Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
NTR415
Study information
Scientific title
Acronym
Study hypothesis
The hypothesis is that multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease of the central nervous system (CNS). In order to start immune reactions in the CNS, myelin antigen needs to be presented on the surface of antigen presenting cells (APCs) in conjunction with MHC class II molecules, and this antigen-MHC II complex needs to be recognised by a specific T cell receptor (TCR) of the anti-myelin T cells. The neurotransmitter norepinephrine inhibits interferon gamma-induced MHC class II antigen expression on astrocytes in vitro through ß2 adrenergic signal transduction mechanisms. We found that astrocytes in MS lack ß2 adrenergic receptors. We hypothesise that a loss of these receptors in MS facilitate the deviation of astrocytes to function as facultative immunocompetent antigen presenting cells. In support of this, we were able to demonstrate that reactive astrocytes in MS lesions express MHC class II and B7-costimulatory molecules, and are therefore equipped to promote APC-dependent T cell activation.
Compounds that elevate cAMP in astrocytes may restore suppression of MHC class II molecules in astrocytes. We investigated other aminergic receptors on astrocytes in MS and found some receptors that are also linked to the regulation of intracellular cAMP formation. An interesting candidate receptor is the 5-HT4 receptor. We intended to start a clinical study in patients in MS with the 5-HT4 agonist cisapride. However, we abandoned this project because of recent serious safety concerns with cisapride.
Astrocytes also contain the 5-HT transporter. Drugs that block this transporter elevate endogenous serotonin concentrations, and it has been shown that serotonin also increases cAMP levels in cultured astrocytes. Fluoxetine is a prototype drug that can be used to achieve this goal. Fluoxetine is occasionally used in patients with MS who are depressed. One investigator (Traugott) noticed that patients using fluoxetine seemed to stabilize with respect to their MS-related symptoms. She also found a beneficial effect of fluoxetine in an animal model of MS, chronic relapsing experimental allergic encephalitis. The aim of this clinical trial is to assess the effects of fluoxetine, a 5-HT transporter blocker, on disease activity in patients with MS. The drug is well tolerated and is off patent.
Ethics approval
Ethics approval received from the local medical ethics committee
Study design
Double blind, randomised, placebo-controlled, parallel group phase II study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Multiple sclerosis (MS)
Intervention
Fluoxetine capsule 20 mg/day orally versus placebo. Medication is taken from week 0 to 24. MRI scans are performed at week -4, 0, 4, 8, 16 and 24, and EDSS, MSFC and questionnaires are assessed at week 0 and 24.
Intervention type
Drug
Phase
Phase II
Drug names
Fluoxetine
Primary outcome measure
Difference between week 0 and week 24 in the cumulative number of active lesions on MRI scans.
Secondary outcome measures
1. Difference between Week 0 and Week 24 in:
1.1. The change in lesion volume on T2 weighted MRI
1.2. The change in gadolinium-enhanced lesion volume on Tl weighted MRI
2. Difference in the number of MS exacerbations over the 24-week period
3. Difference in the change in EDDS, Multiple Sclerosis Functional Composite (MSFC), fatigue severity scale, and QoL (36-item short form health survey [SF-36]) between week 0 and week 24. The MSFC comprises quantitative functional measures of three key clinical dimensions of MS:
3.1. Leg function/ambulation (timed 25-Foot Walk)
3.2. Arm function (Nine-Hole Peg Test)
3.3. Cognitive function (Paced Auditory Serial Addition Test [PASAT])
Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score.
Overall trial start date
01/01/2004
Overall trial end date
01/07/2006
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Written informed consent
2. Male and female patients aged 18 to 65 years inclusive
3. Confirmed diagnosis of MS, as defined by the McDonald criteria
4. Relapsing remitting or relapsing secondary progressive MS, as defined by the Lublin Criteria
5. At least one documented clinical or subclinical (defined as a gadolinium enhanced lesion on magnetic resonance imaging [MRI] examination) exacerbation in the last year or two documented exacerbations in the last 2 years (one of which can be subclinical) or the presence of one gadolinium enhanced lesion on the week 4 MRI scan
6. Baseline Expanded Disability Scoring Scale (EDSS) score of 0.0 - 6.0 inclusive
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
40
Participant exclusion criteria
1. Intolerance or contraindications to MRI scanning
2. Abnormal MRI scan, not attributable to MS
3. Neurological disorder other than MS, acute or chronic infection, malignant neoplasm or metastasis, cardiovascular disorder or pulmonary disorder, severe intercurrent systemic disease, or any other disease that interferes with the assessments
4. Treatment with interferon ß, glatiramer acetate, plasmapheresis, other immunomodulatory drugs, or immunosuppressive drugs including azathioprine, cyclophosphamide and methotrexate, within 6 months of week 0
5. Treatment with systemic corticosteroids in the 30 days prior to week 4, or between week 4 and week 0
6. Women of childbearing potential, who are not using a medically accepted safe method of contraception (medically acceptable safe methods of contraception for the purposes of this study will include surgical sterilisation, oral or depot contraceptives [taken for at least 60 day before week 0], intrauterine devices, diaphragm with spermicidal; other methods i.e. sexual abstinence may be considered by the Investigator as appropriate contraception on a patient-by-patient basis)
7. Pregnancy or women who are lactating
8. Moderate to severe depression measured as a score greater than 18 on the Beck Depression Inventory
9. Bipolar disorder
10. Treatment with antidepressant medications (selective serotonin reuptake inhibitors [SSRI], tricyclic antidepressant [TCA], other) and/or lithium
Recruitment start date
01/01/2004
Recruitment end date
01/07/2006
Locations
Countries of recruitment
Netherlands
Trial participating centre
University Medical Center Groningen
Groningen
9700 RB
Netherlands
Funders
Funder type
Hospital/treatment centre
Funder name
University Medical Center Groningen (UMCG) (Netherlands) - Innovatiefonds
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
Results in http://www.ncbi.nlm.nih.gov/pubmed/18450787
Publication citations
-
Results
Mostert JP, Admiraal-Behloul F, Hoogduin JM, Luyendijk J, Heersema DJ, van Buchem MA, De Keyser J, Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study., J. Neurol. Neurosurg. Psychiatr., 2008, 79, 9, 1027-1031, doi: 10.1136/jnnp.2007.139345.