, IL-13, IL-5, GM-CSF, IFN-gamma)
Measured: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2013 (estimated)
- Study startSep 2013
- Primary completionAug 2018
- Study completionAug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Relapsing-Remitting Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by Charite University, Berlin, GermanyThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Charite University, Berlin, Germany
- Sponsor type
- University, hospital or other
- Collaborators
- Dr. Carmen Infante-Duarte
- Responsible party
- Principal investigator, Jan-Markus Dörr, Charite University, Berlin, Germany
- Investigators
- Jan-Markus Dörr, MD, Principal investigator, Charite Universitätsmedizin Berlin
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01790269
- Sponsor's protocol ID
- NKcells Gilenya®-treated MS
- Status last verified
- Jul 2021
- First submitted
- 8 Feb 2013
- Last updated
- 29 Jul 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Monitoring Natural Killer Cells in Multiple Sclerosis Patients Treated With Fingolimod: a Monocentric, Prospective, One Year, Baseline-to-treatment, Open-label Single Group Pilot Trial
- ClinicalTrials.gov ID
- NCT01790269
- Acronym / sponsor ID
- NKcells Gilenya®-treated MS
- Conditions
- Relapsing-Remitting Multiple Sclerosis
- Keywords
- Relapsing-Remitting Multiple Sclerosis, NK cells, Fingolimod
- Study type
- Observational
- Recruitment status
- Terminated
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Charite University, Berlin, GermanyUniversity, hospital or other
- Collaborators
- Dr. Carmen Infante-Duarte
- Study start
- Sep 2013
- Primary completion
- Aug 2018 (actual)
- Study completion
- Aug 2018 (actual)
- First posted
- 13 Feb 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on fingolimod treated kidney transplant patients showed that NK cells were not influenced in any of the treatment groups. However, more recent reports indicate an increased frequency of NK cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative reduction of immature CD56bright NK cells in fingolimod-treated MS patients. It has been demonstrated that the expression of NK cell relevant sphingosine 1-phosphate (S1P) receptors seems to increase during NK cell maturation. Thus, different NK cell sub-types may response differently to S1P-receptor agonist such as fingolimod.
Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the effects of fingolimod on NK cell maturation/differentiation.
Detailed description
In the past decade, it has become evident that natural killer (NK) cells are more than simply killers and seem to be involved in the regulation of autoimmune conditions such as Multiple Sclerosis (MS). Yet, the complexity of NK cell activation and maturation is only now being understood. Several recent publications have reported on markers characterizing different stages of human NK cell maturation/ differentiation, including CD27, CD62L, CD94 and CD57. In our more recent study, the investigators demonstrated that the chemokine receptor CX3CR1 represents an additional marker for NK cells, which in conjunction with other novel markers, serves to delineate the sequential stages of human NK cell differentiation. CX3CR1 has been suggested to be essential for the protective effects of NK cells in the animal model of MS. In this context, the investigators previously reported on the correlation of the frequency of circulating CX3CR1-positive NK cells with disease activity in patients with MS. Moreover, our unpublished data indicates an association of genetic variation in NK cell-related genes and response to IFN-beta treatment. Thus, it appears that NK cells (or at least certain NK cell fractions) may be not only protective in MS but also mediators of therapeutic benefits.
Fingolimod (GILENYA®) is a modulator of the sphingosine 1-phosphate receptor (S1P-receptors) indicated for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical relapses. Gilenya® is licensed in Germany since April 2011 as an escalation therapy for patients with highly active RRMS.
Data on fingolimod effects on NK cells are so far conflicting. A longitudinal study on fingolimod treated kidney transplant patients showed that NK cells were not influenced in any of the treatment groups. However, more recent reports indicate an increased frequency of NK cells in peripheral blood and CSF of MS patients treated with fingolimod and a relative reduction of immature CD56bright NK cells in fingolimod-treated MS patients. However, this latter study exclusively compared frequencies of NK cells in untreated MS patients and patients treated with fingolimod, while longitudinal intraindividual data during treatment was not presented.
Moreover, these two studies have not considered the potential diverse effects of fingolimod on different NK cells subpopulations. It has been demonstrated that the expression of NK cell relevant sphingosine 1-phosphate (S1P) receptors seems to increase during NK cell maturation. Thus, different NK cell sub-types may response differently to S1P-receptor agonist such as fingolimod.
Therefore, the investigators aim to investigate longitudinally (baseline vs. treatment) the effects of fingolimod on NK cell maturation/differentiation.
Study design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| fingolimod treated patients | – | –Indication for on-label treatment with fingolimod (Gilenya®) according to the current approval |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- Definite diagnosis of Relapsing-Remitting Multiple Sclerosis according to the 2010 revised McDonald criteria (Polman et al., 2011)
Key inclusion criteria (8 listed)
- Definite diagnosis of RRMS according to the 2010 revised McDonald criteria (Polman et al., 2011)
- 18 to 64 years old
- Indication for on-label treatment with fingolimod (Gilenya®) ac-cording to the current approval
- EDSS score ≤ 6,0
- Neurological stable with no evidence of relapse or corticosteroid treatment within 30 days prior to screening
Key exclusion criteria (23 listed)
- Patients with MS manifestations other than RRMS
- Patients with known contraindications to Gilenya® according to the current "Fachinformation", in particular
- Immunodeficiency syndrome
- Increased risk of opportunistic infections
- Severe active or chronic active infections (hepatitis, tuberculosis)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Status of NK cell maturation
Time frame: Baseline to (12 months) treatment
Status of NK cell maturation, defined as the ratio immature NK cells / total NK cells (percentage), before fingolimod treatment vs. after 12 months of treatment (V4). The maturation status is determined by the expression of certain cell surface markers which can be evaluated by flow cytometry.
5 secondary outcomes
NK cell frequency
Time frame: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
Percentage immature NK cells/total NK cells
Time frame: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell activation
Time frame: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell maturation and activation
Time frame: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
NK cell cytotoxicity and the cytokine production
Time frame: Baseline, +1 mo, +3 mo, +6 mo, +12 mo
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2021.
- Related InfoLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jan-Markus Dörr, MD principal investigator
Charite Universitätsmedizin Berlin
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Relapsing-Remitting Multiple Sclerosis, run by Charite University, Berlin, Germany at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Status of NK cell maturation (time frame: Baseline to (12 months) treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2021.