| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Multiple Sclerosis
Depression |
|
| E.1.1.1 | Medical condition in easily understood language |
Multiple Sclerosis
Depression |
|
| 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 | 10012378 |
| E.1.2 | Term | Depression |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 evaluate the safety and tolerability profile of the combination therapy of an antidepressant type SSRI or SNRI with oral fingolimod with respect to adverse events and laboratory parameters |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent from patients capable of giving or withholding full informed consent must be obtained before any assessment is performed.
2. Male or female subjects aged 18-65 years.
3. Subjects with relapsing remitting MS defined by 2010 revised McDonald criteria (see Appendix 4).
4. Patients with Expanded Disability Status Scale (EDSS) score of 0-6.5 (see Appendix 8).
5. 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).
or patients who are already treated with fingolimod within the EU label criteria for at
least 7 days with or without having participated and completed study
CFTY720DDE17
6. Diagnosis of depression according to ICD-10 criteria
7. Mild-moderate depression assessed by BDI-II score between 14-28 inclusively measured on V1 and on V2
8. Sufficient ability to read, write, communicate and understand
|
|
| E.4 | Principal exclusion criteria |
1. 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.
2. History or presence of malignancy (other than localized basal or squamous cell carcinoma of the skin).
3. 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.
4. Negative for varicella-zoster virus IgG antibodies at Screening.
5. Have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 1 month prior to start of fingolimod.
6. Patients who have received total lymphoid irradiation or bone marrow transplantation.
7. 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.
8. 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 Screening visit (V1) (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 14 days prior visit 2 is required
• current treatment with linezolid, a washout period of 1 month prior start of fingolimod is required
9. Patients with any medically unstable condition, as assessed by the primary treating physician at each site.
10. Patients with any of the following cardiovascular conditions:
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 substances which may
decrease heart rate (e.g. digoxin, anticholinesteratic agents or pilocarpine).
2nd degree Mobitz Type II or higher degree AV block, Sick-sinus
syndrome, or Sino-atrial 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
resting
11. Patients with severe hepatic dysfunction (Child-Pugh-Class C)
12. Patients who are not currently treated with fingolimod with the following cell counts: white blood cell (WBC) count <3,500/mm3 or lymphocyte count <800/mm3. Patients who are currently treated with fingolomod with the following cell counts: white blood cell (WBC) count <3,500/mm3 or lymphocyte count <200/mm3
13. 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
• serious psychiatric disorders other than mild to moderate depression, including bipolar disorder or psychotic disorder
• Contemplating suicide with a concrete plan of action
• History of suicide attempt
14. Participation in any clinical research study evaluating a study drug or therapy other than fingolimod within 6 months prior to start of fingolimod (see Appendix 6)
15. 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)
16. Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods, at least 1 of which must be a primary form.
Reliable contraception should be maintained throughout the study and for 2 months after study drug discontinuation.
17. History of hypersensitivity to the active substance or to any other of the excipients of the study drugs. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| safety and tolerability profile of the combination therapy of an antidepressant type SSRI or SNRI with oral fingolimod with respect to adverse events and laboratory parameters |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | No |
| 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 | 74 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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