RebiQoL: Rebif New Formulation (RNF) Quality of Life (QOL) Study

• Sponsor: EMD Serono (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00472797
• Collaborator: (none)
• Enrollment: 232
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 7.5

Study Details

Study Description

Brief Summary

To evaluate the impact on Quality of Life (QOL), tolerability, treatment satisfaction, and injection site redness Rebif treated subjects with relapsing forms of MS who transition to a new formulation of Rebif (RNF).

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis	Drug: Rebif New Formulation Non Titrated; Drug: Rebif New Formulation Titrated	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 232 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Randomized, Multicenter, Two-arm, 12 Week Phase IIIb Study to Evaluate Quality of Life (QOL) Measures in Subjects With Relapsing Forms of Multiple Sclerosis (MS) Who Are Transitioning From Rebif® (Interferon Beta-1a) to Rebif New Formulation (RNF)
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Rebif New Formulation - Non Titrated	Drug: Rebif New Formulation Non Titrated; human interferon beta 1a - Rebif New Formulation
Active Comparator: 2 Rebif New Formulation - Titrated	Drug: Rebif New Formulation Titrated; Human interferon beta 1a Rebif New Formulation

Outcome Measures

Primary Outcome Measures

1. Percent Change in Global Side Effects (GSE) on Multiple Sclerosis Treatment Concerns Quesionnaire (MSTCQ) [% change from Baseline to Week 12]

   The MSTCQ Global Side Effect domain assesses the degree of satisfaction on global side effect questions 9, 10 & 11 on a scale from 3 (not at all satisfied) to 15 (extremely satisfied). Percent change calculated as 100% * (score at week 12 - score at baseline) / score at baseline.

Secondary Outcome Measures

1. Total Score for Global Side Effects on Multiple Sclerosis Treatment Concerns Questionnaire (MSTCQ) [Baseline and Week 12]

   The MSTCQ Global Side Effect domain assesses the subjects degree of satisfaction on global side effect questions 9, 10 & 11 on a scale from 3 (not at all satisfied) to 15 (extremely satisfied).

2. Change in Score From Baseline to Week 12 for All Domains Other Than Global Side Effects on Multiple Sclerosis Treatment Concerns Questionnaire (MSTCQ) [Baseline to Week 12]

   The MSTCQ in all domains assesses quality of life. The score for all domains other than the Global Side Effect ranges from 17 (most favorable) to 85 (least favorable). Change calculated as (score at week 12 - score at baseline.

3. Total Score on Short-Form McGill Pain Questionnaire (SF-MPQ): Change in Baseline to Wk 12 [Baseline to Week 12]

   The SF-MPQ assesses Tolerability of Pain with 15 questions to evaluate the type and severity of pain experienced 60 minutes after an injection of study drug. Scores range from 0 (no pain) to 45 (severe pain).

4. Tolerability in Pain Using Visual Analog Scale (VAS) [Baseline to Week 12]

   The SF-MPQ included a visual analog scale, ranging from 0 to 100 mm, on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm). A rating of <5 mm was considered pain-free.

5. Tolerability - Redness at Injection Site [Baseline to Week 12 (LOCF)]

   Change in Baseline to Week 12 Last Observation Carried Forward(LOCF)- A blinded assessment of injection site redness was conducted by a health care professional (1-72 hours) after the most recent injection measuring redness at its widest diameter in mm. Diameter of Redness, lower is better.

Other Outcome Measures

1. SF-36 Physical and Mental Component Scores [Change from Baseline to Each Visit]

   Change from Baseline to each visit for Physical and Mental Component scores for SF-36. Score is norm-based with a mean of 50 and a standard deviation of 10.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Subject with a relapsing form of MS; diagnosis of MS is in accordance with the McDonald criteria

2. Subject currently taking Rebif 44mcg tiw, and has been on this treatment for at least 6 months (24 weeks) prior to study enrollment

3. Subject currently using Rebiject II and 29 gauge needle

4. Subject is between 18 and 60 years old inclusive

5. Subject is able to read and understand English

6. Subject is willing to follow study procedures

7. Subject has given written informed consent and signed HIPAA

8. Female subjects must not be either pregnant or breast-feeding and must lack childbearing potential, as defined by either: i) Being post-menopausal or surgically sterile, or ii) Using a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide, for the duration of the study. (Confirmation required within 30 days prior to start of the study)

Exclusion Criteria:

1. Use of any other injectable medications on a regular basis during the week prior to the screening period or during the screening or treatment periods. Receiving a single injection for treatment or prophylaxis of a condition unrelated to the subject's multiple sclerosis or the subject's Rebif® therapy (e.g., receiving a influenza or pneumococcus vaccination) is acceptable

2. Subject receiving MS therapy in addition (i.e., combination therapy) to Rebif® within 3 months prior to study enrollment or at any time during study protocol.

3. Subjects who have previously been on Rebif New Formulation (RNF).

4. Subject with progressive forms of Multiple Sclerosis (MS).

5. Subject with history of any chronic pain syndrome.

6. Subject has any other disease apart from MS that could better explain the subjects signs and symptoms.

7. Subject has complete transverse myelitis or bilateral optic neuritis.

8. Subjects that use any investigational drug or experimental procedure within 12 weeks of visit 1.

9. Subject received oral or systemic corticosteroids or ACTH within 30 days of visit 1 (prior to enrollment).

10. Subject has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values.

11. Subject has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 x lower limit of normal.

12. Subject suffers from other current autoimmune disease.

13. Subject suffers from major medical or psychiatric illness that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol

14. Subject is pregnant or attempting to conceive

15. Visual or physical impairment that precludes completion of diaries and questionnaires.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	EMD Serono, Inc.	Rockland	Massachusetts	United States	02370

Sponsors and Collaborators

• EMD Serono

Investigators

• Study Director: Fernando Dangond, MD, EMD Serono

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Full FDA approved prescribing information can be found here

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00472797
• Other Study ID Numbers: 27955
• First Posted: May 14, 2007
• Last Update Posted: Aug 7, 2013
• Last Verified: Aug 1, 2013

• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis; Interferon beta-1a

Study Results

Participant Flow

Recruitment Details	232 subjects were recruited from 25 Multiple Sclerosis (MS) Clinics in the US from April 2007 through November 2007.
Pre-assignment Detail	Run-in period (up to 30 days) on Rebif® 44 mcg tiw: The run-in period included a Screening Visit; assessments consisted of informed consent, medical/disease history, physical exam and laboratory assessments which were performed in the two-week period prior to Study Day 1, (prior to the first dose of a new formulation of rebif)

Arm/Group Title	New Formulation of Rebif - Non-Titrated	New Formulation of Rebif - Titrated
Arm/Group Description	The new formulation of rebif is not approved and under investigation in the US	The new frmulation of rebif is not approved and under investigation in the US
Period Title: Overall Study
STARTED	119	113
COMPLETED	115	112
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	New Formulation of Rebif - Non-Titrated	New Formulation of Rebif - Titrated	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	119	113	232
Age (Count of Participants)
<=18 years	0 0%	0 0%	0.0 0%
Between 18 and 65 years	119 100%	113 100%	232.0 100%
>=65 years	0 0%	0 0%	0.0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.6 (9.0)	42.8 (9.4)	43.7 (9.2)
Sex: Female, Male (Count of Participants)
Female	91 76.5%	89 78.8%	180.0 77.6%
Male	28 23.5%	24 21.2%	52.0 22.4%
Region of Enrollment (participants) [Number]
United States	119 100%	113 100%	232.0 100%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Global Side Effects (GSE) on Multiple Sclerosis Treatment Concerns Quesionnaire (MSTCQ)
Description	The MSTCQ Global Side Effect domain assesses the degree of satisfaction on global side effect questions 9, 10 & 11 on a scale from 3 (not at all satisfied) to 15 (extremely satisfied). Percent change calculated as 100% * (score at week 12 - score at baseline) / score at baseline.
Time Frame	% change from Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Safety: This population includes all subjects who received at least one dose of study drug. To explain difference in number, 1 subject lost to follow-up, 1 subject withdrew consent

Arm/Group Title	All New Formulation of Rebif Subjects
Arm/Group Description	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	230
Mean (Standard Deviation) [percent change]	5.0 (17.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	A one-sided paired t-test across all subjects by combining the titrated and non-titrated new formulation groups was performed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-Value denotes percent change from baseline to week 12 for all combined subjects.
	Method	t-test, 1 sided
	Comments
Method of Estimation	Estimation Parameter	mean
	Estimated Value	2.73
	Confidence Interval	() 97.5%; 2.73 to 2.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Total Score for Global Side Effects on Multiple Sclerosis Treatment Concerns Questionnaire (MSTCQ)
Description	The MSTCQ Global Side Effect domain assesses the subjects degree of satisfaction on global side effect questions 9, 10 & 11 on a scale from 3 (not at all satisfied) to 15 (extremely satisfied).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) and Last Observation Carried Forward (LOCF) Higher scores indicate a more favorable response

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	117	113	230
Mean GSE at Baseline	13.4 (1.7)	13.4 (1.8)	13.4 (1.7)
Mean GSE at Week 12 (LOCF)	14.0 (1.6)	13.8 (1.6)	13.9 (1.6)
Percent Change - Baseline to Week 12 (LOCF)	5.5 (16.5)	4.5 (18.8)	5.0 (17.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects, Titrated
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.466
	Comments	P-value denotes difference between treatment groups
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value denotes the mean percent change from baseline to week 12.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Titrated
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	P-value denotes the mean percent change from baseline to week 12.
	Method	t-test, 1 sided
	Comments

3. Secondary Outcome

Title	Change in Score From Baseline to Week 12 for All Domains Other Than Global Side Effects on Multiple Sclerosis Treatment Concerns Questionnaire (MSTCQ)
Description	The MSTCQ in all domains assesses quality of life. The score for all domains other than the Global Side Effect ranges from 17 (most favorable) to 85 (least favorable). Change calculated as (score at week 12 - score at baseline.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	117	113	230
Injection System Satisfaction Domain	-3.2 (4.0)	-2.9 (4.1)	-3.1 (4.1)
Side Effects Domain	-3.3 (6.4)	-2.3 (5.7)	-2.8 (6.1)
Flu-Like Systems Domain	-0.9 (3.6)	-0.8 (3.6)	-0.8 (3.6)
Injection Site Reactions Domain	-1.9 (3.2)	-1.3 (2.9)	-1.6 (3.1)
Total Scores in all above Domains	-6.7 (8.8)	-5.3 (7.6)	-6.0 (8.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Change in total score from baseline to week 12 for all subjects combined. Lower scores indicate a more favorable response
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value refers to change in total score from baseline to week 12 for all domains, except global side effect score, in the MSTCQ for all subjects combined.
	Method	t-test, 1 sided
	Comments	Paired t-test for change from baseline to week 12

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects, Titrated
	Comments	Analysis evaluated differences between treatment groups in change in total score from baseline to week 12 for all domains, except global side effect score, in the MSTCQ. Lower scores indicate a more favorable response.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments	P-value refers to differences between treatment groups in change in total score from baseline to week 12 for all domains, except global side effect score, in the MSTCQ.
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Total Score on Short-Form McGill Pain Questionnaire (SF-MPQ): Change in Baseline to Wk 12
Description	The SF-MPQ assesses Tolerability of Pain with 15 questions to evaluate the type and severity of pain experienced 60 minutes after an injection of study drug. Scores range from 0 (no pain) to 45 (severe pain).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT and LOCF

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	117	113	229
Mean (Standard Deviation) [score on scale]	0.7 (3.4)	1.1 (3.9)	0.9 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects, Titrated
	Comments	Analysis evaluates total score from baseline to week 12 for differences between each treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.302
	Comments	P-value refers to differneces in total score from baseline to week 12 between treatment groups.
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Tolerability in Pain Using Visual Analog Scale (VAS)
Description	The SF-MPQ included a visual analog scale, ranging from 0 to 100 mm, on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm). A rating of <5 mm was considered pain-free.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	119	113	232
Baseline - No. of Subjects Pain Free	51 42.9%	48 42.5%	101 43.5%
Week 12 - No. of Subjects Pain Free	53 44.5%	48 42.5%	101 43.5%

6. Secondary Outcome

Title	Tolerability - Redness at Injection Site
Description	Change in Baseline to Week 12 Last Observation Carried Forward(LOCF)- A blinded assessment of injection site redness was conducted by a health care professional (1-72 hours) after the most recent injection measuring redness at its widest diameter in mm. Diameter of Redness, lower is better.
Time Frame	Baseline to Week 12 (LOCF)

Outcome Measure Data

Analysis Population Description

ITT and LOCF

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	114	110	224
Mean (Standard Deviation) [mm]	-2.3 (27.7)	-3.1 (28.2)	-2.7 (27.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects, Titrated
	Comments	Analysis evaluates differences between treatment groups in change in diameter of injection site redness from baseline to week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.899
	Comments	P-value denotes differences between treatment groups in change in diameter of injection site redness from baseline to week 12.
	Method	ANOVA
	Comments

7. Other Pre-specified Outcome

Title	SF-36 Physical and Mental Component Scores
Description	Change from Baseline to each visit for Physical and Mental Component scores for SF-36. Score is norm-based with a mean of 50 and a standard deviation of 10.
Time Frame	Change from Baseline to Each Visit

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Non-Titrated	Titrated	All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif	New formulation of rebif	All subjects combined in Intent to Treat (ITT) Population
Measure Participants	119	113	232
Physical Component Score - Baseline	43.4 (9.4)	43.6 (9.3)	43.5 (9.3)
Physical Component -Change from Baseline to Wk 12	1.8 (5.7)	2.0 (4.3)	1.9 (5.0)
Physical Component -Change from Baseline to Wk 36	-0.2 (7.7)	1.5 (6.0)	0.6 (7.0)
Physical Component -Baseline to Ext. Visit 1	2.0 (6.5)	1.7 (6.6)	1.9 (6.5)
Physical Component -Baseline to Ext Visit 3	1.0 (6.5)	2.0 (6.4)	1.5 (6.4)
Physical Component -Baseline to Exit Visit/LOCF	0.4 (6.4)	1.4 (6.4)	0.9 (6.4)
Mental Component - Baseline	46.1 (10.9)	46.1 (10.9)	46.1 (10.9)
Mental Component - Change from Baseline to Week 12	2.5 (8.7)	1.3 (9.1)	1.9 (8.9)
Mental Component - Change from Baseline to Week 36	1.8 (10.6)	-0.8 (10.0)	0.5 (10.4)
Mental Component - Baseline to Ext Visit 1	0.3 (10.7)	-1.2 (8.9)	-0.4 (9.8)
Mental Component - Baseline to Ext Visit 3	1.3 (11.2)	0.1 (10.4)	0.7 (10.8)
Mental Component - Baseline to Exit/LOCF	-0.1 (11.2)	0.1 (9.7)	0.0 (10.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Physical Component - Change from Baseline to Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Physical Component - Change from Baseline to Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.234
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Physical Component - Change from Baseline to Extension Visit 1
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Physical Component - Change from Baseline to Extension Visit 3
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Physical Component - Change from Baseline to Exisit Visit LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Mental Component - Baseline to Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Mental Component - Baseline to Week 36
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.468
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Mental Component - Change from Baseline to Extension Visit 1
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.602
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Change from Baseline to Extension Visit 3
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.414
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	All New Formulation of Rebif Subjects
	Comments	Change from Baseline to Exit Visit LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.991
	Comments
	Method	t-test, 2 sided
	Comments	Paired

Adverse Events

Arm/Group Title	Non-Titrated		Titrated		All New Formulation of Rebif Subjects
Arm/Group Description	New formulation of rebif		New formulation of rebif		All subjects combined in Intent to Treat (ITT) Population
All Cause Mortality
	Non-Titrated		Titrated		All New Formulation of Rebif Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Non-Titrated		Titrated		All New Formulation of Rebif Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/118 (8.5%)		6/113 (5.3%)		16/231 (6.9%)
Cardiac disorders
Artrial fibrillation	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Cardiomiopathy	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Coronary artery disease	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Endocrine disorders
Thyrotoxic crisis	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Gastrointestinal disorders
Retroperitoneal haematoma	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Hepatobiliary disorders
Cholecystitis	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Infections and infestations
Sinusitis	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Injury, poisoning and procedural complications
Facial bones fracture	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Fall	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Femur fracture	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Metabolism and nutrition disorders
Dehydration	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Osteoarthritis	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangiopericytoma	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Renal and urinary disorders
Renal Artery Fibromuscular Dysplasia	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Reproductive system and breast disorders
Menorrhagia	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Skin and subcutaneous tissue disorders
Cellulitis	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Social circumstances
Suicidal ideation	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Vascular disorders
Deep vein thrombosis	1/118 (0.8%)	1	0/113 (0%)	0	1/1 (100%)	1
Secondary Hypertension	0/118 (0%)	0	1/113 (0.9%)	1	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	Non-Titrated		Titrated		All New Formulation of Rebif Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/118 (76.3%)		78/113 (69%)		168/231 (72.7%)
General disorders
Chills	9/118 (7.6%)	9	4/113 (3.5%)	4	13/231 (5.6%)	13
Influenza-like Illness	11/118 (9.3%)	11	9/113 (8%)	9	20/231 (8.7%)	20
Pain	20/118 (16.9%)	20	16/113 (14.2%)	16	36/231 (15.6%)	36
Musculoskeletal and connective tissue disorders
Myalgia	13/118 (11%)	13	1/113 (0.9%)	1	14/231 (6.1%)	14
Nervous system disorders
Headache	38/118 (32.2%)	38	28/113 (24.8%)	28	66/231 (28.6%)	66
Renal and urinary disorders
Urinary tract infection	6/118 (5.1%)	6	9/113 (8%)	9	15/231 (6.5%)	15
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	9/118 (7.6%)	9	9/113 (8%)	9	18/231 (7.8%)	18
Upper Respiratory Tract Infection	8/118 (6.8%)	8	4/113 (3.5%)	4	12/231 (5.2%)	12

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Neither Institution nor any Principal Investigators shall publish or present any results from such Study to any third parties until: (i) EMD Serono publishes the results from all sites participating in such Study; (ii) Institution receives notification from EMD Serono that publication of the multi-site results is no longer planned; or (iii) twenty-four (24) months following the completion of the multi-site study at all sites, whichever occurs first.