Trial Outcomes & Findings for Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) (NCT NCT01665144)

Last Updated: 2024-06-05

Results Overview

The EDSS uses an ordinal scale to assess neurologic impairment in MS based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel \& Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS). 3-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 3 months.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1651 participants

Primary outcome timeframe

Baseline, every 3 month up to the maximum of approximately 3 years

Results posted on

2024-06-05

Participant Flow

Participants took part in 294 investigative sites in 31 countries.

Core Part recruitment completed; eligible patients moved to Extension Part (EP) providing treatment up to additional 7 years. Projected full 7-year final visits for majority patients first quarter 2023. Novartis closed EP slightly earlier than planned (not based on safety issues) to accommodate changes in study operations at a point when objective to provide long-term safety/efficacy data in patients treated up to 7 years met. Consequently, EP considered completed.

Participant milestones

Participant milestones
Measure	Siponimod (BAF312) Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo Matching placebo to BAF312 was administered orally during the Core Part of the trial.	Placebo-BAF312 Participants who received placebo in the Core Part and switched to siponimod in the Extension Part.
Core Part STARTED	1105	546	0
Core Part Safety Set	1099	546	0
Core Part Full Analysis Set	1099	546	0
Core Part COMPLETED	903	424	0
Core Part NOT COMPLETED	202	122	0
Extension Part STARTED	821	0	399
Extension Part COMPLETED	326	0	159
Extension Part NOT COMPLETED	495	0	240

Reasons for withdrawal

Reasons for withdrawal
Measure	Siponimod (BAF312) Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo Matching placebo to BAF312 was administered orally during the Core Part of the trial.	Placebo-BAF312 Participants who received placebo in the Core Part and switched to siponimod in the Extension Part.
Core Part Withdrawal by Subject	96	77	0
Core Part Adverse Event	45	18	0
Core Part Lack of Efficacy	16	11	0
Core Part Lost to Follow-up	9	8	0
Core Part Physician Decision	13	1	0
Core Part Progressive disease	8	4	0
Core Part Non-compliance with study treatment	5	0	0
Core Part Death	3	1	0
Core Part Protocol deviation	3	1	0
Core Part New therapy for study indication	2	1	0
Core Part Technical problems	2	0	0
Extension Part Patient/guardian decision	180	0	98
Extension Part Adverse Event	104	0	59
Extension Part Study closed early	42	0	19
Extension Part Progressive disease	36	0	14
Extension Part Lack of Efficacy	37	0	12
Extension Part Physician Decision	29	0	13
Extension Part Technical problems	20	0	8
Extension Part Death	20	0	4
Extension Part Missing	12	0	6
Extension Part Lost to Follow-up	9	0	5
Extension Part New therapy for study indication	3	0	2
Extension Part Protocol deviation	3	0	0

Baseline Characteristics

Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Siponimod (BAF312) n=1105 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.	Total n=1651 Participants Total of all reporting groups
Age, Continuous	48.0 Years STANDARD_DEVIATION 7.84 • n=93 Participants	48.1 Years STANDARD_DEVIATION 7.94 • n=4 Participants	48.0 Years STANDARD_DEVIATION 7.87 • n=27 Participants
Sex: Female, Male Female	669 Participants n=93 Participants	323 Participants n=4 Participants	992 Participants n=27 Participants
Sex: Female, Male Male	436 Participants n=93 Participants	223 Participants n=4 Participants	659 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	31 Participants n=93 Participants	18 Participants n=4 Participants	49 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants	3 Participants n=4 Participants	10 Participants n=27 Participants
Race (NIH/OMB) White	1050 Participants n=93 Participants	513 Participants n=4 Participants	1563 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=93 Participants	12 Participants n=4 Participants	29 Participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline, every 3 month up to the maximum of approximately 3 years

Population: The Full analysis set (FAS), which comprised all randomized patients with assigned treatments who took at least one dose of study medication, was considered for the analysis. Only participants from the FAS with non-missing covariates were analyzed for this outcome.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1096 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=545 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percentage of Participants With 3-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)	26.3 Percentage of participants	31.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

The Timed 25-Foot Walk Test (T25W) measured the time, in seconds, to walk 25 feet (7.62 meters). A 3-month confirmed worsening of at least 20% from baseline in the T25W was defined as an increase from baseline sustained for at least 3 months. This outcome measure was analyzed using a Cox proportional hazards model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1087 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=543 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percentage of Participants With 3-month Confirmed Worsening in T25W of at Least 20% From Baseline	39.7 Percentage of participants	41.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing covariates for the model.

Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the total volume of T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The change from baseline in T2 lesion volume was analyzed using a mixed model for repeated measures (MMRM) with visit as a categorical factor and an unstructured covariance matrix and with adjustment for baseline covariates.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=995 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=495 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Change From Baseline in T2 Lesion Volume Month 12	204.9 mm^3 Standard Error 67.47	818.0 mm^3 Standard Error 87.29
Change From Baseline in T2 Lesion Volume Month 24	162.9 mm^3 Standard Error 73.90	940.4 mm^3 Standard Error 97.20
Change From Baseline in T2 Lesion Volume Average over Month 12 and Month 24	183.9 mm^3 Standard Error 66.33	879.2 mm^3 Standard Error 85.43

SECONDARY outcome

Timeframe: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

The EDSS uses an ordinal scale to assess neurologic impairment in multiple sclerosis (MS) based on a neurological examination. Scores in each of 7 functional systems (Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel \& Bladder, and Cerebral) and an ambulation score were combined to determine the EDSS steps, ranging from 0 (normal) to 10 (death due to MS). 6-month confirmed disability progression is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5 sustained for at least 6 months. This outcome measure was analyzed using a Cox proportional hazards model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1096 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=545 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percentage of Participants With 6-month Confirmed Disability Progression (CDP) Events as Measured by the Expanded Disability Status Scale (EDSS)	19.9 Percentage of participants	25.5 Percentage of participants

SECONDARY outcome

Timeframe: Up to maximum approximately 3 years

Population: All participants in the FAS

Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or known infection. A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater. ARR was defined as the average number of confirmed relapses per year. ARR was analyzed using a negative binomial regression model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1099 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Annualized Relapse Rate (ARR) for Confirmed Relapses	0.071 relapses/year Interval 0.055 to 0.092	0.160 relapses/year Interval 0.123 to 0.207

SECONDARY outcome

Timeframe: Up to maximum approximately 3 years

Population: Participants from the FAS with non-missing covariates for the model.

Multiple sclerosis (MS) relapse was defined as appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. Additionally, the abnormality had to be present for at least 24 hours and occur in the absence of fever (\<37.5°C) or known infection. A confirmed MS relapse was defined as accompanied by a clinically-relevant change in the EDSS, as defined in the study protocol, performed by the Independent EDSS Rater. Time to first relapse was defined as the time from Day 1 until the start of relapse symptoms. Patients without relapse were censored at the latest known date to be at risk. This outcome measure was analyzed using a Cox proportional hazards model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1061 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=528 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percentage of Participants With First Relapse Events as Measured by Time to First Confirmed Relapse	10.7 Percentage of participants	18.9 Percentage of participants

SECONDARY outcome

Timeframe: Up to maximum approximately 3 years

Population: All participants in the FAS

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1099 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percentage of Patients With Relapse (Confirmed Relapse and Any Relapse) Any relapse (confirmed or unconfirmed)	16.7 Percentage of participants	26.0 Percentage of participants
Percentage of Patients With Relapse (Confirmed Relapse and Any Relapse) Confirmed relapse	10.3 Percentage of participants	18.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

Population: Participants from the FAS with an available value for the MSWS-12 converted score at baseline and at least one post-baseline.

The Multiple Sclerosis Walking Scale (MSWS-12) version 2 is a patient-rated measure of walking consisting of 12 items. Walking limitations were reported by the patients using categories, generating a total transformed score ranging from 0-100. Higher scores reflected greater impairment. The change from baseline in MSWS-12 converted score was analyzed using a repeated measures model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1022 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=516 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Change From Baseline in MSWS-12 Converted Score Month 12	1.53 score on a scale Standard Error 0.678	3.36 score on a scale Standard Error 0.908
Change From Baseline in MSWS-12 Converted Score Month 24	4.16 score on a scale Standard Error 0.848	5.38 score on a scale Standard Error 1.167

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.

Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of T1 gadolinium (Gd)-enhancing lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The number of T1 Gd-enhancing lesions per patient per scan was analyzed using a negative binomial regression model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=996 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=496 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Number of T1 Gd-enhancing Lesions Per Patient Per Scan Month 12	0.080 T1 Gd-enhancing lesions/patient/scan Interval 0.058 to 0.111	0.640 T1 Gd-enhancing lesions/patient/scan Interval 0.488 to 0.839
Number of T1 Gd-enhancing Lesions Per Patient Per Scan Month 24	0.074 T1 Gd-enhancing lesions/patient/scan Interval 0.04 to 0.138	0.418 T1 Gd-enhancing lesions/patient/scan Interval 0.288 to 0.607

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.

Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the number of new or enlarging T2 lesions. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. The number of new or enlarging T2 lesions compared to previous scan was analyzed using a repeated measures negative binomial regression model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=997 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=496 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Number of New or Enlarging T2 Lesions Per Patient Per Year Month 12	1.003 T2 lesions/patient/year Interval 0.858 to 1.172	3.776 T2 lesions/patient/year Interval 3.148 to 4.528
Number of New or Enlarging T2 Lesions Per Patient Per Year Month 24	0.489 T2 lesions/patient/year Interval 0.371 to 0.644	3.437 T2 lesions/patient/year Interval 2.8 to 4.22

SECONDARY outcome

Timeframe: Baseline, Month 12 and Month 24

Population: Participants from the FAS with at least one post-baseline MRI scan and non-missing values for the covariates included in the model.

Magnetic resonance imaging (MRI) scans of the brain were performed every 12 months. MRI evaluation during the Core Part included the percentage change in brain volume. Each MRI scan was reviewed by a local neurologist and by a central blinded MRI reading center. PBVC relative to baseline was analyzed using a repeated measures model (for normally distributed data) with visit as a categorical factor.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=894 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=436 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Percent Brain Volume Change (PBVC) Relative to Baseline Month 12	-0.283 % change from baseline in brain volume Standard Error 0.0264	-0.458 % change from baseline in brain volume Standard Error 0.0341
Percent Brain Volume Change (PBVC) Relative to Baseline Month 24	-0.711 % change from baseline in brain volume Standard Error 0.0356	-0.839 % change from baseline in brain volume Standard Error 0.0476

SECONDARY outcome

Timeframe: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months. The following secondary progressive multiple sclerosis (SPMS) groups were defined for the analysis of this endpoint: * Without superimposed relapses in the 2 years prior to study start (baseline definition) * With superimposed relapses in the 2 years prior to study start (baseline definition) * Without superimposed relapses during the Core Part of study (post-treatment) * With superimposed relapses during the Core Part of study (post-treatment) Data was analyzed using a Cox proportional hazard model

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1099 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses Without superimposed relapses at baseline	190 Participants	101 Participants
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses With superimposed relapses at baseline	98 Participants	72 Participants
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses Without superimposed relapses post-treatment	237 Participants	122 Participants
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of SPMS Patients With/Without Superimposed Relapses With superimposed relapses post-treatment	51 Participants	51 Participants

SECONDARY outcome

Timeframe: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

The Expanded Disability Status Scale (EDSS) assesses neurologic impairment in multiple sclerosis (MS). EDSS scale ranges from 0 (normal) to 10 (death due to MS). Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0 to 5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. The definition of 3-month confirmed disability progression (CDP) was an increase from baseline in EDSS as defined before sustained for at least 3 months. Rapidly evolving patients are defined as subjects with 1.5 or greater EDSS change in the 2 years prior to or at study start and disability progression in the 2 years prior to study start was not adjudicated. Data was analyzed using a Cox proportional hazard model.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1099 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Rapidly and Not Rapidly Evolving Patients Rapidly evolving patients	82 Participants	60 Participants
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Rapidly and Not Rapidly Evolving Patients Not rapidly evolving patients	206 Participants	113 Participants

SECONDARY outcome

Timeframe: Baseline, every 3 months up to the maximum of approximately 3 years

Population: Participants from the FAS in each subgroup with an available value for the outcome measure.

Outcome measures

Outcome measures
Measure	Siponimod (BAF312) n=1099 Participants Participants started on Day 1 and were uptitrated from 0.25 mg to 2 mg of BAF312 orally over a period of 6 days. After Day 7, participants continued on 2 mg BAF312 daily for a variable duration.	Placebo n=546 Participants Matching placebo to BAF312 was administered orally during the Core Part of the trial.
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Patients With and Without Moderate/Severe Disease Course With moderate or severe course of disease	232 Participants	141 Participants
Number of Participants With 3-month CDP Events as Measured by EDSS in the Subgroup of Patients With and Without Moderate/Severe Disease Course Without moderate or severe course of disease	56 Participants	32 Participants

Adverse Events

Core-BAF312

Serious events: 196 serious events

Other events: 778 other events

Deaths: 4 deaths

Core-Placebo

Serious events: 83 serious events

Other events: 348 other events

Deaths: 4 deaths

All BAF312

Serious events: 610 serious events

Other events: 1267 other events

Deaths: 33 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER