REGAIN: Combination of Antidepressants and Fingolimod Relapsing-remitting Multiple Sclerosis (RRMS) Patients With Depression

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01436643
• Collaborator: (none)
• Enrollment: 54
• Locations: 25
• Arms: 3
• Duration (Months): 22
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Depression; Relapsing-remitting Multiple Sclerosis	Drug: Venlafaxine; Drug: Fluoxetine; Drug: Citalopram; Drug: Fingolimod	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 21-week, Multicenter, Open Label Study to Evaluate the Safety and Tolerability Profile of the Combination of a SSRI or SNRI Antidepressive Therapy With Oral Fingolimod in the Treatment of RRMS Patients With Mild to Moderate Depression
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: Fluoxetine; 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; Drug: Fingolimod; 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.
Experimental: 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	Drug: Venlafaxine; 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; Drug: Fingolimod; 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.
Experimental: 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	Drug: Citalopram; 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; Drug: Fingolimod; 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.

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Achim		Germany	28832
2	Novartis Investigative Site	Altenholz-Stift		Germany	24161
3	Novartis Investigative Site	Aschaffenburg		Germany	63739
4	Novartis Investigative Site	Bad Honnef		Germany	53604
5	Novartis Investigative Site	Baesweiler		Germany	52499
6	Novartis Investigative Site	Berlin		Germany	12621
7	Novartis Investigative Site	Bielefeld		Germany	33602
8	Novartis Investigative Site	Bielefeld		Germany	33647
9	Novartis Investigative Site	Bochum		Germany	44787
10	Novartis Investigative Site	Bremerhaven		Germany	27574
11	Novartis Investigative Site	Butzbach		Germany	35510
12	Novartis Investigative Site	Grevenbroich		Germany	41515
13	Novartis Investigative Site	Heidenheim		Germany	89518
14	Novartis Investigative Site	Klingenmünster		Germany	76889
15	Novartis Investigative Site	Leipzig		Germany	04275
16	Novartis Investigative Site	Merzig		Germany	66663
17	Novartis Investigative Site	Nienburg		Germany	31582
18	Novartis Investigative Site	Oberhausen		Germany	46045
19	Novartis Investigative Site	Oldenburg		Germany	26122
20	Novartis Investigative Site	Potsdam		Germany	14471
21	Novartis Investigative Site	Schwalmstadt-Treysa		Germany	34613
22	Novartis Investigative Site	Stadtroda		Germany	07646
23	Novartis Investigative Site	Tübingen		Germany	72076
24	Novartis Investigative Site	Weil am Rhein		Germany	79576
25	Novartis Investigative Site	Zwickau		Germany	08060

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01436643
• Other Study ID Numbers: CFTY720DDE06; 2011-001692-39
• First Posted: Sep 20, 2011
• Last Update Posted: Sep 25, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Novartis Pharmaceuticals: Depression; Multiple Sclerosis; Fingolimod; Venlafaxine; Fluoxetine
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Depression; Depressive Disorder; Fluoxetine; Venlafaxine Hydrochloride; Citalopram; Fingolimod Hydrochloride

Study Results

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

Arm/Group Title	Fluoxetine and Fingolimod	Venlafaxine and Fingolimod	Citalopram and Fingolimod	Pre-treatment With Fingolimod
Arm/Group Description	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	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	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	During 2weeks pre-treatment period patients received Fingolimod 0.5 mg per capsule (hard gelatin capsules) orally once daily.
Period Title: 2-week Pre-treatment
STARTED	0	0	0	54
COMPLETED	0	0	0	44
NOT COMPLETED	0	0	0	10
Period Title: 2-week Pre-treatment
STARTED	17	15	20	0
COMPLETED	16	11	17	0
NOT COMPLETED	1	4	3	0

Baseline Characteristics

Arm/Group Title	Fluoxetine and Fingolimod	Venlafaxine and Fingolimod	Citalopram and Fingolimod	Total
Arm/Group Description	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	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	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	Total of all reporting groups
Overall Participants	17	15	20	52
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.2 (9.22)	40.0 (9.28)	41.2 (10.22)	41.8 (9.87)
Sex: Female, Male (Count of Participants)
Female	15 88.2%	10 66.7%	17 85%	42 80.8%
Male	2 11.8%	5 33.3%	3 15%	10 19.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death
Description	In this analysis patients with all (serious and non-serious) adverse events, and death were reported. See Safety Section.
Time Frame	21 weeks

Outcome Measure Data

Analysis Population Description

The safety set was used for analysis, which consists of 54 patients, of whom 2 patients did not start treatment with any antidepressant

Arm/Group Title	Fluoxetine and Fingolimod	Venlafaxine and Fingolimod	Citalopram and Fingolimod	Fingolimod
Arm/Group Description	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	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	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	2 Week Pre-treatment Period: Fingolimod 0.5 mg per capsule (hard gelatin capsules) was taken p.o. once during 2 week pre-treatment period.
Measure Participants	17	15	20	54
Any Adverse Event	11 64.7%	12 80%	12 60%	15 28.8%
Death	0 0%	0 0%	0 0%	0 0%
Serious Adverse Event	0 0%	1 6.7%	1 5%	1 1.9%

Adverse Events

Adverse Event Reporting Description	The safety set (SS) consists of all enrolled patients for whom safety information was collected. Of note, the statement that a patient had no adverse events also constitutes a safety assessment. Fingolimod 2 week pretreatment included 2 patients who did not receive antidepressant.
Arm/Group Title	Fingolimod		Venlafaxine and Fingolimod		Citalopram and Fingolimod		Fluoxetine and Fingolimod
Arm/Group Description	2 Week Pre-treatment Period: Fingolimod 0.5 mg per capsule (hard gelatin capsules) was taken p.o. once during 2 week pre-treatment period.		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		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		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
All Cause Mortality
	Fingolimod		Venlafaxine and Fingolimod		Citalopram and Fingolimod		Fluoxetine and Fingolimod
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Fingolimod		Venlafaxine and Fingolimod		Citalopram and Fingolimod		Fluoxetine and Fingolimod
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/54 (1.9%)		1/15 (6.7%)		1/20 (5%)		0/17 (0%)
Nervous system disorders
CEREBRAL HAEMORRHAGE	1/54 (1.9%)		0/15 (0%)		0/20 (0%)		0/17 (0%)
MULTIPLE SCLEROSIS RELAPSE	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
Psychiatric disorders
SUICIDAL IDEATION	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Fingolimod		Venlafaxine and Fingolimod		Citalopram and Fingolimod		Fluoxetine and Fingolimod
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/54 (27.8%)		12/15 (80%)		12/20 (60%)		11/17 (64.7%)
Blood and lymphatic system disorders
LYMPHOPENIA	6/54 (11.1%)		0/15 (0%)		0/20 (0%)		0/17 (0%)
Cardiac disorders
TACHYCARDIA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
Eye disorders
ASTHENOPIA	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
CONJUNCTIVAL HAEMORRHAGE	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
Gastrointestinal disorders
ABDOMINAL PAIN	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
CONSTIPATION	0/54 (0%)		1/15 (6.7%)		1/20 (5%)		0/17 (0%)
DIARRHOEA	0/54 (0%)		1/15 (6.7%)		1/20 (5%)		0/17 (0%)
DRY MOUTH	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
GASTROINTESTINAL DISORDER	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
NAUSEA	0/54 (0%)		3/15 (20%)		4/20 (20%)		4/17 (23.5%)
TOOTHACHE	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
General disorders
FATIGUE	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		2/17 (11.8%)
FEELING HOT	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
OEDEMA PERIPHERAL	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
PAIN	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
THIRST	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
Infections and infestations
BRONCHITIS	0/54 (0%)		0/15 (0%)		1/20 (5%)		1/17 (5.9%)
GASTROINTESTINAL INFECTION	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
INFLUENZA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		1/17 (5.9%)
NASOPHARYNGITIS	2/54 (3.7%)		1/15 (6.7%)		1/20 (5%)		2/17 (11.8%)
RHINITIS	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
TONSILLITIS	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
UPPER RESPIRATORY TRACT INFECTION	1/54 (1.9%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
Injury, poisoning and procedural complications
CONTUSION	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
FALL	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
Investigations
BLOOD BILIRUBIN INCREASED	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
ELECTROCARDIOGRAM ABNORMAL	1/54 (1.9%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
LABORATORY TEST ABNORMAL	1/54 (1.9%)		1/15 (6.7%)		1/20 (5%)		1/17 (5.9%)
WEIGHT DECREASED	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		1/17 (5.9%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
ARTHRITIS	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
BACK PAIN	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
SKIN PAPILLOMA	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
Nervous system disorders
DIZZINESS	0/54 (0%)		1/15 (6.7%)		1/20 (5%)		0/17 (0%)
DYSGEUSIA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
HEADACHE	1/54 (1.9%)		1/15 (6.7%)		1/20 (5%)		2/17 (11.8%)
HYPOAESTHESIA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
LOSS OF CONSCIOUSNESS	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
MULTIPLE SCLEROSIS RELAPSE	2/54 (3.7%)		2/15 (13.3%)		0/20 (0%)		2/17 (11.8%)
OPTIC NEURITIS	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
PAROSMIA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
SEDATION	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
SOMNOLENCE	1/54 (1.9%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
TREMOR	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
Psychiatric disorders
AGITATION	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
INSOMNIA	1/54 (1.9%)		2/15 (13.3%)		0/20 (0%)		0/17 (0%)
LIBIDO DISORDER	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
SLEEP DISORDER	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
Reproductive system and breast disorders
EJACULATION DISORDER	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
METRORRHAGIA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
HICCUPS	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
RHINITIS ALLERGIC	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
YAWNING	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
Skin and subcutaneous tissue disorders
ALOPECIA	0/54 (0%)		0/15 (0%)		0/20 (0%)		2/17 (11.8%)
DERMATITIS ALLERGIC	0/54 (0%)		0/15 (0%)		0/20 (0%)		1/17 (5.9%)
ERYTHEMA	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)
HYPERHIDROSIS	0/54 (0%)		2/15 (13.3%)		0/20 (0%)		1/17 (5.9%)
SKIN LESION	0/54 (0%)		0/15 (0%)		1/20 (5%)		0/17 (0%)
Vascular disorders
FLUSHING	0/54 (0%)		1/15 (6.7%)		0/20 (0%)		0/17 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.