Depression, Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
Depression, Multiple Sclerosis, Fingolimod, Venlafaxine, Fluoxetine
Brief summary
This is a prospective, multi-center, open-label study in Relapsing-remitting Multiple Sclerosis (RRMS) patients with mild to moderate depression treated with selected serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) antidepressants over 16 weeks as add-on to fingolimod treatment. It is designed to evaluate the safety and tolerability of this combination in this patient population based on an immunomodulatory treatment with fingolimod.
Interventions
DRUGVenlafaxine
Venlafaxine starting dose was 75 mg and given once daily for at least 7 days and a maximum of 28 days. Dosage was increased afterwards to the individual final dose given once daily, i.e. after at least 7 days and a maximum of 28 days, patients were titrated to their maximum dose of 150 Mg
DRUGFluoxetine
Fluoxetine starting dose was 20 mg and given once daily for at least 7 days and a maximum of 28 days. Dosage was increased afterwards to the individual final dose given once daily, i.e. after at least 7 days and a maximum of 28 days, patients were titrated to their maximum dose of 40 Mg
DRUGCitalopram
Citalopram starting dose was 20 mg and given once daily for at least 7 days and a maximum of 28 days. Dosage was increased afterwards to the individual final dose given once daily, i.e. after at least 7 days and a maximum of 28 days, patients were titrated to their maximum dose of 40 Mg
DRUGFingolimod
Dosage of 0.5 mg per capsule (hard gelatin capsules) was taken p.o. once daily. Fingolimod was supplied in bottles containing 35 capsules each.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with relapsing remitting MS defined by 2010 revised McDonald criteria (see Appendix 4) * Patients with Expanded Disability Status Scale (EDSS) score of 0-6.5 (see Appendix 8) * 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) * Depression according to ICD-10 criteria * Mild-moderate depression assessed by BDI-II score between 14-28 inclusively measured before study inclusion and before fingolimod is administered
Exclusion criteria
* Patients with a history of chronic disease of the immune system other than MS which requires systemic immunosuppressive treatment, or a known immunodeficiency syndrome. Patients with Crohns disease or ulcerative colitis are excluded without exception * History or presence of malignancy (other than localized basal or squamous cell carcinoma of the skin) * 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 Screening * 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 start of fingolimod * Patients who are or have been treated with: * immunoglobulins and/or monoclonal antibodies (including natalizumab) within 3 months prior to start of fingolimod * Systemically applied corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to start of fingolimod (nevertheless, topical application is permitted); * Immunosuppressive medications such as azathioprine or methotrexate, within 3 months prior to start of fingolimod; * Cyclophosphamid and mitoxantrone within 6 months prior to start of fingolimod * cladribine at any time * current psychological or pharmacological treatment for depression (MAO inhibitors in particular), a washout period of 1 month prior start of fingolimod is required * current treatment with linezolid, a washout period of 1 month prior start of fingolimod is required Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | 21 weeks | In this analysis patients with all (serious and non-serious) adverse events, and death were reported. See Safety Section. |
Countries
Germany
Participant flow
Recruitment details
The safety set was used for analysis, which consists of 54 patients, of whom 2 patients did not start treatment with any antidepressant
Participants by arm
| Arm | Count |
|---|---|
| Fluoxetine and Fingolimod Fingolimod 0.5 mg per capsule(hard gelatin capsules) was taken p.o. once daily. Fluoxetine, supplied in blistered packs containing 20 tablets; starting dose 20 mg; final dose 40 mg | 17 |
| Venlafaxine and Fingolimod Fingolimod 0.5 mg per capsule(hard gelatin capsules) was taken p.o. once daily. Venlafaxine, supplied in blistered packs containing 14 capsules; starting dose 75 mg; final dose 150 mg | 15 |
| Citalopram and Fingolimod Fingolimod 0.5 mg per capsule(hard gelatin capsules) was taken p.o. once daily. Citalopram, supplied in blistered packs containing 20 tablets; starting dose 20 mg, final dose 40 mg | 20 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 2-week Pre-treatment | Abnormal test result | 0 | 0 | 0 | 1 |
| 2-week Pre-treatment | Adverse Event | 0 | 0 | 0 | 5 |
| 2-week Pre-treatment | Protocol Violation | 0 | 0 | 0 | 4 |
| Core Phase (16 Weeks) | Abnormal Test result | 0 | 0 | 1 | 0 |
| Core Phase (16 Weeks) | Adverse Event | 0 | 3 | 1 | 0 |
| Core Phase (16 Weeks) | Protocol Violation | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Fluoxetine and Fingolimod | Venlafaxine and Fingolimod | Citalopram and Fingolimod | Total |
|---|---|---|---|---|
| Age, Continuous | 44.2 Years STANDARD_DEVIATION 9.22 | 40.0 Years STANDARD_DEVIATION 9.28 | 41.2 Years STANDARD_DEVIATION 10.22 | 41.8 Years STANDARD_DEVIATION 9.87 |
| Sex: Female, Male Female | 15 Participants | 10 Participants | 17 Participants | 42 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 54 | 12 / 15 | 12 / 20 | 11 / 17 |
| serious Total, serious adverse events | 1 / 54 | 1 / 15 | 1 / 20 | 0 / 17 |
Outcome results
Primary
Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death
In this analysis patients with all (serious and non-serious) adverse events, and death were reported. See Safety Section.
Time frame: 21 weeks
Population: The safety set was used for analysis, which consists of 54 patients, of whom 2 patients did not start treatment with any antidepressant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluoxetine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Any Adverse Event | 11 Participants |
| Fluoxetine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Event | 0 Participants |
| Fluoxetine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Venlafaxine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Any Adverse Event | 12 Participants |
| Venlafaxine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Event | 1 Participants |
| Venlafaxine and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Citalopram and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |
| Citalopram and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Any Adverse Event | 12 Participants |
| Citalopram and Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Event | 1 Participants |
| Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Any Adverse Event | 15 Participants |
| Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Event | 1 Participants |
| Fingolimod | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Death | 0 Participants |