Trial Outcomes & Findings for Efficacy and Safety of Oral BG00012 in Relapsing-Remitting Multiple Sclerosis (NCT NCT00420212)

NCT ID: NCT00420212

Last Updated: 2015-01-26

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1234 participants

Primary outcome timeframe

2 years

Results posted on

2015-01-26

Participant Flow

Subjects were screened and enrolled at 198 investigational sites in 28 countries.

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.

Participant milestones

Participant milestones
Measure	Placebo Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Study STARTED	408	410	416
Overall Study COMPLETED	317	315	320
Overall Study NOT COMPLETED	91	95	96

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Overall Study Adverse Event	22	40	36
Overall Study Lost to Follow-up	9	11	11
Overall Study Withdrawal by Subject	31	22	19
Overall Study Physician Decision	4	4	3
Overall Study Protocol Violation	4	4	8
Overall Study Death	0	0	1
Overall Study Other-Unspecified	21	14	18

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=408 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=410 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=416 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)	Total n=1234 Participants Total of all reporting groups
Age, Continuous	38.5 Years STANDARD_DEVIATION 9.14 • n=5 Participants	38.1 Years STANDARD_DEVIATION 9.11 • n=7 Participants	38.8 Years STANDARD_DEVIATION 8.85 • n=5 Participants	38.5 Years STANDARD_DEVIATION 9.03 • n=4 Participants
Sex: Female, Male Female	306 Participants n=5 Participants	296 Participants n=7 Participants	306 Participants n=5 Participants	908 Participants n=4 Participants
Sex: Female, Male Male	102 Participants n=5 Participants	114 Participants n=7 Participants	110 Participants n=5 Participants	326 Participants n=4 Participants
Mean Expanded Disability Status Scale (EDSS) score	2.48 units on a scale STANDARD_DEVIATION 1.241 • n=5 Participants	2.40 units on a scale STANDARD_DEVIATION 1.290 • n=7 Participants	2.36 units on a scale STANDARD_DEVIATION 1.188 • n=5 Participants	2.42 units on a scale STANDARD_DEVIATION 1.240 • n=4 Participants
Mean number of relapses within the previous 3 years	2.5 Number of relapses STANDARD_DEVIATION 1.56 • n=5 Participants	2.5 Number of relapses STANDARD_DEVIATION 1.44 • n=7 Participants	2.4 Number of relapses STANDARD_DEVIATION 1.27 • n=5 Participants	2.5 Number of relapses STANDARD_DEVIATION 1.43 • n=4 Participants
Mean number of relapses within the past 12 months	1.3 Number of relapses STANDARD_DEVIATION 0.67 • n=5 Participants	1.3 Number of relapses STANDARD_DEVIATION 0.67 • n=7 Participants	1.3 Number of relapses STANDARD_DEVIATION 0.60 • n=5 Participants	1.3 Number of relapses STANDARD_DEVIATION 0.65 • n=4 Participants
Time since first multiple sclerosis (MS) diagnosis	5.8 Years STANDARD_DEVIATION 5.78 • n=5 Participants	5.6 Years STANDARD_DEVIATION 5.39 • n=7 Participants	5.1 Years STANDARD_DEVIATION 5.29 • n=5 Participants	5.5 Years STANDARD_DEVIATION 5.49 • n=4 Participants
Mean number of gadolinium (Gd) enhancing lesions	1.6 Number of Gd enhancing lesions STANDARD_DEVIATION 3.45 • n=5 Participants	1.2 Number of Gd enhancing lesions STANDARD_DEVIATION 3.30 • n=7 Participants	1.2 Number of Gd enhancing lesions STANDARD_DEVIATION 4.10 • n=5 Participants	1.4 Number of Gd enhancing lesions STANDARD_DEVIATION 3.64 • n=4 Participants

PRIMARY outcome

Timeframe: 2 years

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo n=408 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=410 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=416 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Proportion of Subjects Relapsed	0.461 Proportion of subjects,confirmed relapse	0.270 Proportion of subjects,confirmed relapse	0.260 Proportion of subjects,confirmed relapse

SECONDARY outcome

Timeframe: 2 years

Population: 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.

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

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=152 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=152 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Number of New or Newly Enlarging T2 Hyperintense Lesions	17.0 Number of lesions Interval 12.9 to 22.4	2.6 Number of lesions Interval 2.0 to 3.5	4.4 Number of lesions Interval 3.2 to 5.9

SECONDARY outcome

Timeframe: 2 years

Population: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=152 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=152 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Number of Gadolinium-enhancing T1-weighted Lesions	1.8 Number of lesions Standard Deviation 4.15	0.1 Number of lesions Standard Deviation 0.63	0.5 Number of lesions Standard Deviation 1.73

SECONDARY outcome

Timeframe: 2 years

Note: This outcome measure represents the categorical analysis for the previously listed secondary outcome measure "Number of Gadolinium-enhancing T1-weighted lesions"

Outcome measures

Outcome measures
Measure	Placebo n=165 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=152 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=152 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Number of Subjects With Gadolinium (Gd)-Enhancing Lesions 0 lesions	103 Number of subjects	142 Number of subjects	130 Number of subjects
Number of Subjects With Gadolinium (Gd)-Enhancing Lesions 1 lesion	16 Number of subjects	8 Number of subjects	10 Number of subjects
Number of Subjects With Gadolinium (Gd)-Enhancing Lesions 2 lesions	13 Number of subjects	1 Number of subjects	2 Number of subjects
Number of Subjects With Gadolinium (Gd)-Enhancing Lesions 3-4 lesions	15 Number of subjects	0 Number of subjects	3 Number of subjects
Number of Subjects With Gadolinium (Gd)-Enhancing Lesions >=5 lesions	18 Number of subjects	1 Number of subjects	7 Number of subjects

SECONDARY outcome

Timeframe: 2 years

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=408 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=410 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=416 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Annualized Relapse Rate	0.364 Relapses per year Interval 0.303 to 0.436	0.172 Relapses per year Interval 0.138 to 0.214	0.189 Relapses per year Interval 0.153 to 0.234

SECONDARY outcome

Timeframe: 2 years

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=408 Participants Participants received two placebo capsules orally three times daily (TID)	BG00012 240 mg Twice Daily (BID) n=409 Participants Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)	BG00012 240 mg 3 Times Daily (TID) n=416 Participants Participants received two 120 mg BG00012 capsules orally three times daily (TID)
Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS)	0.271 Proportion of participants	0.164 Proportion of participants	0.177 Proportion of participants

Adverse Events

Placebo

Serious events: 86 serious events

Other events: 384 other events

Deaths: 0 deaths

BG00012 240 mg Twice Daily (BID)

Serious events: 74 serious events

Other events: 394 other events

Deaths: 0 deaths

BG00012 240 mg 3 Times Daily (TID)

Serious events: 65 serious events

Other events: 393 other events

Deaths: 0 deaths

Total BG00012

Serious events: 139 serious events

Other events: 787 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Idec Study Medical Director

Biogen Idec

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER