INSPIRE: BG00012 and Delay of Disability Progression in Secondary Progressive Multiple Sclerosis

• Sponsor: Biogen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02430532
• Collaborator: (none)
• Enrollment: 58
• Locations: 18
• Arms: 2
• Duration (Months): 8
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary objective of the study is to investigate whether treatment with BG00012 (dimethyl fumarate) compared with placebo slows the accumulation of disability not related to relapses in participants with secondary progressive multiple sclerosis (SPMS). The secondary objective of the study is to assess the effect of BG00012 compared with placebo on patient-reported outcomes, brain atrophy, and cognitive function.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Secondary Progressive	Drug: dimethyl fumarate; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of BG00012 in Delaying Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dimethyl fumarate BG00012 120 mg (1 BG00012 120 mg capsule + 1 matching placebo capsule) orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID thereafter.	Drug: dimethyl fumarate; capsule; Other Names: DMF BG00012 Tecfidera ; Other: Placebo; matched placebo capsule
Experimental: Placebo BG00012 120 mg capsule orally once a day supplemented with matching placebo capsules for the first 4 weeks of treatment, as an additional blinding measure. Matched placebo capsules only thereafter.	Drug: dimethyl fumarate; capsule; Other Names: DMF BG00012 Tecfidera ; Other: Placebo; matched placebo capsule

Outcome Measures

Primary Outcome Measures

1. Time to Disability Progression Independent of Relapse [Up to 108 weeks]

   Time to onset of confirmed progression of disability is defined as 1 or more of the following criteria, confirmed at ≥ 6 months after start of treatment and at Week 108 using 1 or more of the following assessments: Expanded Disability Status Scale (EDSS) score increased from Baseline of ≥ 1 point if baseline EDSS ≤ 5.5, or ≥ 0.5 point if Baseline EDSS ≥ 6.0; Timed 25-Foot Walk (T25FW) ≥ 20% increase from Baseline in the time taken for the 25-foot walk; worsening on the 9-Hole Peg Test (9HPT; ≥ 20% increase from Baseline in the time taken for the 9HPT, confirmed in the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs.

Secondary Outcome Measures

1. Change From Baseline to 2 Years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) [Baseline, 2 years]

   MSWS-12 is a participant self-assessment of walking limitations due to multiple sclerosis (MS) during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater negative impact on walking.

2. Change From Baseline to Week 108 in ABILHAND Questionnaire Score [Baseline, Week 108]

   The ABILHAND Questionnaire measures the participant's perceived difficulty in performing everyday manual activities in the last 3 months. Participants fill in the 56-item questionnaire by estimating their own difficulty or ease in performing each of the 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability.

3. Percentage Change From Baseline to Week 108 in Whole Brain Volume [Baseline, Week 108]

   Whole brain volume is measured by magnetic resonance imaging (MRI).

4. Change From Baseline to Week 108 in Cognitive Function as Measured by the Symbol Digit Modalities Test (SDMT) [Baseline, Week 108]

   The SDMT measures the time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items from 0-110 in 90 seconds. A higher score indicates a better outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 58 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Onset of SPMS at least 1 to 2 years prior to randomization. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by relapses.

• Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to randomization.

• Have an Expanded Disability Status Scale score of 3.0 to 6.5, inclusive.

• Have a Multiple Sclerosis (MS) Severity Score of 4 or higher.

Key Exclusion Criteria:

• Have a diagnosis of relapsing remitting multiple sclerosis or primary progressive MS as defined by the revised McDonald criteria.

• Had a recent clinical relapse (within 3 months) prior to randomization.

• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; serious or acute liver, kidney, or bone marrow dysfunction; uncontrolled diabetes; serious or acute psychiatric illness that would limit compliance with study requirements.

Note: Other protocol-defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Long Beach	California	United States	90806
2	Research Site	San Francisco	California	United States	94143
3	Research Site	Tampa	Florida	United States	33634
4	Research Site	Vero Beach	Florida	United States	32960
5	Research Site	Charlotte	North Carolina	United States	28207
6	Research Site	Willow Grove	Pennsylvania	United States	19001
7	Research Site	Round Rock	Texas	United States	78681
8	Research Site	Bruxelles		Belgium	1200
9	Research Site	Brno		Czech Republic	656 91
10	Research Site	Hradec Kralove		Czech Republic	500 05
11	Research Site	Sittard-Geleen		Netherlands	6162 BG
12	Research Site	Gdansk		Poland	80-803
13	Research Site	Katowice		Poland
14	Research Site	Krakow		Poland	31-505
15	Research Site	Lodz		Poland	93-121
16	Research Site	Plewiska		Poland	62-064
17	Research Site	Poznan		Poland	61-853
18	Research Site	Banska Bystrica		Slovakia	97404

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT02430532
• Other Study ID Numbers: 109MS308; 2014-003021-18
• First Posted: Apr 30, 2015
• Last Update Posted: Apr 26, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Biogen: INSPIRE; SPMS; Tecfidera; BG00012
• Additional relevant MeSH terms: Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Dimethyl Fumarate

Study Results

Participant Flow

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Period Title: Overall Study
STARTED	30	28
COMPLETED	0	0
NOT COMPLETED	30	28

Baseline Characteristics

Arm/Group Title	Placebo	Tecfidera 240 mg BID	Total
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.	Total of all reporting groups
Overall Participants	30	28	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.7 (6.67)	49.6 (8.05)	50.2 (7.33)
Age, Customized (participants) [Number]
< 20 years	0 0%	0 0%	0 0%
20 to 29 years	0 0%	0 0%	0 0%
30 to 39 years	1 3.3%	4 14.3%	5 8.6%
40 to 49 years	10 33.3%	8 28.6%	18 31%
>= 50 years	19 63.3%	16 57.1%	35 60.3%
Sex: Female, Male (Count of Participants)
Female	19 63.3%	17 60.7%	36 62.1%
Male	11 36.7%	11 39.3%	22 37.9%

Outcome Measures

1. Primary Outcome

Title	Time to Disability Progression Independent of Relapse
Description	Time to onset of confirmed progression of disability is defined as 1 or more of the following criteria, confirmed at ≥ 6 months after start of treatment and at Week 108 using 1 or more of the following assessments: Expanded Disability Status Scale (EDSS) score increased from Baseline of ≥ 1 point if baseline EDSS ≤ 5.5, or ≥ 0.5 point if Baseline EDSS ≥ 6.0; Timed 25-Foot Walk (T25FW) ≥ 20% increase from Baseline in the time taken for the 25-foot walk; worsening on the 9-Hole Peg Test (9HPT; ≥ 20% increase from Baseline in the time taken for the 9HPT, confirmed in the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs.
Time Frame	Up to 108 weeks

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Measure Participants	0	0

2. Secondary Outcome

Title	Change From Baseline to 2 Years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12)
Description	MSWS-12 is a participant self-assessment of walking limitations due to multiple sclerosis (MS) during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater negative impact on walking.
Time Frame	Baseline, 2 years

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Measure Participants	0	0

3. Secondary Outcome

Title	Change From Baseline to Week 108 in ABILHAND Questionnaire Score
Description	The ABILHAND Questionnaire measures the participant's perceived difficulty in performing everyday manual activities in the last 3 months. Participants fill in the 56-item questionnaire by estimating their own difficulty or ease in performing each of the 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Measure Participants	0	0

4. Secondary Outcome

Title	Percentage Change From Baseline to Week 108 in Whole Brain Volume
Description	Whole brain volume is measured by magnetic resonance imaging (MRI).
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Measure Participants	0	0

5. Secondary Outcome

Title	Change From Baseline to Week 108 in Cognitive Function as Measured by the Symbol Digit Modalities Test (SDMT)
Description	The SDMT measures the time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items from 0-110 in 90 seconds. A higher score indicates a better outcome.
Time Frame	Baseline, Week 108

Outcome Measure Data

Analysis Population Description

The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.

Arm/Group Title	Placebo	Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.	BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
Measure Participants	0	0

Adverse Events

Time Frame	Up to approximately 24 weeks (overall mean time on study of 14.34, with an overall mean time on study treatment of 9.58 weeks).
Adverse Event Reporting Description	Data summaries of adverse events are descriptive in nature and the comparison between treatment groups might not be appropriate due to the small number of participants and limited study follow-up duration.
Arm/Group Title	Placebo		Tecfidera 240 mg BID
Arm/Group Description	BG00012 120 mg capsule orally QD supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.		BG00012 120 mg orally BID for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.
All Cause Mortality
	Placebo		Tecfidera 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tecfidera 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		5/28 (17.9%)
Gastrointestinal disorders
Enteritis	0/30 (0%)		1/28 (3.6%)
Injury, poisoning and procedural complications
Fall	0/30 (0%)		1/28 (3.6%)
Femur fracture	0/30 (0%)		1/28 (3.6%)
Nervous system disorders
Multiple sclerosis relapse	0/30 (0%)		1/28 (3.6%)
Trigeminal neuralgia	0/30 (0%)		1/28 (3.6%)
Renal and urinary disorders
Calculus ureteric	0/30 (0%)		1/28 (3.6%)
Nephrolithiasis	0/30 (0%)		1/28 (3.6%)
Renal colic	0/30 (0%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/30 (0%)		1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	Placebo		Tecfidera 240 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/30 (30%)		9/28 (32.1%)
Gastrointestinal disorders
Diarrhoea	0/30 (0%)		2/28 (7.1%)
Nausea	0/30 (0%)		2/28 (7.1%)
Vomiting	0/30 (0%)		2/28 (7.1%)
Infections and infestations
Upper respiratory tract infection	2/30 (6.7%)		0/28 (0%)
Urinary tract infection	3/30 (10%)		2/28 (7.1%)
Nervous system disorders
Multiple sclerosis relapse	0/30 (0%)		2/28 (7.1%)
Vascular disorders
Flushing	5/30 (16.7%)		5/28 (17.9%)

Limitations/Caveats

The study was terminated early by the sponsor for business reasons. Efficacy, patient-reported outcomes, and pharmacodynamic data were not analyzed.

More Information

Certain Agreements

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

Our agreement is 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 an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.