Efficacy and Safety of Oral BG00012 in Relapsing-Remitting Multiple Sclerosis (DEFINE)

• ClinicalTrials.gov Identifier: NCT00420212
• Recruitment Status: Completed
• First Posted: January 11, 2007
• Results First Posted: June 2, 2014
• Last Update Posted: January 26, 2015
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Relapsing-Remitting Multiple Sclerosis
• Interventions: Drug: BG00012; Drug: Placebo
• Enrollment: 1234

Participant Flow

Recruitment Details	Subjects were screened and enrolled at 198 investigational sites in 28 countries.
Pre-assignment Details	From screening, 1237 eligible subjects were equally randomized. Of these, 1234 subjects received at least one dose of study treatment and comprised the intent-to-treat (ITT) and safety populations.

Arm/Group Title	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)
Arm/Group Description	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Period Title: Overall Study
Started	408 [1]	410 [2]	416 [3]
Completed	317	315	320
Not Completed	91	95	96
Reason Not Completed
Adverse Event	22	40	36
Lost to Follow-up	9	11	11
Withdrawal by Subject	31	22	19
Physician Decision	4	4	3
Protocol Violation	4	4	8
Death	0	0	1
Other-Unspecified	21	14	18
[1] 408 participants were dosed; 410 participants were randomized; [2] 410 participants were dosed; 411 participants were randomized; [3] 416 participants were dosed; 416 participants were randomized

Baseline Characteristics

Arm/Group Title		Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)	Total
Arm/Group Description		Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)	Total of all reporting groups
Overall Number of Baseline Participants		408	410	416	1234
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		38.5 (9.14)	38.1 (9.11)	38.8 (8.85)	38.5 (9.03)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
	Female	306 75.0%	296 72.2%	306 73.6%	908 73.6%
	Male	102 25.0%	114 27.8%	110 26.4%	326 26.4%
Mean Expanded Disability Status Scale (EDSS) score [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		2.48 (1.241)	2.40 (1.290)	2.36 (1.188)	2.42 (1.240)
		[1] Measure Description: The EDSS scores range from 0.0 (normal exam) to 10.0 (death due to MS).
Mean number of relapses within the previous 3 years; Mean (Standard Deviation); Unit of measure: Number of relapses
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		2.5 (1.56)	2.5 (1.44)	2.4 (1.27)	2.5 (1.43)
Mean number of relapses within the past 12 months; Mean (Standard Deviation); Unit of measure: Number of relapses
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		1.3 (0.67)	1.3 (0.67)	1.3 (0.60)	1.3 (0.65)
Time since first multiple sclerosis (MS) diagnosis; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		5.8 (5.78)	5.6 (5.39)	5.1 (5.29)	5.5 (5.49)
Mean number of gadolinium (Gd) enhancing lesions [1]; Mean (Standard Deviation); Unit of measure: Number of Gd enhancing lesions
	Number Analyzed	408 participants	410 participants	416 participants	1234 participants
		1.6 (3.45)	1.2 (3.30)	1.2 (4.10)	1.4 (3.64)
		[1] Measure Description: This baseline measure could only be assessed in the magnetic resonance imaging (MRI) cohort. The MRI cohort included 540 intent-to-treat (ITT) subjects who were enrolled at sites that participated in the MRI portion of the study and who had MRI data (180 placebo, 176 BG00012 BID, 184 BG00012 TID). Sites could participate only if their MRI capability was validated by the independent MRI reading center. Approximately 95% of all subjects enrolled at MRI sites participated in the MRI portion of the study.

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects Relapsed
Description	A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurolgic evaluation committee. The proportion of subjects with a relapse was estimated using the Kaplan-Meier method, which was based on the time-to-first-relapse survival distribution.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analysis was based on the ITT population, defined as all subjects who were randomized and received at least 1 dose of study medication. Among subjects who switched to an alternative therapy for multiple sclerosis, all the data before the switch were used for the analysis. In all other subjects, all relapses were included in the analysis.

Arm/Group Title	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	408	410	416
Measure Type: Number; Unit of Measure: Proportion of subjects,confirmed relapse
	0.461	0.270	0.260

2. Secondary Outcome

Title	Number of New or Newly Enlarging T2 Hyperintense Lesions
Description	The number of new or newly enlarging T2 hyperintense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T2 lesion count were calculated from a negative binomial regression model adjusted for region and baselineT2 lesion volume
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Of the 540 subjects included in the MRI cohort, 469 subjects (165 placebo, 152 BG00012 BID, 152 BG00012 TID) had post-baseline T2 data and were included in the analysis. Missing data before the use of alternative MS medications and visits after patients switched to alternative MS medications were imputed with the use of a constant rate assumption.

Arm/Group Title	Placebo	BG00012 240 mg BID	BG00012 240 mg TID
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	165	152	152
Mean (95% Confidence Interval); Unit of Measure: Number of lesions
	17.0; (12.9 to 22.4)	2.6; (2.0 to 3.5)	4.4; (3.2 to 5.9)

3. Secondary Outcome

Title	Number of Gadolinium-enhancing T1-weighted Lesions
Description	The number of Gd-enhancing lesions was assessed using brain MRI scans following administration of gadolinium, a contrast agent. The mean number of Gd-enhancing lesions at 2 years was the average of the number of lesions at 2 years in a treatment group.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Of the 540 subjects included in the MRI cohort, 469 (165 placebo,152 BG00012 BID,152 BG00012 TID) had post-baseline Gd-enhancing lesion data & were included in the analysis. Missing data before the use of alternative MS medications & visits after patients switched to alternative MS medications were imputed with the use of a constant rate assumption

Arm/Group Title	Placebo	BG00012 240 mg BID	BG00012 240 mg TID
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	165	152	152
Mean (Standard Deviation); Unit of Measure: Number of lesions
	1.8 (4.15)	0.1 (0.63)	0.5 (1.73)

4. Secondary Outcome

Title	Number of Subjects With Gadolinium (Gd)-Enhancing Lesions
Description	Note: This outcome measure represents the categorical analysis for the previously listed secondary outcome measure "Number of Gadolinium-enhancing T1-weighted lesions"
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Of the 540 subjects included in the MRI cohort, 469 (165 placebo,152 BG00012 BID,152 BG00012 TID) had post-baseline Gd-enhancing lesion data & were included in the analysis. Missing data before the use of alternative MS medications & visits after patients switched to alternative MS medications were imputed with the use of a constant rate assumption

Arm/Group Title	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	165	152	152
Measure Type: Number; Unit of Measure: Number of subjects
0 lesions	103	142	130
1 lesion	16	8	10
2 lesions	13	1	2
3-4 lesions	15	0	3
>=5 lesions	18	1	7

5. Secondary Outcome

Title	Annualized Relapse Rate
Description	A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The adjusted annualized relapse rate was calculated from a negative binomial regression model, adjusted for baseline EDSS (≤ 2.0 vs. >2.0), age (<40 versus ≥40 years), region, and the number of relapses in the 1 year prior to enrollment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all subjects who were randomized and received at least 1 dose of study medication. Among subjects who switched to an alternative therapy for multiple sclerosis, all the data before the switch were used for the analysis. In all other subjects, all relapses were included in the analysis.

Arm/Group Title	Placebo	BG00012 240 mg BID	BG00012 240 mg TID
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	408	410	416
Mean (95% Confidence Interval); Unit of Measure: Relapses per year
	0.364; (0.303 to 0.436)	0.172; (0.138 to 0.214)	0.189; (0.153 to 0.234)

6. Secondary Outcome

Title	Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS)
Description	The EDSS is based on a standardized neurological examination and focuses on symptoms that commonly occur in MS. EDSS scores range from 0.0 (normal) to 10.0 (death due to MS). Disability progression was defined as ≥ 1.0 point increase in subjects with a baseline EDSS of ≥1.0, or a ≥1.5 point increase in subjects with a baseline EDSS = 0, and required that the increase from baseline was confirmed ≥12 weeks later. The proportion of subjects with confirmed (12-week) disability progression was estimated using the Kaplan-Meier method, which was based on the time-to-first-progression survival distribution.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the ITT population (all subjects who were randomized and received at least 1 dose of study medication) who had a baseline EDSS assessment. Analysis were based on all observed data. Onset of disability progression must begin before a subject switched to alternative MS medication.

Arm/Group Title	Placebo	BG00012 240 mg BID	BG00012 240 mg TID
Arm/Group Description:	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Number of Participants Analyzed	408	409	416
Measure Type: Number; Unit of Measure: Proportion of participants
	0.271	0.164	0.177

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	The safety population consisted of all subjects who received at least 1 dose of study treatment. Safety data were analyzed by actual treatment received. Among subjects who switched to an alternative therapy for MS, all the data before the switch were used for the analysis. In all other subjects, all data were included in the analysis.
Arm/Group Title	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)	Total BG00012
Arm/Group Description	Participants received two placebo capsules orally three times daily (TID)	Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	Participants received two 120 mg BG00012 capsules orally three times daily (TID)	Combined BG00012 240 mg twice daily (BID) dose group and BG00012 240 mg 3 times daily (TID) dose group
All-Cause Mortality
	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)	Total BG00012
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)	Total BG00012
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	86/408 (21.08%)	74/410 (18.05%)	65/416 (15.63%)	139/826 (16.83%)
Blood and lymphatic system disorders
Anaemia † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Microcytic Anaemia † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Cardiac disorders
Acute Coronary Syndrome † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Cardiac Failure † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Cardiac Failure Congestive † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Congenital, familial and genetic disorders
Hydrocele † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Ear and labyrinth disorders
Vertigo Positional † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Endocrine disorders
Goitre † 1	0/408 (0.00%)	1/410 (0.24%)	2/416 (0.48%)	2/826 (0.24%)
Endocrinopathy Diencephalic † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Gastrointestinal disorders
Gastritis † 1	0/408 (0.00%)	0/410 (0.00%)	3/416 (0.72%)	3/826 (0.36%)
Vomiting † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Abdominal Hernia † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Abdominal Pain Lower † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Constipation † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Gastrontestinal Disorder † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Hiatus Hernia † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Colitis † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Colitis Ulcerative † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Gastrointestinal Haemorrhage † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Peritoneal Haemorrhage † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
General disorders
Pyrexia † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Non-Cardiac Chest Pain † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Influenza Like Illness † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Pelvic Mass † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Hepatobiliary disorders
Cholelithiasis † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Hepatitis Cholestatic † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Immune system disorders
Hypersensitivity † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Anaphylactoid Reaction † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Infections and infestations
Gastroenteritis † 1	0/408 (0.00%)	4/410 (0.98%)	1/416 (0.24%)	5/826 (0.61%)
Pneumonia † 1	1/408 (0.25%)	2/410 (0.49%)	0/416 (0.00%)	2/826 (0.24%)
Sinusitis † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Viral Infection † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Appendicitis † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
H1N1 Influenza † 1	1/408 (0.25%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Influenza † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Peritonsillar Abscess † 1	0/408 (0.00%)	0/410 (0.00%)	0/416 (0.00%)	1/826 (0.12%)
Post Viral Fatigue Syndrome † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Urinary Tract Infection † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Vulval Abscess † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Anal Abscess † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Diarrhoea Infectious † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Nasopharyngitis † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Pelvic Inflammatory Disease † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Reiter's Syndrome † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Sepsis † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Tuberculosis Gastrointestinal † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Cellulitis † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Injury, poisoning and procedural complications
Road Traffic Accident † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Ankle Fracture † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Concussion † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Meniscus Lesion † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Postoperative Fever † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Procedural Hypotension † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Radius Fracture † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Traumatic Brain Injury † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Wrist Fracture † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Femoral Neck Fracture † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Tendon Rupture † 1	2/408 (0.49%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Tibia Fracture † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Investigations
Allergy Test † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Blood Glucose Increased † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Colonoscopy † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Investigation † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Medical Observation † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Hepatic Enzyme Increased † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Metabolism and nutrition disorders
Hypoglycaemia † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Musculoskeletal and connective tissue disorders
Back Pain † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Sjogren's Syndrome † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Osteoarthritis † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Polyarthritis † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Synovial Cyst † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign Lung Neoplasm † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Breast Cancer † 1	1/408 (0.25%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Cervix Carcinoma † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Neurilemmoma † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Transitional Cell Carcinoma † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Uterine Leiomyoma † 1	2/408 (0.49%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Basal Cell Carcinoma † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Haemangioma † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Nervous system disorders
Multiple Sclerosis Relapse † 1	60/408 (14.71%)	39/410 (9.51%)	32/416 (7.69%)	71/826 (8.60%)
Headache † 1	0/408 (0.00%)	0/410 (0.00%)	2/416 (0.48%)	2/826 (0.24%)
Neurological Symptom † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Altered State of Conciousness † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Epilepsy † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Glossopharyngeal Neuralgia † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Ischaemic Stroke † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Multiple Sclerosis † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Transient Global Amnesia † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Transient Ischaemic Attack † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Transverse Sinus Thrombosis † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Viith Nerve Paralysis † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Convulsion † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Encephalopathy † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Grand Mal Convulsion † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Loss of Conciousness † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Migraine † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Restless Legs Syndrome † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Psychiatric disorders
Adjustment Disorder with Depressed Mood † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Depression † 1	2/408 (0.49%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Generalized Anxiety Disorder † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Mania † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Narcissistic Personality Disorder † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Suicidal Ideation † 1	1/408 (0.25%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Renal and urinary disorders
Renal Colic † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Ureterocele † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Reproductive system and breast disorders
Ovarian Cyst † 1	1/408 (0.25%)	1/410 (0.24%)	2/416 (0.48%)	3/826 (0.36%)
Adenomyosis † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Endometriosis † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Ovarian Cyst Ruptured † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Menstrual Disorder † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Pelvic Pain † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Uterine Haemorrhage † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pleural Effusion † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Pneumonia Aspiration † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Skin and subcutaneous tissue disorders
Pruritus † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Stevens-Johnson Syndrome † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Dermatitis Allergic † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
Surgical and medical procedures
Female Sterilization † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Hysterectomy † 1	0/408 (0.00%)	1/410 (0.24%)	0/416 (0.00%)	1/826 (0.12%)
Venous Stent Insertion † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Vascular disorders
Flushing † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Varicose Vein † 1	0/408 (0.00%)	1/410 (0.24%)	1/416 (0.24%)	2/826 (0.24%)
Deep Vein Thrombosis † 1	0/408 (0.00%)	0/410 (0.00%)	1/416 (0.24%)	1/826 (0.12%)
Peripheral Ischaemia † 1	1/408 (0.25%)	0/410 (0.00%)	0/416 (0.00%)	0/826 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 13.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	BG00012 240 mg Twice Daily (BID)	BG00012 240 mg 3 Times Daily (TID)	Total BG00012
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	384/408 (94.12%)	394/410 (96.10%)	393/416 (94.47%)	787/826 (95.28%)
Ear and labyrinth disorders
VERTIGO † 1	15/408 (3.68%)	13/410 (3.17%)	29/416 (6.97%)	42/826 (5.08%)
Gastrointestinal disorders
DIARRHEA † 1	55/408 (13.48%)	62/410 (15.12%)	78/416 (18.75%)	140/826 (16.95%)
NAUSEA † 1	38/408 (9.31%)	53/410 (12.93%)	54/416 (12.98%)	107/826 (12.95%)
ABDOMINAL PAIN UPPER † 1	28/408 (6.86%)	40/410 (9.76%)	52/416 (12.50%)	92/826 (11.14%)
ABDOMINAL PAIN † 1	22/408 (5.39%)	46/410 (11.22%)	37/416 (8.89%)	83/826 (10.05%)
VOMITING † 1	24/408 (5.88%)	40/410 (9.76%)	29/416 (6.97%)	69/826 (8.35%)
DYSPEPSIA † 1	12/408 (2.94%)	23/410 (5.61%)	24/416 (5.77%)	47/826 (5.69%)
CONSTIPATION † 1	19/408 (4.66%)	14/410 (3.41%)	18/416 (4.33%)	32/826 (3.87%)
GASTROINTESTINAL DISORDER † 1	6/408 (1.47%)	9/410 (2.20%)	20/416 (4.81%)	29/826 (3.51%)
General disorders
FATIGUE † 1	54/408 (13.24%)	57/410 (13.90%)	63/416 (15.14%)	120/826 (14.53%)
PYREXIA † 1	21/408 (5.15%)	16/410 (3.90%)	18/416 (4.33%)	34/826 (4.12%)
Infections and infestations
NASOPHARYNGITIS † 1	101/408 (24.75%)	108/410 (26.34%)	109/416 (26.20%)	217/826 (26.27%)
UPPER RESPIRATORY TRACT INFECTION † 1	53/408 (12.99%)	63/410 (15.37%)	51/416 (12.26%)	114/826 (13.80%)
URINARY TRACT INFECTION † 1	53/408 (12.99%)	55/410 (13.41%)	54/416 (12.98%)	109/826 (13.20%)
INFLUENZA † 1	39/408 (9.56%)	34/410 (8.29%)	48/416 (11.54%)	82/826 (9.93%)
SINUSITIS † 1	20/408 (4.90%)	17/410 (4.15%)	34/416 (8.17%)	51/826 (6.17%)
BRONCHITIS † 1	18/408 (4.41%)	21/410 (5.12%)	26/416 (6.25%)	47/826 (5.69%)
GASTROENTERITIS † 1	21/408 (5.15%)	26/410 (6.34%)	20/416 (4.81%)	46/826 (5.57%)
RHINITIS † 1	19/408 (4.66%)	12/410 (2.93%)	16/416 (3.85%)	28/826 (3.39%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED † 1	13/408 (3.19%)	29/410 (7.07%)	27/416 (6.49%)	56/826 (6.78%)
ALBUMIN URINE PRESENT † 1	12/408 (2.94%)	24/410 (5.85%)	22/416 (5.29%)	46/826 (5.57%)
Musculoskeletal and connective tissue disorders
BACK PAIN † 1	57/408 (13.97%)	59/410 (14.39%)	46/416 (11.06%)	105/826 (12.71%)
ARTHRALGIA † 1	39/408 (9.56%)	46/410 (11.22%)	37/416 (8.89%)	83/826 (10.05%)
PAIN IN EXTREMITY † 1	29/408 (7.11%)	37/410 (9.02%)	29/416 (6.97%)	66/826 (7.99%)
MUSCLE SPASMS † 1	20/408 (4.90%)	13/410 (3.17%)	27/416 (6.49%)	40/826 (4.84%)
MUSCULAR WEAKNESS † 1	26/408 (6.37%)	12/410 (2.93%)	14/416 (3.37%)	26/826 (3.15%)
MUSCULOSKELETAL PAIN † 1	21/408 (5.15%)	11/410 (2.68%)	10/416 (2.40%)	21/826 (2.54%)
Nervous system disorders
MULTIPLE SCLEROSIS RELAPSE † 1	181/408 (44.36%)	109/410 (26.59%)	107/416 (25.72%)	216/826 (26.15%)
HEADACHE † 1	80/408 (19.61%)	81/410 (19.76%)	78/416 (18.75%)	159/826 (19.25%)
PARAESTHESIA † 1	38/408 (9.31%)	35/410 (8.54%)	38/416 (9.13%)	73/826 (8.84%)
HYPOAESTHESIA † 1	27/408 (6.62%)	20/410 (4.88%)	24/416 (5.77%)	44/826 (5.33%)
DIZZINESS † 1	23/408 (5.64%)	19/410 (4.63%)	22/416 (5.29%)	41/826 (4.96%)
Psychiatric disorders
DEPRESSION † 1	32/408 (7.84%)	29/410 (7.07%)	33/416 (7.93%)	62/826 (7.51%)
INSOMNIA † 1	19/408 (4.66%)	20/410 (4.88%)	20/416 (4.81%)	40/826 (4.84%)
Renal and urinary disorders
PROTEINURIA † 1	34/408 (8.33%)	38/410 (9.27%)	50/416 (12.02%)	88/826 (10.65%)
HAEMATURIA † 1	19/408 (4.66%)	26/410 (6.34%)	26/416 (6.25%)	52/826 (6.30%)
MICROALBUMINURIA † 1	11/408 (2.70%)	21/410 (5.12%)	17/416 (4.09%)	38/826 (4.60%)
Respiratory, thoracic and mediastinal disorders
OROPHARYNGEAL PAIN † 1	19/408 (4.66%)	25/410 (6.10%)	21/416 (5.05%)	46/826 (5.57%)
COUGH † 1	18/408 (4.41%)	22/410 (5.37%)	19/416 (4.57%)	41/826 (4.96%)
Skin and subcutaneous tissue disorders
PRURITIS † 1	19/408 (4.66%)	42/410 (10.24%)	33/416 (7.93%)	75/826 (9.08%)
RASH † 1	13/408 (3.19%)	34/410 (8.29%)	27/416 (6.49%)	61/826 (7.38%)
ERYTHEMA † 1	5/408 (1.23%)	20/410 (4.88%)	33/416 (7.93%)	53/826 (6.42%)
Vascular disorders
FLUSHING † 1	20/408 (4.90%)	153/410 (37.32%)	132/416 (31.73%)	285/826 (34.50%)
HOT FLUSH † 1	8/408 (1.96%)	31/410 (7.56%)	29/416 (6.97%)	60/826 (7.26%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (13.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The provisions of the agreements are subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.

Results Point of Contact

• Name/Title: Biogen Idec Study Medical Director
• Organization: Biogen Idec
• EMail: clinicaltrials@biogenidec.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gold R, Arnold DL, Bar-Or A, Fox RJ, Kappos L, Chen C, Parks B, Miller C. Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE. Ther Adv Neurol Disord. 2020 May 12;13:1756286420915005. doi: 10.1177/1756286420915005. eCollection 2020. Erratum In: Ther Adv Neurol Disord. 2020 Oct 21;13:1756286420968357.

Mehta D, Miller C, Arnold DL, Bame E, Bar-Or A, Gold R, Hanna J, Kappos L, Liu S, Matta A, Phillips JT, Robertson D, von Hehn CA, Campbell J, Spach K, Yang L, Fox RJ. Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice. Neurology. 2019 Apr 9;92(15):e1724-e1738. doi: 10.1212/WNL.0000000000007262. Epub 2019 Mar 27.

Fox RJ, Gold R, Phillips JT, Okwuokenye M, Zhang A, Marantz JL. Efficacy and Tolerability of Delayed-release Dimethyl Fumarate in Black, Hispanic, and Asian Patients with Relapsing-Remitting Multiple Sclerosis: Post Hoc Integrated Analysis of DEFINE and CONFIRM. Neurol Ther. 2017 Dec;6(2):175-187. doi: 10.1007/s40120-017-0077-5. Epub 2017 Aug 2.

Fernandez O, Giovannoni G, Fox RJ, Gold R, Phillips JT, Potts J, Okwuokenye M, Marantz JL. Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM. Clin Ther. 2017 Aug;39(8):1671-1679. doi: 10.1016/j.clinthera.2017.06.012. Epub 2017 Jul 25.

Fox RJ, Chan A, Zhang A, Xiao J, Levison D, Lewin JB, Edwards MR, Marantz JL. Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of multiple sclerosis. Curr Med Res Opin. 2017 Feb;33(2):175-183. doi: 10.1080/03007995.2016.1248380. Epub 2016 Nov 10.

Gold R, Giovannoni G, Phillips JT, Fox RJ, Zhang A, Marantz JL. Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies. Neurol Ther. 2016 Jun;5(1):45-57. doi: 10.1007/s40120-016-0042-8. Epub 2016 Mar 1.

Giovannoni G, Gold R, Fox RJ, Kappos L, Kita M, Yang M, Sarda SP, Zhang R, Viglietta V, Havrdova E. Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies. Clin Ther. 2015 Nov 1;37(11):2543-51. doi: 10.1016/j.clinthera.2015.09.011. Epub 2015 Oct 31.

Nakamura K, Brown RA, Narayanan S, Collins DL, Arnold DL; Alzheimer's Disease Neuroimaging Initiative. Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations. Neuroimage. 2015 Sep;118:126-32. doi: 10.1016/j.neuroimage.2015.05.077. Epub 2015 Jun 3.

Kita M, Fox RJ, Gold R, Giovannoni G, Phillips JT, Sarda SP, Kong J, Viglietta V, Sheikh SI, Okwuokenye M, Kappos L. Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. Clin Ther. 2014 Dec 1;36(12):1958-1971. doi: 10.1016/j.clinthera.2014.08.013. Epub 2014 Oct 12. Erratum In: Clin Ther. 2018 Mar 7;:

Fox RJ, Kita M, Cohan SL, Henson LJ, Zambrano J, Scannevin RH, O'Gorman J, Novas M, Dawson KT, Phillips JT. BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin. 2014 Feb;30(2):251-62. doi: 10.1185/03007995.2013.849236. Epub 2013 Oct 22.

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107. doi: 10.1056/NEJMoa1114287. Erratum In: N Engl J Med. 2012 Dec 13;367(24):2362.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT00420212
• Other Study ID Numbers: 109MS301
• First Submitted: January 8, 2007
• First Posted: January 11, 2007
• Results First Submitted: May 5, 2014
• Results First Posted: June 2, 2014
• Last Update Posted: January 26, 2015