The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis

Figures & data

Table 1. Patient demographics and baseline disease characteristics.

	All MS data sources, excluding Danish MS Registry^1		Danish MS Registry
	Cladribine cohort n = 606	Fingolimod cohort n = 475	Cladribine cohort n = 136	Fingolimod cohort n = 392
Age at inclusion, years
Mean (SD)	41.0 (12.6)	40.0 (11.0)	40.6 (10.8)	40.0 (11.2)
Range (min, max)	(19.0, 76.0)	(16.0, 78.0)	NR	NR
Female, n (%)	449 (74.1)	331 (69.7)	82 (60.3)	262 (66.8)
Duration of follow-up at the time of data cut-off, years
Mean (SD)	0.9 (0.5)	1.3 (0.7)	1.0 (0.6)	1.6 (0.7)
Range (min, max)	(0.0, 2.3)	(0.0, 2.5)	NR	NR
Patient-years	545.5	613.1	142.1	633.5
Mean time since MS diagnosis at inclusion, years (SD)	6.7 (7.7)	6.0 (6.7)	6.4 (6.9)	6.5 (6.8)
EDSS score closest to inclusion, mean (SD)	2.5 (2.0)	2.0 (1.5)	2.4 (1.7)	2.4 (1.5)
Number of relapses within 1 year prior to inclusion
Mean (SD)	0.6 (0.8)	0.7 (0.8)	0.7 (0.8)	0.6 (0.8)
Median (Q1, Q3)	0 (0, 1)	0 (0, 1)	0.0 (0, 1)	0 (0, 1)
Data source, n
Finnish MS Registry	73	123	–	–
MSBase	132	49	–	–
MSDS3D	130	104	–	–
Norwegian MS Registry and Biobank	183	136	–	–
Swedish MS Registry	80	50	–	–
Swiss MS Cohort	8	13	–	–
Danish MS Registry	–	–	136	392

Abbreviations. EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; MSDS3D, Multiple Sclerosis Documentation System 3D; NR, not reported; SD, standard deviation.

¹Patients from the Danish MS Registry were excluded from the ‘All MS data sources’ group and are reported separately, due to restrictions of reporting small number of observations (<5).

Table 2. Incidence rate of infections per 1000 patient-years: ITT exposure definition.

	Number of events	Total time at risk (PY)	IR (95% CI)	Number of events	Total time at risk (PY)	IR (95% CI)	IR difference (95% CI)
All MS data sources, excluding the Danish MS Registry^1
	Cladribine cohort n = 606			Fingolimod cohort n = 475
Severe infections^2	4	543	7.37 (2.76, 19.6)	4	611	6.55 (2.46, 17.4)	0.82 (−10.30, 13.0)
Herpes zoster	3	544	5.51 (1.78, 17.1)	2	611	3.27 (0.82, 13.1)	2.24 (−6.98, 13.1)
Opportunistic infections	0	546	0 (0, 6.76)	1	612	1.63 (0.23, 11.6)	−1.63 (−9.20, 5.37)
Danish MS Registry
	Cladribine cohort n = 136			Fingolimod cohort n = 392
Severe infections^3	0	142	0 (0, 25.9)	8	622	12.9 (6.43, 25.7)	−12.9 (−25.2, 13.5)
Herpes zoster	0	142	0 (0, 25.9)	[1–4]	632	3.50 (0.58, 21.2)	−3.50 (NE)
Tuberculosis	0	142	0 (0, 25.9)	[1–4]	632	3.50 (0.58, 21.2)	−3.50 (NE)

Abbreviations. CI, confidence interval; IR, incidence rate; ITT, intention-to-treat; MS, multiple sclerosis; NE: not estimated; PY, patient-years.

¹Patients from the Danish MS Registry were excluded from the ‘All MS data sources’ group and are reported separately, due to restrictions of reporting small number of observations (<5).

²Excluding tuberculosis, progressive multifocal leukoencephalopathy, and other opportunistic infections.

³Excluding progressive multifocal leukoencephalopathy and other opportunistic infections.

CIs of incidence rates were estimated for each cohort using interval-censored Poisson regression. For incidence rates of zero, the 95% CI was estimated using the exact method.

Table 3. Incidence rate of malignancies (all) per 1000 patient-years: ITT exposure definition¹.

	Main analysis (patients without known prior malignancy)		Sensitivity analysis (including patients with any history of prior malignancy)
	Cladribine cohort	Fingolimod cohort	Cladribine cohort	Fingolimod cohort
Total number of patients at risk	1035	843	1058	855
Number of first events	6	5	6	5
Total time at risk (PY)	1690	1409	1731	1434
IR (95% CI)	3.55 (1.59, 7.90)	3.55 (1.48, 8.52)	3.47 (1.56, 7.72)	3.49 (1.45, 8.38)
IR difference (95% CI)	0.00 (−5.10, 4.66)		−0.02 (−5.03, 4.53)

Abbreviations. CI, confidence internal; IR, incidence rate; IR difference, cladribine minus fingolimod (i.e. IR difference for cladribine cohort relative to fingolimod cohort); ITT, intention-to-treat; MS, multiple sclerosis; MSDS3D, Multiple Sclerosis Documentation System 3D; PY, patient-years.

¹Patients from MSBase, MSDS3D, and the Swiss MS Cohort are included in the analysis (cut-off date: 01-April-2022).

Table 4. Incidence rate of malignancy per 1000 patient-years by malignancy type and cohort: ITT exposure definition (patients without known prior known malignancy)¹.

Type	Cladribine cohort n = 1035			Fingolimod cohort n = 843
	Patients	Events	IR (95% CI)	Patients	Events	IR (95% CI)
Colon	1	1	0.59 (0.08, 4.19)	0	0	0.00 (0.00, 2.61)
Non-melanoma skin cancer	0	0	0.00 (0.00, 2.18)	1	1	0.71 (0.10, 5.02)
Breast (in women)	2	2	1.18 (0.30, 4.72)	1	1	0.71 (0.10, 5.02)
Cervical	2	2	1.18 (0.30, 4.72)	1	1	0.71 (0.10, 5.02)
Testicular	0	0	0.00 (0.00, 2.18)	1	1	0.71 (0.10, 5.02)
Kidney and renal pelvis	1	1	0.59 (0.08, 4.19)	0	0	0.00 (0.00, 2.61)
Ill-defined, secondary and unspecified sites or independent (primary) multiple sites	0	0	0.00 (0.00, 2.18)	1	1	0.71 (0.10, 5.02)

Abbreviations. CI, confidence internal; IR, incidence rate; ITT, intention-to-treat; MS, multiple sclerosis; MSDS3D, Multiple Sclerosis Documentation System 3D.

¹Patients from MSBase, MSDS3D, and the Swiss MS Cohort are included in the analysis (cut-off date: 01-April-2022).

Table 5. Incidence rate of severe lymphopenia per 1000 patient-years in the cladribine cohort¹.

Definition of exposure	Number of patients	Number of (first) events	Total time at risk (PY)	IR (95% CI)
+6-month latency as-treated	349	19	298	63.9 (40.7, 100.1)
+12-month latency as-treated (sensitivity analysis)	346	19	297	64.0 (40.8, 100.3)

Abbreviations. CI, confidence interval; IR, incidence rate; MS, multiple sclerosis; MSDS3D, Multiple Sclerosis Documentation System 3D; PY, patient-years.

¹Patients from the Finnish MS Registry, MSBase, MSDS3D, and the Swiss MS Cohort are included in the analysis.

CIs of incidence rates were estimated using interval-censored Poisson regression.

Table 6. History of prior DMT use before initiation of study treatment.

	All MS data sources, excluding Danish MS Registry^1		Danish MS Registry
	Cladribine cohort n = 606	Fingolimod cohort n = 475	Cladribine cohort n = 136	Fingolimod cohort n = 392
Any prior DMT use for MS, n (%)
No DMT	223 (36.8)	130 (27.4)	25 (18.4)	54 (13.8)
One DMT	193 (31.8)	168 (35.4)	39 (28.7)	169 (43.1)
Two DMTs	104 (17.2)	113 (23.8)	38 (27.9)	121 (30.9)
Three or more DMTs	86 (14.2)	64 (13.5)	34 (25.0)	48 (12.2)
Any prior DMT use by type, n (%)	383 (63.2)	345 (72.6)	111 (81.6)	338 (86.2)
Dimethyl fumarate^2	135 (35.2)	116 (33.6)	36 (32.4)	56 (16.6)
Interferon beta-1a^2	130 (33.9)	152 (44.1)	50 (45.0)	172 (50.9)
Glatiramer acetate^2	128 (33.4)	112 (32.5)	32 (28.8)	49 (14.5)
Teriflunomide^2	110 (28.7)	106 (30.7)	47 (42.3)	173 (51.2)
Natalizumab^2	79 (20.6)	48 (13.9)	47 (42.3)	94 (27.8)
Interferon beta-1b^2	50 (13.1)	54 (15.7)	5 (4.5)	16 (4.7)

Abbreviations. DMT, disease-modifying therapy; MS, multiple sclerosis.

¹Patients from the Danish MS Registry were excluded from the ‘All MS data sources’ group and are reported separately, due to restrictions of reporting small observations (<5).

²Among patients with prior DMT use.

Only DMTs used by 10% or more of patients in at least one cohort are included in the table.

Data availability statement

Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck’s Data Sharing Policy. All requests should be submitted in writing to Merck’s data sharing portal https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html. When Merck has a co-research, co-development, or co-marketing or co-promotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.