Evaluation of Patient Reported Outcomes in RRMS Patients Candidates for MS Therapy Change and Transitioned to Fingolimod 0.5 mg (EPOC)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01534182
• Collaborator: (none)
• Enrollment: 298
• Locations: 26
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

A 6-month, Randomized, Active Comparator, Open-label, Multi-Center Study to Evaluate Patient Outcomes, Safety and Tolerability of (fingolimod) 0.5 mg/day in Patients with Relapsing Remitting Multiple Sclerosis who are candidates for MS therapy change from Previous Disease Modifying Therapy.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: Fingolimod; Drug: Interferon beta - 1a (IFN); Drug: Glatiramer acetate (GA)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 298 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 6-month, Randomized, Active Comparator, Open-label, Multi-Center Study to Evaluate Patient Outcomes, Safety and Tolerability of (Fingolimod) 0.5 mg/Day in Patients With Relapsing Remitting Multiple Sclerosis Who Are Candidates for Multiple Sclerosis (MS) Therapy Change From Previous Disease Modifying Therapy (DMT)
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fingolimod Participants received 0.5 mg orally once a day.	Drug: Fingolimod; 0.5 mg orally once a day; Other Names: Gilenya
Active Comparator: Standard Disease Modifying Therapy (DMT) Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.	Drug: Interferon beta - 1a (IFN); 44 mcg subcutaneously three times a week; Other Names: Rebif ; Drug: Glatiramer acetate (GA); 20 mg subcutaneously once a day; Other Names: Copaxone

Outcome Measures

Primary Outcome Measures

1. Change in Patient-reported Treatment Satisfaction [Baseline, 6 months]

   The Treatment Satisfaction Questionnaire for Medication (TSQM) contains 14 items assessing the following 4 domains: effectiveness (items 1 - 3), side effects (items 4 - 8), convenience (items 9 - 11) and global satisfaction (items 12 - 14). The primary outcome was measured on the global satisfaction domain. Item 12 scored as 1 (not at all confident) to 5 (extremely confident); item 13 scored as 1 (not at all certain) to 5 (extremely certain); and item 14 scored as 1 (extremely dissatisfied) to 7 (extremely satisfied). Responses to items were summed and transformed: specifically, TSQM v 1.4 domain scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.

Secondary Outcome Measures

1. Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death [6 months]

   Participants were monitored for adverse events, serious adverse events and death throughout the study.

2. Changes in Patient-reported Effectiveness, Side Effects and Convenience [Baseline, 6 months]

   TSQM v 1.4 domains for effectiveness, side effects and convenience were used to evaluate this outcome. The effectiveness domain for items 1 - 3 was scored as: 1 (extremely dissatisfied) to 7 (extremely satisfied). For the side effects domain, item 4 scored as 0(no) or 1(yes); item 5 scored as 1 (extremely bothersome) to 5 (not at all bothersome); and items 6 - 8 scored as 1 (a great deal) to 5 (not at all). For the convenience domain, items 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy), and item 11 scored as 1 (extremely inconvenient) to 7 (extremely convenient). For each domain, scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.

3. Change in Patient-reported Depression [Baseline, 6 months]

   The Beck Depression Inventory (BDI-I) scale was used to measure this outcome. The scale consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. Each item was scored from 0 - 3. If more than one score was provided for an item, the maximum score was considered the item score. The total score was calculated as the sum of all individual items and then compared to a key to determine the depression's severity. The standard key ranges were: 0 - 9 indicated minimal depression; 10 - 18 indicated mild depression; 19 - 29 indicated moderate depression and 30 - 63 indicated severe depression. Higher total scores indicate more severe depressive symptoms.

4. Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute) [Baseline, 6 months]

   The SF-36 is a health-related quality of life instrument used in numerous disease states, including MS (Brazier et al 1992). It is a self-administered survey that measures 8 domains of health including: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and general mental health. Two summary scale scores can be calculated: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain was scored by adding the individual items from the domain and transforming the resulting scores into a 0 to 100 scale with higher scores indicating better health status or functioning.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent must be obtained before any assessment is performed.

• Patients must be diagnosed with relapsing remitting MS (RRMS) as defined by 2005 revised McDonald criteria (McDonald et al 2001, Polman et al 2005) (Appendix 2).

• Patients who explicitly agree to be assigned to a treatment group that may receive or DMT after having been informed about their respective benefits and possible adverse events by the investigator.

• Male or female patients aged 18-70 years.

• An Expanded Disability Status Scale (EDSS) score of 0-6 inclusive.

• Must have received continuous treatment with a single approved and indicated MS DMT for a minimum of 6 months prior to the screening visit. Patients must continue with this MS DMT until the randomization visit.

• Naïve to treatment with fingolimod.

Exclusion Criteria:

• A manifestation of MS other than those defined in the inclusion criteria.

• A history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome.

• History of malignancy of any organ system.

• Diagnosis of macular edema during Screening Phase.

• Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS or to have positive HIV antibody test.

• Patients who have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to baseline.

• Patients who have received total lymphoid irradiation or bone marrow transplantation.

• History of selected immune system treatments and/or medications.

• Any medically unstable condition, as assessed by the investigator.

• Selected cardiovascular, or hepatic conditions

• Selected abnormal laboratory values.

• Patients with any other disease or clinical condition (including neurologic or psychiatric disorders) which may affect patient enrollment into the study and study medication use by the Investigators' opinion.

• Participation in any clinical research study evaluating another not approved in Russia investigational drug or therapy within 6 months prior to baseline.

• History of hypersensitivity to the study drug or to drugs of similar chemical classes.

• Pregnant or nursing (lactating) women.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Arkhangelsk	Russia	Russian Federation	163045
2	Novartis Investigative Site	Barnaul		Russian Federation	656024
3	Novartis Investigative Site	Belgorod		Russian Federation	308007
4	Novartis Investigative Site	Kazan		Russian Federation	420021
5	Novartis Investigative Site	Kemerovo		Russian Federation	650066
6	Novartis Investigative Site	Khanty-Mansiysk		Russian Federation	628012
7	Novartis Investigative Site	Kirov		Russian Federation	610014
8	Novartis Investigative Site	Krasnodar		Russian Federation	350086
9	Novartis Investigative Site	Kursk		Russian Federation	305007
10	Novartis Investigative Site	Moscow		Russian Federation	119992
11	Novartis Investigative Site	Moscow		Russian Federation	127018
12	Novartis Investigative Site	N.Novgorod		Russian Federation	603126
13	Novartis Investigative Site	Nizhniy Novgorod		Russian Federation	603076
14	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603155
15	Novartis Investigative Site	Novosibirsk		Russian Federation	630087
16	Novartis Investigative Site	Perm		Russian Federation	614990
17	Novartis Investigative Site	Saransk		Russian Federation	430032
18	Novartis Investigative Site	Saratov		Russian Federation	410030
19	Novartis Investigative Site	Smolensk		Russian Federation	214019
20	Novartis Investigative Site	St. Petersburg		Russian Federation	197376
21	Novartis Investigative Site	Tomsk		Russian Federation	634050
22	Novartis Investigative Site	Tumen		Russian Federation	625048
23	Novartis Investigative Site	Tver		Russian Federation	170036
24	Novartis Investigative Site	Ufa		Russian Federation	450000
25	Novartis Investigative Site	Ulyanovsk		Russian Federation	432063
26	Novartis Investigative Site	Yaroslavl		Russian Federation	150030

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: NCT01534182
• Other Study ID Numbers: CFTY720DRU01
• First Posted: Feb 16, 2012
• Last Update Posted: Aug 8, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Novartis Pharmaceuticals: Relapsing Remitting Multiple Sclerosis (RRMS); Fingolimod; Disease Modifying Therapy (DMT); TSQM-9
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferons; Interferon-beta; Glatiramer Acetate; Fingolimod Hydrochloride; (T,G)-A-L

Study Results

Participant Flow

Recruitment Details	Participants at screening received standard DMT with either interferon beta-1a or glatiramer acetate from day -30 to day -1.
Pre-assignment Detail	Eligible participants were then randomized in a 3:1 ratio to fingolimod or a standard DMT. For participants who were randomized to the standard DMT group, those who received IFN during screening were switched to GA at randomization and those who received GA during screening were switched to IFN at randomization.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Period Title: Overall Study
STARTED	230	68
Safety Set	230	64
Full Analysis Set	229	62
COMPLETED	218	58
NOT COMPLETED	12	10

Baseline Characteristics

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)	Total
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.	Total of all reporting groups
Overall Participants	230	68	298
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.4 (9.9)	36.4 (9.3)	35.6 (9.8)
Sex: Female, Male (Count of Participants)
Female	162 70.4%	50 73.5%	212 71.1%
Male	68 29.6%	18 26.5%	86 28.9%

Outcome Measures

1. Primary Outcome

Title	Change in Patient-reported Treatment Satisfaction
Description	The Treatment Satisfaction Questionnaire for Medication (TSQM) contains 14 items assessing the following 4 domains: effectiveness (items 1 - 3), side effects (items 4 - 8), convenience (items 9 - 11) and global satisfaction (items 12 - 14). The primary outcome was measured on the global satisfaction domain. Item 12 scored as 1 (not at all confident) to 5 (extremely confident); item 13 scored as 1 (not at all certain) to 5 (extremely certain); and item 14 scored as 1 (extremely dissatisfied) to 7 (extremely satisfied). Responses to items were summed and transformed: specifically, TSQM v 1.4 domain scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): This set included all randomized participants who had taken at least one dose of study medication and had at least one post-baseline assessment of the TSQM. The last observation carried forward (LOCF) method was applied.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Measure Participants	229	62
Mean (Standard Deviation) [scores on a scale]	22.69 (28.12)	13.92 (30.63)

2. Secondary Outcome

Title	Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death
Description	Participants were monitored for adverse events, serious adverse events and death throughout the study.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Safety Set: This set included all randomized participants who received at least one dose of study medication.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Measure Participants	230	64
Adverse events (serious and non-serious)	73 31.7%	26 38.2%
Serious adverse events	2 0.9%	0 0%
Deaths	0 0%	0 0%

3. Secondary Outcome

Title	Changes in Patient-reported Effectiveness, Side Effects and Convenience
Description	TSQM v 1.4 domains for effectiveness, side effects and convenience were used to evaluate this outcome. The effectiveness domain for items 1 - 3 was scored as: 1 (extremely dissatisfied) to 7 (extremely satisfied). For the side effects domain, item 4 scored as 0(no) or 1(yes); item 5 scored as 1 (extremely bothersome) to 5 (not at all bothersome); and items 6 - 8 scored as 1 (a great deal) to 5 (not at all). For the convenience domain, items 9 and 10 scored as 1(extremely difficult) to 7 (extremely easy), and item 11 scored as 1 (extremely inconvenient) to 7 (extremely convenient). For each domain, scale scores were computed by adding the items loading on each domain. The lowest possible score was subtracted from the composite score and divided by the greatest possible score range. This provided a transformed score between 0 and 1 that was then multiplied by 100. The final transformed score ranges from 0 to 100, with higher scores indicating better treatment satisfaction.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

FAS: The LOCF method was applied.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Measure Participants	229	62
Effectiveness	21.57 (24.01)	11.56 (20.70)
Side effects	26.75 (35.83)	13.07 (40.19)
Convenience	25.38 (20.72)	10.57 (20.93)

4. Secondary Outcome

Title	Change in Patient-reported Depression
Description	The Beck Depression Inventory (BDI-I) scale was used to measure this outcome. The scale consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. Each item was scored from 0 - 3. If more than one score was provided for an item, the maximum score was considered the item score. The total score was calculated as the sum of all individual items and then compared to a key to determine the depression's severity. The standard key ranges were: 0 - 9 indicated minimal depression; 10 - 18 indicated mild depression; 19 - 29 indicated moderate depression and 30 - 63 indicated severe depression. Higher total scores indicate more severe depressive symptoms.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

FAS: The LOCF method was applied.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Measure Participants	229	62
Mean (Standard Deviation) [scores on a scale]	-2.88 (6.80)	-1.86 (8.04)

5. Secondary Outcome

Title	Change in Patient-reported Health-related Quality-of-life Using the Short Form Health Survey v2 Acute (SF-36 v2 Acute)
Description	The SF-36 is a health-related quality of life instrument used in numerous disease states, including MS (Brazier et al 1992). It is a self-administered survey that measures 8 domains of health including: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and general mental health. Two summary scale scores can be calculated: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain was scored by adding the individual items from the domain and transforming the resulting scores into a 0 to 100 scale with higher scores indicating better health status or functioning.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

Participants from the full analysis set were considered for this analysis. However, for a given time frame, participants analyzed had both baseline and 6 month asssessment values.

Arm/Group Title	Fingolimod	Standard Disease Modifying Therapy (DMT)
Arm/Group Description	Participants received 0.5 mg orally once a day.	Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week or glatiramer acetate (GA), 20 mg subcutaneously once a day.
Measure Participants	229	62
Physical functioning (n=225,61)	3.62 (16.23)	1.39 (14.23)
Role limitations due to physical health (n=226,61)	6.50 (21.99)	4.30 (27.52)
Bodily pain (n=225,61)	5.24 (23.79)	0.93 (22.95)
General health (n=226,61)	4.28 (17.72)	4.43 (22.57)
Vitality (n=226,61)	7.72 (18.61)	1.95 (21.97)
Social functioning (n=226,61)	5.59 (23.36)	1.64 (23.77)
Role limit. due to emotional problems (n=224,61)	7.18 (25.98)	5.33 (27.00)
Mental health (n=226,61)	5.60 (18.55)	2.79 (22.09)
Physical component summary (n=222,61)	1.51 (5.69)	0.68 (6.57)
Mental component summary (n=222,61)	3.16 (9.66)	1.68 (11.31)

Adverse Events

Arm/Group Title	Fingolimod		Standard Disease Modifying Therapy (DMT): Interferon Beta-1a		Standard Disease Modifying Therapy: Glatiramer Acetate
Arm/Group Description	Participants received 0.5 mg orally once a day.		Participants received interferon beta-1a (IFN), 44 mcg subcutaneously 3 times a week		Patients who received glatiramer acetate (GA), 20 mg subcutaneously once a day.
All Cause Mortality
	Fingolimod		Standard Disease Modifying Therapy (DMT): Interferon Beta-1a		Standard Disease Modifying Therapy: Glatiramer Acetate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Fingolimod		Standard Disease Modifying Therapy (DMT): Interferon Beta-1a		Standard Disease Modifying Therapy: Glatiramer Acetate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/230 (0.9%)		0/28 (0%)		0/36 (0%)
Injury, poisoning and procedural complications
Foot Fracture	1/230 (0.4%)		0/28 (0%)		0/36 (0%)
Renal and urinary disorders
Renal colic	1/230 (0.4%)		0/28 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Fingolimod		Standard Disease Modifying Therapy (DMT): Interferon Beta-1a		Standard Disease Modifying Therapy: Glatiramer Acetate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/230 (17%)		13/28 (46.4%)		10/36 (27.8%)
Blood and lymphatic system disorders
Lymphopenia	27/230 (11.7%)		0/28 (0%)		2/36 (5.6%)
General disorders
Influenza like illness	0/230 (0%)		10/28 (35.7%)		0/36 (0%)
Injection site pain	0/230 (0%)		1/28 (3.6%)		6/36 (16.7%)
Injection site erythema	0/230 (0%)		0/28 (0%)		3/36 (8.3%)
Injection site extravasation	0/230 (0%)		0/28 (0%)		2/36 (5.6%)
Investigations
Gamma-Glutamyltransferase increased	13/230 (5.7%)		1/28 (3.6%)		0/36 (0%)
Alanine aminotransferase increased	11/230 (4.8%)		2/28 (7.1%)		0/36 (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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.