Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses

Figures & data

Table 1. Design of trials included in this study.

Trial name	ClinicalTrials.gov identifier	Pivotal publication (author, year)	Phase	Randomization and blinding	MS population	Sample size	Treatment(s)	Comparator	Trial duration
EXPAND	NCT01665144	Kappos, 2018 [11]	III	Randomized Double-blind	SPMS	1651	Siponimod 2 mg PO QD	Placebo PO QD	Up to 3 years
INFORMS	NCT00731692	Lublin, 2016 [16]	III	Randomized Double-blind	PPMS	970	Fingolimod 1.25 mg PO QD, 0.5 mg PO QD^a	Placebo PO QD	Up to 5 years
FREEDOMS	NCT00289978	Kappos, 2010 [18]	III	Randomized Double-blind	RRMS	1272	Fingolimod 1.25 mg PO QD, 0.5 mg PO QD	Placebo PO QD	2 years
FREEDOMS II	NCT00355134	Calabresi, 2014 [17]	III	Randomized Double-blind	RRMS	1083	Fingolimod 1.25 mg PO QD, 0.5 mg PO QD	Placebo PO QD	2 years
TRANSFORMS	NCT00340834	Cohen, 2010 [5]	III	Randomized Double-blind	RRMS	1280	Fingolimod 1.25 mg PO QD, 0.5 mg PO QD	IFNB-1a IM 30 µg QW	1 year
ASCLEPIOS I	NCT02792218	Hauser, 2020 [28]	III	Randomized Double-blind	RMS (94.1% RRMS and 5.9% active SPMS)	927	Ofatumumab 20 mg SC Q4W^b	Teriflunomide 14 mg PO QD	Up to 30 months
ASCLEPIOS II	NCT02792231	Hauser, 2020 [28]	III	Randomized Double-blind	RMS (94.5% RRMS and 5.5% active SPMS)	955	Ofatumumab 20 mg SC Q4W^b	Teriflunomide 14 mg PO QD	Up to 30 months

Abbreviations. IFNB: interferon beta; MS: multiple sclerosis; PO: oral; PPMS: primary progressive multiple sclerosis; Q4W: every four weeks; QD: daily; QW: weekly; RMS: relapsing multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SC: subcutaneous; SPMS: secondary progressive multiple sclerosis.

^a All patients in the fingolimod group were administered 1.25 mg fingolimod at study commencement but switched to 0.5 mg mid-study because of a protocol amendment. All patients assigned to the fingolimod group completed the study on 0.5 mg fingolimod.

^b All patients in the ofatumumab group were initially administered 20 mg loading doses on days 1, 7, and 14.

Table 2. Comparison of patient eligibility criteria for included trials.

Trial name	Inclusion criteria
	MS type	MS diagnostic criteria	Age	Baseline EDSS score	Required documented progression in prior years	Required absence of relapses in months prior	History of RRMS	Prior DMT and corticosteroid use	Required T25FW test score	Disease duration
EXPAND	SPMS	2010 revised McDonald criteria	18–60	3.0–6.5	Documented EDSS progression in the 2 years before the study ≥1.0 point for patients with EDSS < 6.0 ≥0.5 point for patients with EDSS ≥ 6.0 at screening	No relapse in 3 months prior	History of RRMS	Prior IFN or GA: allowed Prior corticosteroid: disallowed within 3 months Multiple additional criteria regarding specific prior DMTs	NR	Documented SPMS ≥6 months before study enrollment (and preceding history of RRMS)
INFORMS	PPMS	2005 revised McDonald criteria	25–65	3.5–6.0	≥1 year of disease progression^a Documented EDSS progression in the 2 years before the study ≥0.5 point for all patients	No history of relapses allowed	No history of RRMS allowed	Prior IFN or GA: disallowed within 3 months Prior corticosteroid: disallowed within 3 months Multiple additional criteria regarding specific prior DMTs	<30 s	Time since reported PPMS symptoms between 2 and 10 years
FREEDOMS	RRMS	2005 revised McDonald criteria	18–55	0.0–5.5	n/a – not progressive MS	No relapse in 1 month prior	Current diagnosis of RRMS	Prior IFN or GA: disallowed within 3 months Prior corticosteroid: Disallowed within 30 days	NR	NR
FREEDOMS II	RRMS	2005 revised McDonald criteria	18–55	0.0–5.5	n/a – not progressive MS	No relapse in 1 month prior	Current diagnosis of RRMS	Prior IFN or GA: disallowed within 3 months Prior corticosteroid: disallowed within 30 days	NR	NR
TRANSFORMS	RRMS	2005 revised McDonald criteria	18–55	0.0–5.5	n/a – not progressive MS	No relapse in 1 month prior	Current diagnosis of RRMS	Prior IFN or GA: Allowed Prior corticosteroid: disallowed within 30 days	NR	NR
ASCLPEIOS I	RMS	2010 revised McDonald criteria	18–55	0.0–5.5	Not required for SPMS patients	Neurologically stable within 1 month prior	Current diagnosis of RMS	Prior IFN or GA: allowed Prior corticosteroid: disallowed within 30 days Multiple additional criteria regarding specific prior DMTs	NR	≤10 years in patients with EDSS score ≤2.0
ASCLEPIOS II	RMS	2010 revised McDonald criteria	18–55	0.0–5.5	Not required for SPMS patients	Neurologically stable within 1 month prior	Current diagnosis of RMS	Prior IFN or GA: allowed Prior corticosteroid: disallowed within 30 days Multiple additional criteria regarding specific prior DMTs	NR	≤10 years in patients with EDSS score ≤2.0

Abbreviations. CSF: cerebrospinal fluid; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; GA: glatiramer acetate; Gd+: gadolinium-enhancing; IFN: interferon; MRI: magnetic resonance imaging; MS: multiple sclerosis; n/a: not applicable; NR: not reported; PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; T25FW: timed 25-foot walk.

^aPlus two of the following: positive brain MRI, positive spinal cord MRI, positive CSF.

Figure 1. Distribution of baseline patient characteristics across trials in different MS phenotypes: EXPAND (SPMS), FREEDOMS (RRMS), and INFORMS (PPMS). Note: The INFORMS trial was not included in the number of relapses plots because the PPMS patients did not have relapses. For the time since first MS symptom and time since MS diagnosis, comparisons with INFORMS (PPMS) may be biased by the systematic underestimation of MS duration in PPMS patients (who typically have accumulated lesions but not acute neurological events). Additional comparisons between trials included in this study can be found in Supplemental Appendix B. Abbreviations. EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; PPMS: primary progressive multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.

Table 3. Published patient baseline characteristics for the siponimod, fingolimod (0.5 mg), or ofatumumab treatment arm of included trials.

Characteristic	EXPAND (SPMS) (n = 1105)	INFORMS (PPMS) (n = 336)	FREEDOMS (RRMS) (n = 425)	FREEDOMS II (RRMS) (n = 358)	TRANSFORMS (RRMS) (n = 431)	ASCLEPIOS I (RMS) (n = 465)	ASCLEPIOS II (RMS) (n = 481)
Age (mean years)	48.0	48.5	36.6	40.6	36.7	38.9	38.0
Proportion female (%)	61%	49%	70%	77%	65%	68%	66%
EDSS score (mean)	5.4	4.7	2.3	2.4	2.2	3.0	2.9
EDSS score (median)	6.0	4.5	2.0	2.0	2.0	3.0	3.0
Time since first MS symptom (mean years)	17.1	5.8	8.0	10.4	7.5	8.4	8.2
Time since MS diagnosis (mean years)	12.9	2.8	4.8	6.0	4.8	5.8	5.6
Time since conversion to SPMS (mean years)	3.9	N/A	N/A	N/A	N/A	N/A	N/A
Proportion of patients with Gd + lesions on T1 weighted images (%)	21%	14%	38%	39%	33%	37%	44%
Total volume of T2 lesions (mean mm^3)	15 632	9443	6128	5484	5170	13 168	14 254
Normalized brain volume (cm^3)	1422	1491	1521	1522	1524	1439	1440
Time since most recent relapse (mean years)	5.2	N/A	0.52	0.58	0.44	0.59	0.65
Proportion of patients who were relapse-free in prior year (%)	79%	100%	2%	3%	3%	6%	6%
Proportion of patients who were relapse-free in prior 2 years (%)	64%	100%	0%	0%	0%	2%	3%
Number of relapses per patient in the previous year (mean)	0.2	0	1.5^a	1.4	1.5	1.2	1.3
Number of relapses per patient in the previous 2 years (mean)	0.7	0	2.1	2.2	2.3	2.1	2.0
Proportion of patients without previous use of a DMT (%)	22%	81%	60%	26%	45%	41%	41%

Abbreviations. DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; Gd+: gadolinium-enhancing; MS: multiple sclerosis; N/A: not applicable; PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.

Table 4. Summary of trial-specific outcome definitions.

EXPAND	INFORMS	FREEDOMS	FREEDOMS II	TRANSFORMS	ASCLEPIOS I/II
Time to 6mCDP: 1.0-point increase in EDSS score if the baseline score was 3.0–5.0 0.5-point increase in EDSS score if the baseline score was 5.5–6.5	Time to 6mCDP: 1.0-point increase in EDSS score if the baseline score was ≤5.0 0.5-point increase in EDSS score if the baseline score was ≥5.5	Time to 6mCDP: 1.0-point increase in EDSS scores if the baseline score was <5.5 0.5-point increase in EDSS scores if the baseline score was 5.5	Time to 6mCDP: 1.0-point increase in EDSS score if the baseline score was ≤5.0 0.5-point increase in EDSS score if the baseline score was >5.0	Not available	Time to 6mCDP: 1.5-point increase in EDSS score if the baseline score was 0.0 1.0-point increase in EDSS score if the baseline score was 0.5–5.0 0.5-point increase in EDSS score if the baseline score was >5.0
Time to 3mCDP: 1.0-point increase in EDSS score if the baseline score was 3.0–5.0 0.5-point increase in EDSS score if the baseline score was 5.5–6.5	Time to 3mCDP: 1.0-point increase in EDSS score if the baseline score was ≤5.0 0.5-point increase in EDSS score if the baseline score was ≥5.5	Time to 3mCDP: 1.0-point increase in EDSS score if the baseline score was <5.5 0.5-point increase in EDSS score if the baseline score was 5.5	Time to 3mCDP: 1.0-point increase in EDSS score if the baseline score was ≤5.0 0.5-point increase in EDSS score if the baseline score was >5.0	Time to 3mCDP: 1.0-point increase in EDSS score if the baseline score was ≤5.0 0.5-point increase in EDSS score if the baseline score was ≥5.5	Time to 3mCDP: 1.5-point increase in EDSS score if the baseline score was 0.0 1.0-point increase in EDSS score if the baseline score was 0.5–5.0 0.5-point increase in EDSS score if the baseline score was >5.0
ARR: Average number of confirmed relapses per year (the total number of confirmed relapses divided by the total number of days in the study multiplied by 365.25)	ARR: Not applicable	ARR: Average number of confirmed relapses per year (the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25)	ARR: Average number of confirmed relapses per year (the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25)	ARR: The number of confirmed relapses during a 12-month period	ARR: The number of confirmed relapses of multiple sclerosis per year
Relapse: Appearance of a new neurological abnormality^a Separated by at least 30 days from the onset of a preceding clinical demyelinating event Abnormality must have been present for at least 24 h Occurs in the absence of fever or infection	Relapse: Not applicable	Relapse: Appearance of a new or worsening neurological abnormality^a Separated by at least 30 days from onset of a preceding relapse Abnormality must be present for at least 24 h Occurs in the absence of fever or infection	Relapse: Appearance of a new neurological abnormality^a Separated by at least 30 days from the onset of a preceding clinical demyelinating event Abnormality must have been present for at least 24 h Occurs in the absence of fever or infection Accompanied by an increase of at least 0.5 points on the EDSS score, or an increase of at least 1 point on two FS scores, or an increase of at least 2 points on one FS score^b	Relapse: New, worsening, or recurrent neurological symptoms Occurs at least 30 days after the onset of preceding relapse Duration of at least 24 h without fever or infection Accompanied by an increase of ≥0.5-point on the EDSS or an increase of ≥ 1-point in two FS scores or an increase of ≥ 2-points in one FS score^b	Relapse: Appearance of a new or worsening neurological abnormality^a Separated by at least 30 days from onset of a preceding clinical demyelinating event Abnormality must have been present for at least 24 h Occurs in the absence of fever or known infection Accompanied by an increase of at least 0.5 points on the EDSS score, or an increase of at least 1 point on at least two FS scores, or an increase of at least 2 points on at least one FS score^b

Abbreviations. 3mCDP: 3-month confirmed disability progression; 6mCDP: 6-month confirmed disability progression; ARR: annualized relapse rate; EDSS: Expanded Disability Status Scale; FS: functional system; IPD: individual patient data.

Note. INFORMS and TRANSFORMS did not report time to 6mCDP in their pivotal publications. However, time to 6mCDP outcome data for INFORMS was obtained from the IPD and so the definition of 6mCDP was assumed to reflect the published definition of 3mCDP. This outcome was not available from the TRANSFORMS IPD.

Note. INFORMS did not report ARR.

Note. In all trials, disability progression had to be confirmed at a scheduled visit at least 6 months later (time to 6mCDP) or at least 3 months later (time to 3mCDP).

^aIncludes worsening of the previous stable or improving pre-existing neurological abnormalities.

^bExcluding changes in bowel or bladder function and cognition.

Figure 2. Time to confirmed disability progression in placebo arms of the EXPAND, FREEDOMS, FREEDOMS II, and INFORMS trials. Note: The shaded areas of the plot that surround the curves represent the 95% confidence intervals around the point estimates at each time point. Curves were derived from IPD for the placebo arms of the indicated trials: EXPAND (SPMS), FREEDOMS (RRMS), FREEDOMS II (RRMS), and INFORMS (PPMS). Curves were generated before excluding relapsing patients from EXPAND and before conducting PSM on treatment arms (EXPAND and INFORMS). The TRANSFORMS (in RRMS) and ASCLEPIOS I/II (in RMS) trials were not included because they were not placebo-controlled. Abbreviations. 3mCDP: 3-month confirmed disability progression; 6mCDP: 6-month confirmed disability progression; IPD: individual patient data; PPMS: primary progressive multiple sclerosis; PSM: propensity score matching; RMS: relapsing multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.

Table 5. Propensity score matching analysis results.

Pre-PSM population			Post-PSM population			PSM ITC results
Siponimod (N)	Fingolimod 0.5 mg (N)	Mean SMD	Siponimod (N)	Fingolimod 0.5 mg (N)	Mean SMD	Outcome	Siponimod vs. Fingolimod 0.5 mg HR (95% CI)
678	332	0.383	117	117	0.094	Time to 6mCDP	0.76 (0.48–1.20)
						Time to 3mCDP	0.80 (0.52–1.22)

Abbreviations. 3mCDP: 3-month confirmed disability progression; 6mCDP: 6-month confirmed disability progression; CI: confidence interval; HR: hazard ratio; ITC: indirect treatment comparison; N: sample size; PSM: propensity score matching; SMD: standardized mean difference.

Note. HRs are doubly robust. Without being doubly robust, the ITC results were 0.84 (0.54–1.31) and 0.87 (0.58–1.31) for time to 6mCDP and 3mCDP, respectively.

Note. SMD was calculated as the mean absolute difference in a baseline covariate between two comparison groups (i.e. siponimod and fingolimod) divided by the pooled standard deviation of the covariate for the entire analysis sample. The mean SMD represents the average SMD across all ranked characteristics.

Note. The “pre-PSM population” excludes relapsing patients from EXPAND and does not include patients with missing values in covariates required for the PSM analysis.

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