REFORMS: RNF and Betaseron® Tolerability Study

• Sponsor: EMD Serono (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00428584
• Collaborator: Pfizer (Industry)
• Enrollment: 129
• Location: 1
• Arms: 2
• Duration (Months): 33
• Patients Per Site Per Month: 3.9

Study Details

Study Description

Brief Summary

To evaluate the tolerability of a new formulation of rebif and Betaseron in subjects with relapsing-remitting multiple sclerosis (RRMS) by comparing the mean change in injection site pain scores from pre-injection to 30 minutes post therapy administration.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Remitting Multiple Sclerosis (RRMS)	Drug: New Formulation of rebif - human interferon beta-1a; Drug: Interferon beta -1b	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 129 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Two Arm, Open Label, Twelve Week Phase IIIb Study to Evaluate the Tolerability of Rebif (New Formulation) (IFN Beta-1a) and Betaseron (IFN Beta-1b) in IFN-naive Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) Followed by a Single Arm, Eighty-two Week Minimum, Rebif (New Formulation) Only Safety Extension
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 interferon beta-1a	Drug: New Formulation of rebif - human interferon beta-1a; New Formulation of rebif- 44 mcg, SC (sub-cutaneous) thrice weekly (tiw) injection.
Active Comparator: 2 interferon beta-1b	Drug: Interferon beta -1b; Betaseron - 250 mcg, SC (sub-cutaneous) every other day injection.

Outcome Measures

Primary Outcome Measures

1. Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints [From pre-injection to 30 minutes post injection of the VAS pain scores across the first 21 injections of full dose therapy of a new formulation of rebif and Betaseron]

   Subject reported perception of pain on the VAS where the slash drawn by the patient represents pain of increasing intensity from 0 (no pain) to 100 (worse possible pain), measured in millimeters. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 30 minutes post-injection

Secondary Outcome Measures

1. Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints [Pre-Injection to Immediately after Injection]

   A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.

2. Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints [Pre-injection to 10 minutes post-injection]

   A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 10 minutes post injection.

3. Number of Pain Free Patients at 30 Minutes Post-injection [30 minutes post injection]

   A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Pain-free was defined as a VAS score of 0 for all 21 full-dose injections for the Intent-to-Treat (ITT) population.

4. Diameter of Injection Site Redness [1-72 hours post injection over the first 12 weeks including the titration period]

   Blinded assessment of mean change in diameter of redness (in mm) at an injection site following an injection

Other Outcome Measures

1. Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints [Pre-injection and immediately after injection]

   A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.

2. Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection [Pre-injection and 10 minutes post injection]

3. Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection [Pain free patients at 30 minutes post injection]

4. Secondary Outcome - Extension Phase: Diameter in Injection Site Redness [1 to 72 hours post injection]

5. Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection [Pre-injection and 30 minutes post injection]

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 diagnosis of RRMS according to McDonald criteria or Poser

2. Subject is between 18 and 60 years old inclusive

3. Subject is willing to follow study procedures

4. Subject has given written informed consent

5. Female subjects must be neither pregnant nor breast-feeding and must lack childbearing potential, as defined by either:

• Being post-menopausal or surgically sterile, or

• Using a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide, for the duration of the study.

Exclusion Criteria:

1. Subject has Clinically Isolated Syndrome (CIS), Primary Progressive MS, or Secondary Progressive MS without superimposed relapses.

2. Subject has had any prior interferon beta therapy (either beta-1b or beta-1a) prior to study Day 1.

3. Subject received any other approved disease modifying therapy for MS (glatiramer acetate) or any cytokine or anti-cytokine therapy within the 3 months prior to Study Day 1.

4. Subject received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, mitoxantrone, teriflunomide, natalizumab, laquinimod, Campath and cladribine) within the 12 months prior to Study Day 1.

5. Subject had prior use of Cladribine or has previously received total lymphoid irradiation.

6. Subject has known allergy to natural or recombinant interferon or any other component of formulation excipient(s) of Rebif® or Betaseron®: Mannitol, Poloxamer 188, Methionine, Benzyl alcohol or Albumin (human).

7. 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® or Betaseron® therapy (e.g. receiving a influenza or pneumococcus vaccination) is acceptable.

8. History of any chronic pain syndrome.

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

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

11. Subjects who used any investigational drug or experimental procedure within 12 weeks prior to visit 1.

12. 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.

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

14. Subject suffers from current autoimmune disease (other than RRMS).

15. 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

16. Subject is pregnant or attempting to conceive

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

18. Subject received oral or systemic corticosteroids or ACTH within 30 days of visit 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	EMD Serono Med Info	Rockland	Massachusetts	United States	02370

Sponsors and Collaborators

• EMD Serono
• Pfizer

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: NCT00428584
• Other Study ID Numbers: 27133
• First Posted: Jan 30, 2007
• Last Update Posted: Aug 7, 2013
• Last Verified: Aug 1, 2013

• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferons; Interferon-beta; Interferon beta-1a

Study Results

Participant Flow

Recruitment Details	129 subjects were recruited from 27 Multiple Sclerosis (MS) Clinics in the US from December 2006 through August 2007.
Pre-assignment Detail	Subjects had a pre-study evaluation period (screening) within 14 days of Study Day 1 which consisted of informed consent, medical/disease history, physical exam and laboratory assessments.

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	The new formulation of rebif is not approved and under investigation in the US
Period Title: Comparative Phase
STARTED	65	64
COMPLETED	56	63
NOT COMPLETED	9	1
Period Title: Comparative Phase
STARTED	56	63
COMPLETED	35	34
NOT COMPLETED	21	29

Baseline Characteristics

Arm/Group Title	New Formulation of Rebif	Betaseron	Total
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day	Total of all reporting groups
Overall Participants	65	64	129
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.26 (9.80)	40.78 (9.56)	40.52 (9.68)
Sex: Female, Male (Count of Participants)
Female	46 70.8%	44 68.8%	90 69.8%
Male	19 29.2%	20 31.3%	39 30.2%
Region of Enrollment (participants) [Number]
United States	65 100%	64 100%	129 100%

Outcome Measures

1. Primary Outcome

Title	Visual Analog Scale (VAS) of Patient Reported Pain: Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 30 Minutes Post-injection Timepoints
Description	Subject reported perception of pain on the VAS where the slash drawn by the patient represents pain of increasing intensity from 0 (no pain) to 100 (worse possible pain), measured in millimeters. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 30 minutes post-injection
Time Frame	From pre-injection to 30 minutes post injection of the VAS pain scores across the first 21 injections of full dose therapy of a new formulation of rebif and Betaseron

Outcome Measure Data

Analysis Population Description

One subject from the new formulation of rebif group discontinued due to pregnancy therefore, data for the Full Dose Calculation 30min Mean Change was not calculated

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	64	64
Mean Pre-Injection VAS Score	0.43 (2.06)	0.40 (1.64)
Mean VAS at 30 minutes Post-Injection	1.10 (4.24)	1.54 (5.19)
Mean Change to 30 Minutes Post-Injection	0.67 (2.32)	1.14 (4.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	New Formulation of Rebif, Betaseron
	Comments	The primary efficacy endpoint was analyzed by using a two-way ANOVA model on ranked data including treatment group and site as fixed effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.524
	Comments	P value refers to mean change to 30 minute post injection
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and Immediately After Injection Timepoints
Description	A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.
Time Frame	Pre-Injection to Immediately after Injection

Outcome Measure Data

Analysis Population Description

One subject from the new formulation of rebif group discontinued due to pregnancy

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	64	64
Mean (Full Range) [millimeters]	1.46 (2.93)	4.63 (10.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	New Formulation of Rebif, Betaseron
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.484
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change in Mean VAS for the 21 Full-dose Injections at Pre-injection and 10 Minutes Post-injection Timepoints
Description	A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient 10 minutes post injection.
Time Frame	Pre-injection to 10 minutes post-injection

Outcome Measure Data

Analysis Population Description

One subject from the new formulation of Rebif group discontinued due to pregnancy

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	64	64
Mean (Full Range) [Millimeters]	0.70 (1.89)	1.89 (5.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	New Formulation of Rebif, Betaseron
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.838
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Number of Pain Free Patients at 30 Minutes Post-injection
Description	A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Pain-free was defined as a VAS score of 0 for all 21 full-dose injections for the Intent-to-Treat (ITT) population.
Time Frame	30 minutes post injection

Outcome Measure Data

Analysis Population Description

One subject from the new formulation of rebif group discontinued due to pregnancy

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	64	64
Number [Participants]	31 47.7%	28 43.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	New Formulation of Rebif, Betaseron
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.451
	Comments	No pain is defined as a VAS = 0 for all 21 full dose injections.
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Diameter of Injection Site Redness
Description	Blinded assessment of mean change in diameter of redness (in mm) at an injection site following an injection
Time Frame	1-72 hours post injection over the first 12 weeks including the titration period

Outcome Measure Data

Analysis Population Description

One subject from the new formulation of rebif group discontinued due to pregnancy

Arm/Group Title	New Formulation of Rebif	Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	64	64
Mean (Standard Deviation) [mm]	8.28 (9.51)	6.87 (7.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	New Formulation of Rebif, Betaseron
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments
	Method	ANOVA
	Comments

6. Other Pre-specified Outcome

Title	Secondary Outcome - Extension Phase: Change in Mean (mm) VAS for Pre-injection and Immediately After Injection Timepoints
Description	A visual analog scale (VAS) ranging from 0 to 100 mm on which subjects rate pain from no pain (0 mm) to worst possible pain (100 mm) was used. Mean VAS of 21 injections for each patient at pre-injection compared to mean VAS of 21 injections for each patient immediately after injection.
Time Frame	Pre-injection and immediately after injection

Outcome Measure Data

Analysis Population Description

3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase

Arm/Group Title	New Formulation of Rebif	Betaseron to New Formulation of Rebif
Arm/Group Description	Human interferon beta 1a, new formualation of rebif- 44 mcg, subcutaneous injection, three times a week	Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
Measure Participants	55	58
Mean (Full Range) [millimeters]	1.67	2.50

7. Other Pre-specified Outcome

Title	Secondary Outcome - Extension Phase: Change in Mean VAS at Pre-injection and 10 Minutes Post Injection
Time Frame	Pre-injection and 10 minutes post injection

Outcome Measure Data

Analysis Population Description

3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase

Arm/Group Title	New Formulation of Rebif	Betaseron to the New Formulation of Rebif
Arm/Group Description	Human interferon beta 1a, Rebif (New Formulation) 44 mcg, subcutaneous injection, three times a week
Measure Participants	55	58
Mean (Full Range) [Millimeters]	0.40	0.91

8. Other Pre-specified Outcome

Title	Secondary Outcome - Extension Phase: Number of Pain Free Patients at 30 Minutes Post Injection
Time Frame	Pain free patients at 30 minutes post injection

Outcome Measure Data

Analysis Population Description

3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase

Arm/Group Title	New Formulation of Rebif	Betaseron to the New Formulation of Rebif
Arm/Group Description	Human interferon beta 1a, Rebif (New Formulation) 44 mcg, subcutaneous injection, three times a week
Measure Participants	55	58
Number [Participants]	30 46.2%	36 56.3%

9. Other Pre-specified Outcome

Title	Secondary Outcome - Extension Phase: Diameter in Injection Site Redness
Time Frame	1 to 72 hours post injection

Outcome Measure Data

Analysis Population Description

3 subjects discontinued and withdrew consent from the Betaseron to Rebif New Formulation Group in the Extension Phase

Arm/Group Title	New Formulation of Rebif	Betaseron to the New Formulation of Rebif
Arm/Group Description	Human interferon beta 1a, Rebif (New Formulation) 44 mcg, subcutaneous injection, three times a week
Measure Participants	55	58
Mean (Standard Deviation) [Millimeters]	10.79 (13.89)	7.46 (10.57)

10. Other Pre-specified Outcome

Title	Primary Outcome - Extension Phase: Visual Analog Scale (VAS) of Patients Reported Pain; Change in Mean VAS at Pre-injection and 30 Minutes Post Injection
Time Frame	Pre-injection and 30 minutes post injection

Outcome Measure Data

Analysis Population Description

3 subjects discontinued and withdrew consent from the Betaseron to the new formulation of rebif group in the Extension Phase

Arm/Group Title	New Formulation of Rebif	Betaseron to the New Formulation of Rebif
Arm/Group Description	Human interferon beta 1a, Rebif (New Formulation) 44 mcg, subcutaneous injection, three times a week
Measure Participants	55	58
Mean (Full Range) [Millimeters]	0.34	0.42

Adverse Events

Arm/Group Title	New Formulation of Rebif		Betaseron
Arm/Group Description	Human interferon beta 1a, (new formulation of rebif) 44 mcg, subcutaneous injection, three times a week		Human interferon beta-1b, Betaseron 250 mcg, subcutaneous injection, every other day
All Cause Mortality
	New Formulation of Rebif		Betaseron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	New Formulation of Rebif		Betaseron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/65 (6.2%)		5/64 (7.8%)
Ear and labyrinth disorders
Vertigo	1/65 (1.5%)	1	0/64 (0%)	0
Gastrointestinal disorders
Intestinal Obstruction	0/65 (0%)	0	1/64 (1.6%)	1
Hepatobiliary disorders
Cholecystitis	1/65 (1.5%)	1	0/64 (0%)	0
Cholelithiasis / gallstones	0/65 (0%)	0	1/64 (1.6%)	1
Chronic Hepatits	1/65 (1.5%)	1	0/64 (0%)	0
Infections and infestations
Diverticulitis	0/65 (0%)	0	1/64 (1.6%)	1
Injury, poisoning and procedural complications
Accidental Overdose	1/65 (1.5%)	1	1/64 (1.6%)	1
Hip Fracture	0/65 (0%)	0	1/64 (1.6%)	1
Other (Not Including Serious) Adverse Events
	New Formulation of Rebif		Betaseron
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/65 (95.4%)		57/64 (89.1%)
Blood and lymphatic system disorders
Iron Defficiency Anamia	2/65 (3.1%)	2	0/64 (0%)	0
Leukopenia	3/65 (4.6%)	3	0/64 (0%)	0
Lymphopenia	1/65 (1.5%)	1	0/64 (0%)	0
Neutropenia	2/65 (3.1%)	2	1/64 (1.6%)	1
Platelet Disorder	1/65 (1.5%)	1	0/64 (0%)	0
Thrombocytopenia	1/65 (1.5%)	1	0/64 (0%)	0
Cardiac disorders
Coronary Artery Disease	1/65 (1.5%)	1	0/64 (0%)	0
Tachycardia	1/65 (1.5%)	1	1/64 (1.6%)	1
Ear and labyrinth disorders
Ear Pain	1/65 (1.5%)	1	1/64 (1.6%)	1
Eustachian Tube Obstruction	0/65 (0%)	0	1/64 (1.6%)	1
Middle Ear Effusion	1/65 (1.5%)	1	0/64 (0%)	0
Tinnitus	1/65 (1.5%)	1	3/64 (4.7%)	4
Vertigo	4/65 (6.2%)	4	3/64 (4.7%)	3
Endocrine disorders
Hypothyroidism	3/65 (4.6%)	3	1/64 (1.6%)	1
Eye disorders
Blepharospasm	1/65 (1.5%)	1	0/64 (0%)	0
Blindness	0/65 (0%)	0	1/64 (1.6%)	1
Cataract	0/65 (0%)	0	1/64 (1.6%)	1
Conjunctivitis	1/65 (1.5%)	1	0/64 (0%)	0
Eye Pain	1/65 (1.5%)	1	3/64 (4.7%)	3
Glaucoma	1/65 (1.5%)	1	0/64 (0%)	0
Halo Vision	1/65 (1.5%)	1	0/64 (0%)	0
Iritis	0/65 (0%)	0	1/64 (1.6%)	1
Vision Blurred	0/65 (0%)	0	2/64 (3.1%)	4
Visual Disturbance	1/65 (1.5%)	1	2/64 (3.1%)	2
Gastrointestinal disorders
Abdominal Discomfort	1/65 (1.5%)	1	0/64 (0%)	0
Abdominal Distension	1/65 (1.5%)	1	0/64 (0%)	0
Abdominal Pain	3/65 (4.6%)	4	0/64 (0%)	0
Abdominal Pain Lower	0/65 (0%)	0	1/64 (1.6%)	1
Abdominal PainUpper	4/65 (6.2%)	4	2/64 (3.1%)	2
Constipation	2/65 (3.1%)	2	5/64 (7.8%)	5
Dental Caries	1/65 (1.5%)	3	0/64 (0%)	0
Dental Discomfort	1/65 (1.5%)	1	0/64 (0%)	0
Diarrhoea	3/65 (4.6%)	3	7/64 (10.9%)	9
Dry Mouth	2/65 (3.1%)	4	0/64 (0%)	0
Dyspepsia	3/65 (4.6%)	3	1/64 (1.6%)	9
Flatulence	0/65 (0%)	0	1/64 (1.6%)	1
Gastritis	0/65 (0%)	0	2/64 (3.1%)	2
Gastrooesophageal Reflux Disease	0/65 (0%)	0	3/64 (4.7%)	3
Gingival Pain	0/65 (0%)	0	1/64 (1.6%)	1
Glossitis	0/65 (0%)	0	1/64 (1.6%)	1
Intestinal Obstruction	0/65 (0%)	0	1/64 (1.6%)	1
Lip Dry	0/65 (0%)	0	1/64 (1.6%)	1
Mouth Ulceration	0/65 (0%)	0	1/64 (1.6%)	1
Nausea	9/65 (13.8%)	22	5/64 (7.8%)	9
Stomach Discomfort	2/65 (3.1%)	3	1/64 (1.6%)	2
Tongue Ulceration	0/65 (0%)	0	1/64 (1.6%)	1
Tooth Disorder	1/65 (1.5%)	1	0/64 (0%)	0
Toothache	0/65 (0%)	0	2/64 (3.1%)	2
Vomiting	4/65 (6.2%)	6	0/64 (0%)	0
General disorders
General Disorders and Administration site condition	44/65 (67.7%)	236	45/64 (70.3%)	244
Hepatobiliary disorders
Cholecystitis	1/65 (1.5%)	1	0/64 (0%)	0
Cholelithiasis	2/65 (3.1%)	2	1/64 (1.6%)	1
Chronic Hepatitis	1/65 (1.5%)	1	0/64 (0%)	0
Immune system disorders
Anaphylactic Reaction	1/65 (1.5%)	1	0/64 (0%)	0
Drug Hypersensitivity	1/65 (1.5%)	1	0/64 (0%)	0
Hypersensitivity	1/65 (1.5%)	1	0/64 (0%)	0
Infections and infestations
Infections and Infestations	38/65 (58.5%)	98	33/64 (51.6%)	76
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	14/65 (21.5%)	35	10/64 (15.6%)	23
Investigations
Investigations	28/65 (43.1%)	58	15/64 (23.4%)	21
Metabolism and nutrition disorders
Metabolism and nutrition disorders	4/65 (6.2%)	4	5/64 (7.8%)	6
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	28/65 (43.1%)	61	27/64 (42.2%)	83
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	1/65 (1.5%)	1	0/64 (0%)	0
Nervous system disorders
Nervous system disorders	29/65 (44.6%)	150	29/64 (45.3%)	211
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/65 (1.5%)	1	0/64 (0%)	0
Psychiatric disorders
Phychiatric	16/65 (24.6%)	25	25/64 (39.1%)	36
Renal and urinary disorders
Renal Disorder	5/65 (7.7%)	5	4/64 (6.3%)	5
Reproductive system and breast disorders
Reproductive system and breast disorder	4/65 (6.2%)	4	4/64 (6.3%)	5
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorder	14/65 (21.5%)	26	13/64 (20.3%)	26
Skin and subcutaneous tissue disorders
Skin disorders	11/65 (16.9%)	16	11/64 (17.2%)	15
Vascular disorders
Vascular disorders	4/65 (6.2%)	4	3/64 (4.7%)	14

Limitations/Caveats

[Not Specified]

More Information

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.