Trial Outcomes & Findings for Effect of Physical ACtivity in Fingolimod Treated patiEnts (PACE) With Relapsing-remitting Multiple Sclerosis (NCT NCT01490840)

Last Updated: 2016-05-12

Results Overview

The mFIS provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. It is a 21-item, structured, self-report questionnaire that generally can be completed with little or no intervention from an interviewer. The mFIS score ranged from 0 (not tired) to 84 (tired). A negative change from baseline indicates improvement.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

178 participants

Primary outcome timeframe

Baseline, 6 months

Results posted on

2016-05-12

Participant Flow

Participants were randomized1:1 to receive a structured physical intervention (e-training) or no physical intervention (waiting).

At the end of the 6 month core phase (phase 1), participants in the waiting group had the option to receive e-training for 6 months in the phase 2 optional extension. Participants in the e-training group had the option to continue their e-training for another 6 months in the phase 2 extension.

Participant milestones

Participant milestones
Measure	E-training Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Phase 1 STARTED	94	84
Phase 1 Modified Full Analysis Set	56	83
Phase 1 COMPLETED	84	78
Phase 1 NOT COMPLETED	10	6
Phase 2 STARTED	81	74
Phase 2 COMPLETED	75	68
Phase 2 NOT COMPLETED	6	6

Reasons for withdrawal

Reasons for withdrawal
Measure	E-training Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Phase 1 Lost to Follow-up	1	0
Phase 1 Adverse Event	2	1
Phase 1 Withdrawal by Subject	6	5
Phase 1 Visit 6a omitted	1	0
Phase 2 Withdrawal by Subject	4	3
Phase 2 Permanent interruption of fingolimod	0	1
Phase 2 Lost to Follow-up	1	1
Phase 2 Adverse Event	1	1

Baseline Characteristics

Effect of Physical ACtivity in Fingolimod Treated patiEnts (PACE) With Relapsing-remitting Multiple Sclerosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Total n=178 Participants Total of all reporting groups	E-training n=94 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=84 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Age, Continuous	40.2 Years STANDARD_DEVIATION 9.6 • n=5 Participants	40.9 Years STANDARD_DEVIATION 10.4 • n=5 Participants	39.4 Years STANDARD_DEVIATION 8.7 • n=7 Participants
Sex: Female, Male Female	122 Participants n=5 Participants	65 Participants n=5 Participants	57 Participants n=7 Participants
Sex: Female, Male Male	56 Participants n=5 Participants	29 Participants n=5 Participants	27 Participants n=7 Participants

PRIMARY outcome

Timeframe: Baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Fatigue as Measured by the Modified Fatigue Impact Scale (mFIS ).	-3.57 score on a scale 95% Confidence Interval 11.3 • Interval -6.81 to -0.34	-2.10 score on a scale 95% Confidence Interval 12.1 • Interval -4.69 to 0.49

SECONDARY outcome

Timeframe: baseline, 6 months

Population: The ModFAS, which included participants with sufficient e-training compliance, was considered for the analysis. Only participants with both baseline and month 6 values were analyzed.

The Sit to Stand Test is a functional outcome measure of the lower-extremity muscle power. The test was performed 3 times with one minute rest in between. The best attempt out of three was used for the analysis. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=55 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Sit-to-stand Test	0.03 watt/kilogram body weight Interval -0.31 to 0.36	0.27 watt/kilogram body weight Interval -0.01 to 0.55

SECONDARY outcome

Timeframe: baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

Isometric and dynamic muscular strength was measured by an Isomed 2000 isometric measurement device (knee flexion/tension, trunk flexion/extension). Isomed 2000 device measures muscular flexion and tension under standardized training conditions. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Change in Leg Strength and Trunk Strength Leg strength	0.50 newton meter Interval -1.83 to 2.83	1.63 newton meter Interval -0.32 to 3.58
Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Change in Leg Strength and Trunk Strength Trunk strength	0.08 newton meter Interval -0.01 to 0.18	0.12 newton meter Interval 0.04 to 0.2

SECONDARY outcome

Timeframe: baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Isometric and Dynamic Muscular Strength as Measured by Leg Strength Endurance	51.28 joule Interval -50.7 to 153.3	130.80 joule Interval 47.53 to 214.1

SECONDARY outcome

Timeframe: Baseline, 6 months, 12 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

The Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) consists of 44 items, 28 of which are the basis for computation of five subscale scores reflecting major dimensions of health-related quality of life (HRQoL) in MS: Fatigue/Thinking (4 items), Mobility lower limb (5 items), Mobility upper limb (5 items), Social function (6 items) and Mood (eight items). Subscales and total score range from 1 to 5, with high scores indicating a lower quality of life. In this study, the total score and following 3 subscales: fatigue/thinking, mobility lower limb and mobility upper limb only were analyzed. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Quality of Life as Measured by the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) Total score	-0.11 score on a scale Interval -0.21 to -0.01	-0.02 score on a scale Interval -0.1 to 0.06
Change From Baseline in Quality of Life as Measured by the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) Fatigue/thinking	-0.30 score on a scale Interval -0.48 to -0.12	-0.16 score on a scale Interval -0.3 to -0.01
Change From Baseline in Quality of Life as Measured by the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) Mobility lower limb	-0.00 score on a scale Interval -0.16 to 0.15	0.08 score on a scale Interval -0.04 to 0.2
Change From Baseline in Quality of Life as Measured by the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) Mobility upper limb	-0.00 score on a scale Interval -0.1 to 0.1	0.12 score on a scale Interval 0.04 to 0.2

SECONDARY outcome

Timeframe: Baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

The WEIMuS (Würzburg Fatigue Inventory for MS) scale is a validated self-assessment instrument to quantify the degree of fatigue. The scale consists of 17 items with 5 categories that are scored from '0' to '4'. The subscores for cognitive and physical fatigue range from 0 to 36 and from 0 to 32, respectively, with the total sum score ranging from 0 to 68; higher scores indicate higher degrees of fatigue. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Fatigue as Measured by the WEIMuS (Würzburg Fatigue Inventory for MS)	-1.90 score on a scale Interval -4.91 to 1.11	-1.12 score on a scale Interval -3.55 to 1.31

SECONDARY outcome

Timeframe: Baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

The Beck Depression Inventory Second Edition (BDI-II) is a 21-item self-report instrument intended to assess the existence and severity of symptoms of depression as listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders Fourth Edition. Each of the 21 items corresponding to a symptom of depression is summed to give a single score for the BDI-II. There is a four-point scale for each item ranging from 0 to 3. The total score ranges from 0 - 63. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Depression as Measured by the Beck Depression Inventory Second Edition (BDI-II)	-2.62 score on a scale Interval -4.42 to -0.81	-1.97 score on a scale Interval -3.43 to -0.52

SECONDARY outcome

Timeframe: Baseline, 6 months

Population: Modified Full Analysis Set (ModFAS): The ModFAS included participants with sufficient e-training compliance.

Physical endurance spiroergometry was accomplished. Ergometry was assessed according to national guidelines of the German society for sports medicine. Ergometry is a combined examination of circulation and lung function and was performed as a submaximal or maximal test depending on the participant's individual performance. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=56 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=83 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Aerobic Capacity (VO2max) as Measured by a Physical Endurance Spiroergometry on a Treadmill	-0.52 [ml/min/kg][watt/kg body weight] Interval -1.6 to 0.56	-0.79 [ml/min/kg][watt/kg body weight] Interval -1.66 to 0.08

SECONDARY outcome

Timeframe: Baseline, 6 months

Population: The ModFAS, which included participants with sufficient e-training compliance, was considered for the analysis. Only participants with both baseline and month 6 values were analyzed.

Physical endurance spiroergometry was accomplished. Ergometry was assessed according to national guidelines of the German society for sports medicine. Ergometry is a combined examination of circulation and lung function and was performed as a submaximal or maximal test depending on the participant's individual performance. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	E-training n=46 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=78 Participants Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Change From Baseline in Peak Expiratory Flow as Measured by a Physical Endurance Spiroergometry on a Treadmill	0.05 L/s Interval -0.15 to 0.24	0.01 L/s Interval -0.15 to 0.17

Adverse Events

E-training

Serious events: 5 serious events

Other events: 58 other events

Deaths: 0 deaths

Waiting

Serious events: 9 serious events

Other events: 59 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	E-training n=94 participants at risk Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=84 participants at risk Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Cardiac disorders ARRHYTHMIA	0.00% 0/94	1.2% 1/84
Cardiac disorders EXTRASYSTOLES	0.00% 0/94	1.2% 1/84
Cardiac disorders PALPITATIONS	0.00% 0/94	1.2% 1/84
Infections and infestations APPENDICITIS PERFORATED	0.00% 0/94	1.2% 1/84
Infections and infestations CONJUNCTIVITIS	0.00% 0/94	1.2% 1/84
Injury, poisoning and procedural complications BONE CONTUSION	0.00% 0/94	1.2% 1/84
Injury, poisoning and procedural complications CONCUSSION	0.00% 0/94	1.2% 1/84
Injury, poisoning and procedural complications DISLOCATION OF VERTEBRA	1.1% 1/94	0.00% 0/84
Injury, poisoning and procedural complications RADIUS FRACTURE	1.1% 1/94	0.00% 0/84
Injury, poisoning and procedural complications SPINAL FRACTURE	1.1% 1/94	1.2% 1/84
Investigations GAMMA-GLUTAMYLTRANSFERASE INCREASED	0.00% 0/94	1.2% 1/84
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC PROTRUSION	1.1% 1/94	0.00% 0/84
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ASTROCYTOMA, LOW GRADE	0.00% 0/94	1.2% 1/84
Neoplasms benign, malignant and unspecified (incl cysts and polyps) UTERINE LEIOMYOMA	0.00% 0/94	1.2% 1/84
Nervous system disorders EPILEPSY	1.1% 1/94	0.00% 0/84
Nervous system disorders GENERALISED TONIC-CLONIC SEIZURE	0.00% 0/94	1.2% 1/84
Nervous system disorders HEMIPARESIS	1.1% 1/94	0.00% 0/84
Nervous system disorders ISCHAEMIC CEREBRAL INFARCTION	1.1% 1/94	0.00% 0/84
Nervous system disorders MUSCLE SPASTICITY	1.1% 1/94	0.00% 0/84
Reproductive system and breast disorders MENORRHAGIA	0.00% 0/94	1.2% 1/84

Other adverse events

Other adverse events
Measure	E-training n=94 participants at risk Fingolimod as baseline immunomodulatory multiple sclerosis treatment was prescribed as per clinical practice. During phase 1, participants randomized to this arm had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day. After 6 months, Phase 2, the same Phase 1 regimen applied.	Waiting n=84 participants at risk Fingolimod as baseline immunomodulatory multiple sclerosis treatment is prescribed as per clinical practice. During Phase 1, participants randomized to this arm did not receive e-training exercise. After a 6 month waiting period, phase 2, participants had an introductory group session, hosted by a sports therapist. The individual training schedule was comprised of strength exercises twice a week for 30-45 minutes and endurance training once a week for 20-60 minutes for 6 months. The participants documented each training session thoroughly via the web-based application (duration, type of exercises, number of repetitions and sets, perceived exertion). A standard course of corticosteroids (methylprednisolone) on an inpatient or outpatient basis was allowed for treatment of relapses as clinically warranted. Steroid treatment consisted of 3-5 days and up to 1,000 mg methylprednisolone/day.
Gastrointestinal disorders DIARRHOEA	5.3% 5/94	2.4% 2/84
Infections and infestations BRONCHITIS	3.2% 3/94	9.5% 8/84
Infections and infestations NASOPHARYNGITIS	36.2% 34/94	39.3% 33/84
Infections and infestations ORAL HERPES	6.4% 6/94	2.4% 2/84
Infections and infestations SINUSITIS	5.3% 5/94	1.2% 1/84
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	0.00% 0/94	6.0% 5/84
Investigations BLOOD CHOLESTEROL INCREASED	2.1% 2/94	6.0% 5/84
Musculoskeletal and connective tissue disorders BACK PAIN	5.3% 5/94	6.0% 5/84
Nervous system disorders HEADACHE	4.3% 4/94	7.1% 6/84
Nervous system disorders MULTIPLE SCLEROSIS RELAPSE	23.4% 22/94	17.9% 15/84
Psychiatric disorders DEPRESSION	4.3% 4/94	9.5% 8/84
Psychiatric disorders SLEEP DISORDER	10.6% 10/94	4.8% 4/84
Respiratory, thoracic and mediastinal disorders COUGH	3.2% 3/94	9.5% 8/84
Vascular disorders HYPERTENSION	4.3% 4/94	10.7% 9/84

Additional Information

Study Director

Novartis

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER