RELIEF: A Study of Rebif® in Subjects With Relapsing Multiple Sclerosis

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02064816
• Collaborator: (none)
• Enrollment: 200
• Location: 1
• Arms: 2
• Actual Duration (Months): 23
• Patients Per Site Per Month: 8.7

Study Details

Study Description

Brief Summary

This is an open-label, multi-center, 12-week, randomized, controlled, parallel group, Phase 4 study to assess whether the morning administration of interferon beta 1a (Rebif®) leads to a lower severity of flu-like symptoms (FLS) as compared to the evening administration, in subjects with relapsing multiple sclerosis (RMS).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-Remitting	Drug: Rebif®; Drug: Rebif®	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter, Open-label, 12 Week, Phase IV Prospective Randomized Study Aimed at Evaluating Whether sc IFN Beta 1a (Rebif®) Administered in the Morning May Affect the Severity of Flu-like Syndrome and Patient-perceived Invisible Symptoms in Subjects With Relapsing Multiple Sclerosis
• Actual Study Start Date: May 31, 2014
• Actual Primary Completion Date: Apr 30, 2016
• Actual Study Completion Date: Apr 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rebif® Morning Administration	Drug: Rebif®; Rebif® will be administered at a dose of 44 microgram (mcg) subcutaneously three times a week in the morning using RebiSmart® self-injector device for 12 weeks.
Experimental: Rebif® Evening Administration	Drug: Rebif®; Rebif® will be administered at a dose of 44 mcg subcutaneously three times a week in the evening using RebiSmart® self-injector device for 12 weeks.

Outcome Measures

Primary Outcome Measures

1. Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 12 [Week 12]

   The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 12 is presented in statistical analysis section.

Secondary Outcome Measures

1. Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4 and 8 [Week 4 and 8]

   The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 4 and 8 is presented in statistical analysis section.

2. Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Subscale Scores Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4, 8 and 12 [Week 4, 8 and 12]

   MSTCQ was used as a tool to measure treatment satisfaction, focusing on attributes specific to MS medications. Following sub-scales were assessed: Injection site reactions (ISRs), Global side-effects, Benefits, Pain, Visual Analog Scale (VAS), and Rating of Pain. ISR subscale was defined as sum of scores for questions 17 to 20, with a minimum possible total score of 4 and a maximum possible total score of 20. Global side-effects subscale was defined as sum of scores for questions 21 to 23 with minimum possible total score of 3 and a maximum possible total score of 15. Benefits (question 35); description of pain (question 36); VAS (question 37); rating of pain (question 38) subscales ranged from minimum possible score of 1 and a maximum possible total score of 5. For each of the subscales, lower scores indicated better satisfaction. Difference between both the groups at Week 4, 8 and 12 for individual sub-scales is presented in statistical analysis section.

3. Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score at Week 4, 8 and 12 [Baseline, Week 4, 8 and 12]

   HADS was used to measure depression and anxiety in subjects. The scale was limited to 14 questions. Seven of the items related to anxiety and 7 related to depression. Each item on the questionnaire was scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression where higher score indicates more anxiety/depression.

4. Change From Baseline in Fatigue Severity Scale (FSS) Score at Week 4, 8 and 12 [Baseline, Week 4, 8 and 12]

   FSS is a method designed to assess disabling fatigue in all the individuals. The Fatigue Severity Scale is a 9-item questionnaire developed to assess the level of fatigue due to neurological disease, were each item assessed on a 1-7 scale (1= no fatigue and 7= severe fatigue). The total score was calculated as the average of individual 9-items and ranged from 1 to 7 with a higher value indicating greater impairment due to fatigue.

5. Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4, 8 and 12 [Baseline, Week 4, 8 and 12]

   PSQI is a self-rated questionnaire which assess sleep quality and disturbances over a 1-month interval using seven clinically derived components of sleep difficulties: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. PSQI is a summary of 7 components. Each component is scored from 0 to 3, therefore PSQI has a range of 0 (better) to 21 (worse). Interpretation of the PSQI is that a score less than 5 is associated with good sleep quality and a score of 5 or greater is associated with poor sleep quality.

6. Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQOL) Score at Week 4, 8 and 12 [Baseline, Week 4, 8 and 12]

   The MusiQoL is a validated 31-item questionnaire describing 9 dimensions: activities of daily living (8 items); psychological well-being (4 items); symptoms (3 items); relationships with friends (4 items); relationships with family (3 items); relationship with healthcare system (3 items); sentimental and sexual life (2 items); coping (2 items); and rejection (2 items). Each of the questions was answered using a 6-point Likert scale ranging from 1 (never/not at all) to 6 (always/very much). The scores of each dimension were obtained by computing mean of the item scores of dimension with negatively worded item scores reversed so that higher scores indicated higher health-related quality of life (QoL). All 9 dimension scores were linearly transformed to a 0 to 100 scale and the average of the 9 dimensions was used to give a Global Score ranging from 0 to 100, where higher scores indicated higher health-related quality of life (QoL).

7. Percentage of Subjects With Treatment Adherence at Week 4, 8 and 12 [Week 4, 8 and 12]

   Adherence to treatment was calculated as 100 x the number of completed injections the subject administered divided by the expected number of injections. Treatment adherence was divided in two categories: percentage of subjects with less than (<) 80 percent adherence and percentage of subjects with more than or equal to (>=) 80 percent adherence.

8. Change From Baseline in Circulating Levels of Cytokines at Week 12 [Baseline and Week 12]

   Results are presented for three cytokines: leptin, resistin and adiponectin.

9. Correlation Between Change From Baseline in Circulating Levels of Cytokines (Leptin, Resistin and Adiponectin) and in Flu Like Symptom (FLS) Score at Week 12 [Baseline and Week 12]

   Correlation was assessed by using Pearson correlation coefficient. The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to MS medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction.

10. Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Other MSTCQ Items, HADS, FSS, PSQI and MusiQOL Scores at Week 12 [Baseline and Week 12]

    Correlation was assessed by using Pearson correlation coefficient. MSTCQ, HADS, FSS, PSQI and MusiQOL are described in the above endpoints. Following abbreviations used in the categories: Global side-effects (GLOBSE); description of pain (PAINDESCR).

11. Change From Baseline in Cytokines (Leptin and Resistin) Levels at Week 12 [Baseline and Week 12]

    Results are presented for cytokines: leptin and resistin.

12. Change From Baseline in Cytokine (Adiponectin) Level at Week 12 [Baseline and Week 12]

13. Change From Baseline in Hormone-Like Cytokine (Interleukin-6, 10 and 12) Levels at Week 12 [Baseline and Week 12]

14. Change From Baseline in Total Sleep Time (TST) and Rapid Eye Movement (REM) Sleep Time at Week 12 [Baseline and Week 12]

    Polysomnography (PSG) was performed for subjects who participated in the sub study. PSG is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. Total sleep time is the total of all REM and non-REM sleep in a sleep episode.

15. Correlation Between Change From Baseline in Cytokines (Leptin, Resistin and Adiponectin) and Hormone-like Cytokine Levels (Interleukin-6, 10 and 12), and TST and REM Sleep Time at Week 12 [Baseline and Week 12]

    Correlations between change from baseline at Week 12 in TST or REM sleep and the area under the curve (AUC) calculated using the trapezoidal method for cytokine levels (i.e., leptin, resistin, adiponectin, Interleukin (IL)-12, IL 10, and IL 6) were analyzed using Pearson's correlation coefficient. Polysomnography (PSG) was performed for subjects who participated in the sub study.

16. Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation [Baseline up to Week 12]

    An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males and females between 18 and 60 years of age

• Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential. Furthermore, female subjects must not have been pregnant from at least three months prior to enter in the study

• Subjects have RMS according to the revised McDonald Criteria (2010)

• Subjects with an expanded disability status scale (EDSS) score of less than 6.0

• Subjects naive to treatment and eligible for treatment with Rebif® 44 three times a week, or patients having received glatiramer acetate with a wash-out from at least one month, or patients having received treatment with natalizumab or fingolimod with a wash-out from at least three months

• Subjects able to self-inject treatment using RebiSmart®

• Subjects willing and able to comply with the protocol for the duration of the study

• Subjects have given written informed consent to take part in the study

Exclusion Criteria:

• Subjects have any disease other than MS that could better explain his/her signs and symptoms

• Subjects who have received any immunosuppressive agents within 3 months prior to Baseline

• Subjects who have received any corticosteroids within 30 days prior to Baseline

• Subjects have a MS relapse within 30 days prior to Baseline

• Subjects have inadequate liver function and bone marrow reserve as defined in the protocol

• Subjects have moderate to severe renal impairment

• Subjects have any visual or physical impairment that precludes the subjects from self-injecting the treatment using RebiSmart®

• Subjects have hypersensitivity to natural or recombinant interferon, or to any of its excipients

• Subjects have any contra-indications to treatment with interferon (IFN) beta 1a according to Summary of Product Characteristics (SmPC)

• Subjects have any contra-indications to treatment with ibuprofen/paracetamol according to SmPC

• Obese subjects, defined by body mass index greater than 30 kilogram per square meter (kg/m^2)

• Subjects have participated in any other investigational trial within 30 days from Baseline

• Subjects have any other significant disease that in the Investigator's opinion would exclude the subject from the trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Please contact the Merck KGaA Communication Center	Darmstadt		Germany

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible, Merck Serono S.P.A., Italy

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT02064816
• Other Study ID Numbers: 200136-570; 2013-004450-21
• First Posted: Feb 17, 2014
• Last Update Posted: Sep 20, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Merck KGaA, Darmstadt, Germany: Multiple Sclerosis, Relapsing-Remitting; Interferon beta 1a; Rebif®
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferon beta-1a

Study Results

Participant Flow

Recruitment Details	The study was conducted at 29 clinical trial sites in Italy.
Pre-assignment Detail	A total of 200 subjects were enrolled in the study, of which 104 were randomized to Rebif morning treatment group, and 96 were randomized to Rebif evening treatment group. A subgroup of subjects also took part in a sub study assessing cytokines and other immunological biomarkers.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Period Title: Overall Study
STARTED	104	96
COMPLETED	96	88
NOT COMPLETED	8	8

Baseline Characteristics

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration	Total
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.	Total of all reporting groups
Overall Participants	104	96	200
Age, Customized (subjects) [Number]
<18 years	0	0	0
>=18 years to 64 years	104	96	200
>64 years	0	0	0
Sex: Female, Male (Count of Participants)
Female	76 73.1%	62 64.6%	138 69%
Male	28 26.9%	34 35.4%	62 31%

Outcome Measures

1. Primary Outcome

Title	Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 12
Description	The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 12 is presented in statistical analysis section.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Missing data on FLS were imputed using the last observation carried forward (LOCF) method.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	99	88
Mean (Standard Deviation) [units on scale]	12.3 (3.87)	11.8 (3.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.277763
	Comments
	Method	Mann-Whitney Non Parametric test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -0.46 to 1.56
	Parameter Dispersion	Type: Standard Deviation; Value: 3.50
	Estimation Comments

2. Secondary Outcome

Title	Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4 and 8
Description	The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 4 and 8 is presented in statistical analysis section.
Time Frame	Week 4 and 8

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	99	88
Week 4	12.4368	11.0876
Week 8	13.0039	11.6672

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0083
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean difference
	Estimated Value	1.3492
	Confidence Interval	(2-Sided) 95%; 0.3495 to 2.3489
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0079
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	1.3367
	Confidence Interval	(2-Sided) 95%; 0.3534 to 2.3200
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Subscale Scores Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4, 8 and 12
Description	MSTCQ was used as a tool to measure treatment satisfaction, focusing on attributes specific to MS medications. Following sub-scales were assessed: Injection site reactions (ISRs), Global side-effects, Benefits, Pain, Visual Analog Scale (VAS), and Rating of Pain. ISR subscale was defined as sum of scores for questions 17 to 20, with a minimum possible total score of 4 and a maximum possible total score of 20. Global side-effects subscale was defined as sum of scores for questions 21 to 23 with minimum possible total score of 3 and a maximum possible total score of 15. Benefits (question 35); description of pain (question 36); VAS (question 37); rating of pain (question 38) subscales ranged from minimum possible score of 1 and a maximum possible total score of 5. For each of the subscales, lower scores indicated better satisfaction. Difference between both the groups at Week 4, 8 and 12 for individual sub-scales is presented in statistical analysis section.
Time Frame	Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	103	93
ISRs subscale Week 4	10.8459	10.4456
ISRs subscale Week 8	11.5363	11.4515
ISRs subscale Week 12	11.6380	11.9625
Global side-effect subscale: Week 4	10.2144	10.2852
Global side-effect subscale: Week 8	10.4111	10.2214
Global side-effect subscale: Week 12	10.5879	10.1782
Benefits: Week 4	3.1325	3.5408
Benefits: Week 8	3.5779	3.7137
Benefits: Week 12	3.6059	3.6640
Description of pain: Week 4	4.3755	3.7846
Description of pain: Week 8	5.3132	6.0821
Description of pain: Week 12	5.7853	5.6431
VAS: Week 4	11.8837	11.2293
VAS: Week 8	17.2316	19.4610
VAS: Week 12	16.1757	21.5953
Rating of pain: Week 4	1.3073	1.3004
Rating of pain: Week 8	1.5653	1.6522
Rating of pain: Week 12	1.4994	1.7218

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	ISRs subscale Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4311
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.4003
	Confidence Interval	(2-Sided) 95%; -0.5992 to 1.3998
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	ISRs subscale Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8635
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.08479
	Confidence Interval	(2-Sided) 95%; -0.8850 to 1.0546
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	ISRs subscale Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5099
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.3245
	Confidence Interval	(2-Sided) 95%; -1.2927 to 0.6437
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Global side-effect subscale: Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8574
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.07079
	Confidence Interval	(2-Sided) 95%; -0.8452 to 0.7036
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Global side-effect subscale: Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6338
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.1897
	Confidence Interval	(2-Sided) 95%; -0.5926 to 0.9720
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Global side-effect subscale: Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3042
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.4097
	Confidence Interval	(2-Sided) 95%; -0.3734 to 1.1929
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Benefits: Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1038
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.4083
	Confidence Interval	(2-Sided) 95%; -0.9008 to 0.08419
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Benefits: Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5940
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.1358
	Confidence Interval	(2-Sided) 95%; -0.6370 to 0.3653
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Benefits: Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8217
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.05809
	Confidence Interval	(2-Sided) 95%; -0.5651 to 0.4489
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Description of pain: Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4890
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.5909
	Confidence Interval	(2-Sided) 95%; -1.0873 to 2.2690
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Description of pain: Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3719
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.7689
	Confidence Interval	(2-Sided) 95%; -2.4607 to 0.9229
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Description of pain: Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8690
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.1422
	Confidence Interval	(2-Sided) 95%; -1.5521 to 1.8364
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	VAS: Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8328
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.6544
	Confidence Interval	(2-Sided) 95%; -5.4393 to 6.7482
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	VAS: Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4764
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-2.2294
	Confidence Interval	(2-Sided) 95%; -8.3800 to 3.9212
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	VAS: Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0852
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-5.4196
	Confidence Interval	(2-Sided) 95%; -11.5939 to 0.7547
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Rating of pain: Week 4
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9639
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.006873
	Confidence Interval	(2-Sided) 95%; -0.2918 to 0.3055
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Rating of pain: Week 8
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5715
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.08689
	Confidence Interval	(2-Sided) 95%; -0.3886 to 0.2148
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Rebif Morning Administration, Rebif Evening Administration
	Comments	Rating of pain: Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1502
	Comments
	Method	linear mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-0.2224
	Confidence Interval	(2-Sided) 95%; -0.5256 to 0.08090
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score at Week 4, 8 and 12
Description	HADS was used to measure depression and anxiety in subjects. The scale was limited to 14 questions. Seven of the items related to anxiety and 7 related to depression. Each item on the questionnaire was scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression where higher score indicates more anxiety/depression.
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	101	93
Anxiety score: Change at Week 4	-0.6625	-0.4604
Anxiety score: Change at Week 8	-0.7222	-0.3763
Anxiety score: Change at Week 12	-0.6435	0.05023
Depression score: Change at Week 4	-0.1539	0.2211
Depression score: Change at Week 8	-0.2397	0.1999
Depression score: Change at Week 12	0.1906	0.1162

5. Secondary Outcome

Title	Change From Baseline in Fatigue Severity Scale (FSS) Score at Week 4, 8 and 12
Description	FSS is a method designed to assess disabling fatigue in all the individuals. The Fatigue Severity Scale is a 9-item questionnaire developed to assess the level of fatigue due to neurological disease, were each item assessed on a 1-7 scale (1= no fatigue and 7= severe fatigue). The total score was calculated as the average of individual 9-items and ranged from 1 to 7 with a higher value indicating greater impairment due to fatigue.
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	98	94
Change at Week 4	0.2089	0.06901
Change at Week 8	0.2062	0.1366
Change at Week 12	0.1464	0.1942

6. Secondary Outcome

Title	Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4, 8 and 12
Description	PSQI is a self-rated questionnaire which assess sleep quality and disturbances over a 1-month interval using seven clinically derived components of sleep difficulties: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. PSQI is a summary of 7 components. Each component is scored from 0 to 3, therefore PSQI has a range of 0 (better) to 21 (worse). Interpretation of the PSQI is that a score less than 5 is associated with good sleep quality and a score of 5 or greater is associated with poor sleep quality.
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	69	55
Change at Week 4	-0.08889	0.5747
Change at Week 8	-0.4513	0.7092
Change at Week 12	0.07841	0.4293

7. Secondary Outcome

Title	Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQOL) Score at Week 4, 8 and 12
Description	The MusiQoL is a validated 31-item questionnaire describing 9 dimensions: activities of daily living (8 items); psychological well-being (4 items); symptoms (3 items); relationships with friends (4 items); relationships with family (3 items); relationship with healthcare system (3 items); sentimental and sexual life (2 items); coping (2 items); and rejection (2 items). Each of the questions was answered using a 6-point Likert scale ranging from 1 (never/not at all) to 6 (always/very much). The scores of each dimension were obtained by computing mean of the item scores of dimension with negatively worded item scores reversed so that higher scores indicated higher health-related quality of life (QoL). All 9 dimension scores were linearly transformed to a 0 to 100 scale and the average of the 9 dimensions was used to give a Global Score ranging from 0 to 100, where higher scores indicated higher health-related quality of life (QoL).
Time Frame	Baseline, Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	89	85
Global Score: Change at Week 4	1.6283	0.1174
Global Score: Change at Week 8	1.1439	-2.2945
Global Score: Change at Week 12	0.9670	-1.3948

8. Secondary Outcome

Title	Percentage of Subjects With Treatment Adherence at Week 4, 8 and 12
Description	Adherence to treatment was calculated as 100 x the number of completed injections the subject administered divided by the expected number of injections. Treatment adherence was divided in two categories: percentage of subjects with less than (<) 80 percent adherence and percentage of subjects with more than or equal to (>=) 80 percent adherence.
Time Frame	Week 4, 8 and 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	92	85
< 80 percent adherence at Week 4	3.3	5.9
>= 80 percent adherence at Week 4	96.7	94.1
< 80 percent adherence at Week 8	2.9	1.5
>= 80 percent adherence at Week 8	97.1	98.5
< 80 percent adherence at Week 12	4.8	6.3
>= 80 percent adherence at Week 12	95.2	93.7

9. Secondary Outcome

Title	Change From Baseline in Circulating Levels of Cytokines at Week 12
Description	Results are presented for three cytokines: leptin, resistin and adiponectin.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	89	77
Leptin: Change at Week 12	-2.6 (3.42)	-2.6 (3.90)
Resistin: Change at Week 12	-3.1 (3.31)	-3.0 (3.77)
Adiponectin: Change at Week 12	2.8 (6.38)	2.8 (5.51)

10. Secondary Outcome

Title	Correlation Between Change From Baseline in Circulating Levels of Cytokines (Leptin, Resistin and Adiponectin) and in Flu Like Symptom (FLS) Score at Week 12
Description	Correlation was assessed by using Pearson correlation coefficient. The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to MS medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	77	70
Leptin and FLS: Change at Week 12	0.08822	0.03944
Resistin and FLS: Change at Week 12	-0.20200	-0.01069
Adiponectin and FLS: Change at Week 12	0.04616	-0.13571

11. Secondary Outcome

Title	Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Other MSTCQ Items, HADS, FSS, PSQI and MusiQOL Scores at Week 12
Description	Correlation was assessed by using Pearson correlation coefficient. MSTCQ, HADS, FSS, PSQI and MusiQOL are described in the above endpoints. Following abbreviations used in the categories: Global side-effects (GLOBSE); description of pain (PAINDESCR).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	85	77
Leptin and MSTCQ-ISR: Week 12	0.00595	-0.10214
Resistin and MSTCQ-ISR: Week 12	-0.22380	0.04855
Adiponectin and MSTCQ-ISR: Week 12	-0.13365	-0.14865
Leptin and MSTCQ-GLOBSE: Week 12	0.03121	0.21425
Resistin and MSTCQ-GLOBSE: Week 12	0.20285	-0.12730
Adiponectin and MSTCQ-GLOBSE: Week 12	0.00169	-0.06398
Leptin and MSTCQ-benefits: Week 12	0.13023	-0.10915
Resistin and MSTCQ-benefits: Week 12	-0.13544	-0.15636
Adiponectin and MSTCQ-benefits: Week 12	0.10726	0.04081
Leptin and MSTCQ-PAINDESCR: Week 12	0.09118	0.01165
Resistin and MSTCQ-PAINDESCR: Week 12	-0.13918	0.04150
Adiponectin and MSTCQ-PAINDESCR: Week12	0.07093	0.01535
Leptin and MSTCQ-VAS: Week 12	0.34840	-0.01433
Resistin and MSTCQ-VAS: Week 12	-0.15231	0.16220
Adiponectin and MSTCQ-VAS: Week 12	-0.07840	0.02109
Leptin and MSTCQ-pain rating: Week 12	0.16675	-0.14381
Resistin and MSTCQ-pain rating: Week 12	-0.23531	0.12355
Adiponectin and MSTCQ-pain rating: Week12	-0.08060	-0.08718
Leptin and HADS-anxiety: Week 12	0.00754	-0.06360
Resistin and HADS-anxiety: Week 12	0.02447	0.07986
Adiponectin and HADS-anxiety: Week 12	0.06295	0.08818
Leptin and HADS-depression: Week 12	0.05226	-0.14953
Resistin and HADS-depression: Week 12	0.01970	-0.04154
Adiponectin and HADS-depression: Week 12	0.03228	0.19209
Leptin and FSS: Week 12	0.04256	0.14284
Resistin and FSS: Week 12	-0.23755	-0.10961
Adiponectin and FSS: Week 12	-0.00326	0.03090
Leptin and PSQI: Week 12	0.00873	0.00099
Resistin and PSQI: Week 12	-0.03765	0.12085
Adiponectin and PSQI: Week 12	0.25795	0.24406
Leptin and MusiQoL- Global: Week 12	-0.25650	0.17917
Resistin and MusiQoL-Global: Week 12	0.12190	0.21936
Adiponectin and MusiQoL-Global: Week 12	0.07152	-0.05924

12. Secondary Outcome

Title	Change From Baseline in Cytokines (Leptin and Resistin) Levels at Week 12
Description	Results are presented for cytokines: leptin and resistin.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The Sub study Analysis Set (SSAS) included all subjects in the ITT who were enrolled in the sub study. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	8	7
Leptin: Change at Week 12	-2.7826	-0.7936
Resistin: Change at Week 12	-3.6628	-5.8360

13. Secondary Outcome

Title	Change From Baseline in Cytokine (Adiponectin) Level at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The SSAS included all subjects in the ITT who were enrolled in the sub study. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	8	7
Least Squares Mean (95% Confidence Interval) [microgram per milliliter (mcg/mL)]	2.7093	4.3574

14. Secondary Outcome

Title	Change From Baseline in Hormone-Like Cytokine (Interleukin-6, 10 and 12) Levels at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The SSAS included all subjects in the ITT who were enrolled in the sub study. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	8	7
Interleukin-6: Change at Week 12	-0.5173	-0.6970
Interleukin-10: Change at Week 12	-0.05819	-0.6660
Interleukin-12: Change at Week 12	-0.3490	-0.4384

15. Secondary Outcome

Title	Change From Baseline in Total Sleep Time (TST) and Rapid Eye Movement (REM) Sleep Time at Week 12
Description	Polysomnography (PSG) was performed for subjects who participated in the sub study. PSG is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. Total sleep time is the total of all REM and non-REM sleep in a sleep episode.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The SSAS included all subjects in the ITT who were enrolled in the sub study. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	7	6
Total Sleep Time: Change at Week 12	10.0	33.0
REM sleep: Change at Week 12	-3.0	6.0

16. Secondary Outcome

Title	Correlation Between Change From Baseline in Cytokines (Leptin, Resistin and Adiponectin) and Hormone-like Cytokine Levels (Interleukin-6, 10 and 12), and TST and REM Sleep Time at Week 12
Description	Correlations between change from baseline at Week 12 in TST or REM sleep and the area under the curve (AUC) calculated using the trapezoidal method for cytokine levels (i.e., leptin, resistin, adiponectin, Interleukin (IL)-12, IL 10, and IL 6) were analyzed using Pearson's correlation coefficient. Polysomnography (PSG) was performed for subjects who participated in the sub study.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

The SSAS included all subjects in the ITT who were enrolled in the sub study. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	7	6
AUC Leptin and TST: Week 12	0.10816	0.46984
AUC Resistin and TST: Week 12	-0.56278	-0.05056
AUC Adiponectin and TST: Week 12	0.17402	0.58181
AUC IL-12 and TST: Week 12	-0.44328	0.24717
AUC IL-10 and TST: Week 12	1.00000	NA
AUC IL-6 and TST: Week 12	0.18626	-0.51662
AUC Leptin and REM: Week 12	0.99732	0.63155
AUC Resistin and REM: Week 12	0.22684	-0.38234
AUC Adiponectin and REM: Week 12	0.98335	-0.05732
AUC IL-12 and REM: Week 12	1.00000	-0.76606
AUC IL-10 and REM: Week 12	-1.00000	NA
AUC IL-6 and REM: Week 12	0.06269	-0.34860

17. Secondary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation
Description	An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set (SAF) included all subjects in the ITT who received at least 1 dose of the planned study treatment.

Arm/Group Title	Rebif Morning Administration	Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.	Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
Measure Participants	104	96
TEAEs	82	77
Serious TEAEs	1	2
TEAEs Leading to Death	0	0
TEAE leading to Discontinuation	6	3

Adverse Events

Time Frame	Baseline up to Week 12
Arm/Group Title	Rebif Morning Administration		Rebif Evening Administration
Arm/Group Description	Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.		Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
All Cause Mortality
	Rebif Morning Administration		Rebif Evening Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rebif Morning Administration		Rebif Evening Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/104 (1%)		2/96 (2.1%)
General disorders
Influenza Like Illness	1/104 (1%)		0/96 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	0/104 (0%)		1/96 (1%)
Vascular disorders
Deep Vein Thrombosis	0/104 (0%)		1/96 (1%)
Other (Not Including Serious) Adverse Events
	Rebif Morning Administration		Rebif Evening Administration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/104 (74%)		70/96 (72.9%)
Gastrointestinal disorders
Nausea	10/104 (9.6%)		2/96 (2.1%)
General disorders
Influenza Like Illness	52/104 (50%)		42/96 (43.8%)
Pyrexia	15/104 (14.4%)		11/96 (11.5%)
Injection Site Erythema	14/104 (13.5%)		8/96 (8.3%)
Fatigue	9/104 (8.7%)		2/96 (2.1%)
Asthenia	7/104 (6.7%)		4/96 (4.2%)
Injection Site Pain	5/104 (4.8%)		5/96 (5.2%)
Investigations
Alanine Aminotransferase Increased	4/104 (3.8%)		7/96 (7.3%)
Aspartate Aminotransferase Increased	4/104 (3.8%)		5/96 (5.2%)
Transaminases Increased	4/104 (3.8%)		6/96 (6.3%)
Musculoskeletal and connective tissue disorders
Myalgia	10/104 (9.6%)		6/96 (6.3%)
Arthralgia	5/104 (4.8%)		7/96 (7.3%)
Pain In Extremity	4/104 (3.8%)		6/96 (6.3%)
Nervous system disorders
Headache	23/104 (22.1%)		16/96 (16.7%)
Multiple Sclerosis Relapse	3/104 (2.9%)		7/96 (7.3%)
Psychiatric disorders
Insomnia	2/104 (1.9%)		9/96 (9.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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