The CLARION study design and status update: a long-term, registry-based study evaluating adverse events of special interest in patients with relapsing multiple sclerosis newly started on cladribine tablets

Figures & data

Table 1. Objectives and cohort level outcomes in CLARION.

Primary objective	Primary outcome
To further characterize and compare the risk, in terms of incidence of AESI (malignancies, severe infections, tuberculosis, PML, other opportunistic infections, and herpes zoster)	Number of AESI in the cladribine and fingolimod cohorts
Secondary objectives	Secondary outcomes
To assess the impact of prior use of immunomodulatory/immunosuppressive agents on the incidence of AESI	Number of AESI by prior use of immunomodulatory/ immunosuppressive agents in the cladribine and fingolimod cohorts
To characterize the incidence and duration of severe lymphopenia among users of cladribine tablets	Number and duration of severe lymphopenia events in the cladribine cohort
To describe DMTs prescribed subsequent to cladribine tablets when disease activity recurs	DMT (immunomodulatory or immunosuppressive agents) after cladribine tablets treatment in patients with relapsing MS newly initiating cladribine tablets who experience a recurrence of the disease activity
Exploratory objectives	Exploratory outcomes
To characterize treatment discontinuation and the reasons for discontinuation	Number of patients discontinuing treatment, overall and by reason(s) for discontinuation, in the cladribine and fingolimod cohorts
To further characterize the relationship between severe lymphopenia and AESI among users of cladribine tablets	Number and time points of severe lymphopenia and AESI in the cladribine cohort

Abbreviations. AESI, adverse events of special interest; DMT, disease-modifying therapy; PML, progressive multifocal leukoencephalopathy.

Table 2. Planned data sources, population coverage, and data elements to be included in CLARION.

Data source, per country	Population coverage	Data elements
DENMARK
Danish MS Registry	100% of Danish MS patients with DMT (personal communication with the register holder (February 2017))	Treatment discontinuation and reasons Exposure to DMTs Covariates
Registry of Medicinal Product Statistics	100% of the population with prescribed drugs purchased in community pharmacies in Denmark	Covariates
Danish National Patient Register	100% of the population with somatic inpatient or special outpatient care in Denmark	Severe infections, TB, PML, other OI, and HZ Covariates
Danish Cancer Register	100% of the population with cancer in Denmark	Malignancies Covariates
Danish Register of Causes of Death	100% of the deceased population in Denmark	Covariates
Danish Civil Registration System	100% of the population in Denmark	Covariates
FINLAND
Finnish MS Registry	16/20 hospital regions in Finland (as of April 2021)	Severe infections,^a TB, PML, other OI, and HZ Malignancies Severe lymphopenia Treatment discontinuation and reasons Exposure to DMTs Covariates
Prescription registers	100% of the population with prescribed reimbursed drugs purchased in community pharmacies in Finland e-register: 100% of the population with prescribed drugs purchased in community pharmacies in Finland	Covariates
Care Register for Health Care (HILMO; secondary care)	100% of the population with inpatient or special outpatient care visits in Finland	Severe infections, TB, PML, other OI, and HZ Malignancies Covariates
Register of Primary Health Care Visits (AvoHILMO)	100% of the population, all healthcare visits in primary care since 2011 in Finland	Severe infections, TB, PML, other OI, and HZ Malignancies Covariates
Finnish Cancer Registry	100% of the population with cancer in Finland	Malignancies Covariates
National Infectious Diseases Register	100% of the population diagnosed with one of the 70 selected infectious diseases in Finland	Severe infections, TB, PML, other OI, and HZ Covariates
Cause of Death Register	100% of the deceased population in Finland	Covariates
Finnish Population Information System	100% of the population in Finland	Severe infections, TB, PML, other OI, and HZ
FRANCE
OFSEP	Approximately 50% of MS patients in France	All outcomes Exposure to DMTs Covariates
GERMANY
MSDS 3D +/− NTD	The database is used purely for specific studies and all patients will be included per study protocol	All outcomes Exposure to DMTs Covariates
ITALY
Italian MS Registry	57 sites across Italy, approximately 80% (20,000 patients) of the Italian MS patient population^15	All outcomes Exposure to DMTs Covariates
NORWAY
Norwegian MS Registry and Biobank	Approximately 55% (6000 patients) of the Norwegian MS patient population^16	Severe lymphopenia Treatment discontinuation and reasons Exposure to DMTs Covariates
Norwegian Prescription Database (Nor PD)	100% of the population with prescribed drugs dispensed in pharmacies in Norway	Covariates
Norwegian Patient Registry	100% of the population with inpatient or special outpatient care visits in Norway	Severe infections, TB, PML, other OI, and HZ Severe lymphopenia Covariates
Cancer Registry of Norway	100% of the population with cancer in Norway	Malignancies Covariates
Cause of Death Registry	100% of the deceased population in Norway	Covariates
National Registry	100% of the population in Norway	Covariates
SWEDEN
Swedish MS Registry	Approximately 80% (14,500 patients) of the Swedish MS patient population^17	Severe lymphopenia Treatment discontinuation and reasons Exposure to DMTs Covariates
Swedish Prescribed Drug Register	100% of the population with prescribed drugs purchased in community pharmacies in Sweden	Covariates
National Patient Register	100% of the population with inpatient or special outpatient care visits in Sweden	Severe infections, TB, PML, other OI, and HZ Covariates
Swedish Cancer Register	100% of the population with cancer in Sweden	Malignancies Covariates
Cause of Death Register	100% of the deceased population in Sweden	Covariates
Total Population Register	100% of the population in Sweden	Covariates
SWITZERLAND
Swiss MS Cohort-Study	8 MS centers, 1302 MS patients in Switzerland	All outcomes Exposure to DMTs Covariates
US
Department of Defense (under feasibility)	Between 2004–2016, 8695 patients with a new diagnosis of MS^18	All outcomes Exposure to DMTs Covariates
MULTI-COUNTRY
MSBase	Multi-country, current participating sites: Australia: n = 8; Turkey: n = 2	All outcomes Exposure to DMTs Covariates

Abbreviations. DMT, disease-modifying therapy; HZ, herpes zoster; MS, multiple sclerosis; MSBase, Multiple Sclerosis database; MSDS 3D, Multiple Sclerosis Management System 3 Dimension; NTD, NeuroTransData; OFSEP, Observatoire Français de la Sclérose en Plaques; OI, opportunistic infections; PML, progressive multifocal leukoencephalopathy; TB, tuberculosis.

^aSeverity via linkage with national registries using hospitalization and diagnosis as proxy.

Table 3. Additional exposure definitions.

For all primary outcomes	Description
On-treatment	ITT, with patient FU time censored 6 (or 12 months) after first discontinuation or switch (only the first treatment episode is considered)
Time-on-drug (VERISMO)^14	Equivalent to the time-on-drug exposure in the VERISMO study As-treated, but a patient would contribute to both cohorts in case of overlapping exposure. Two pairs of treatment-specific risk windows will be used
For malignancies	Description
ITT with an induction period of 6 (or 24) months	ITT, with events and FU time from 6 (or 24) months after cohort entry not counted
Time since last dose exposure	Categories: Current, recent (1–365 days after last dose), or past (>365 days after last dose) exposure to cladribine tablets or fingolimod tablets (6 categories)
Cumulative exposure	Categories: 0, 0–12, 12–24, 24–36, 36–48, and >48 months of cumulative exposure to cladribine tablets or fingolimod tablets (12 categories)
Ever-exposed (VERISMO)^14	Equivalent to the ever-exposed exposure in the VERISMO study ITT, but a patient can contribute to both cohorts

Abbreviations. FU, follow-up; ITT, intention to treat.

Figure 1. Overview of data flow from collection to the consolidated database in the CLARION study. CRO, clinical research organization; MSDS 3D, Multiple Sclerosis management system 3 Dimension; MSBase, Multiple Sclerosis database: NTD, NeuroTransData database; OFSEP, Observatoire Français de la Sclérose en Plaques; SMSC, Swish MS Cohort.

Table 4. Overview of planned analyses.

	1st interim analysis (Q3 2021)	2nd interim analysis (Q3 2024)	3rd interim analysis (Q3 2027)	4th interim analysis (Q3 2030)	Final analysis (Q4 2034)
Summary of disposition	x	x	x	x	x
Patient characteristics at inclusion	x	x	x	x	x
IR (and time) to malignancy (primary objective)	–	–	–	–	x
IR for first/recurrent event (primary objective)	x^a	x	x	x	x
CAIRR, first/recurrent event (primary objective)	–	x	x	x	x
IR difference for first/recurrent event (primary objective)	x^a	x	x	x	x
Analyses for secondary objective	x^b	x	x	x	x
Analyses for exploratory objectives	x^c	x	x	x	x

Abbreviations. IR, incidence rate; CAIRR, covariate adjusted incidence rate ratio.

Note. Sensitivity and other analyses to support the primary analysis will be conducted following the plan for the primary analyses.

^aThis interim analysis will not be conducted for malignancies; ^bThis interim analysis will not be conducted for the secondary objective “to assess the impact of the prior use of immunomodulatory/immunosuppressive agents on the incidence of AESI in patients with relapsing MS newly initiating cladribine tablets or fingolimod tablets”; ^cThis interim analysis will not be conducted for the exploratory objective “to further characterize the relationship between severe lymphopenia and AESI in patients with relapsing MS newly initiating cladribine tablets”.

Figure 2. Inclusion status in the CLARION study over time. The figure shows the number of patients included in the study at different data cut-offs, and this is regardless of the initial treatment time (some patients added in 2020 were already treated in 2019).

Table 5. Registry participation in the CLARION study, over time.

19.Nov.2018	01.May.2019	01.Nov.2019	01.Feb.2020	10.May.2020	01.Aug.2020	01.Nov.2020	01.Feb.2021	01.May.2021
MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD	MSDS 3D / NTD
	Finnish MS	Finnish MS	Finnish MS	Finnish MS	Finnish MS	Finnish MS	Finnish MS	Finnish MS
	Nor MS	Nor MS	Nor MS	Nor MS	Nor MS	Nor MS	Nor MS	Nor MS
	Swedish MS	Swedish MS	Swedish MS	Swedish MS	Swedish MS	Swedish MS	Swedish MS	Swedish MS
		Swiss MS	Swiss MS	Swiss MS	Swiss MS	Swiss MS	Swiss MS	Swiss MS
		Danish MS	Danish MS	Danish MS	Danish MS	Danish MS	Danish MS	Danish MS
			MSBase	MSBase	MSBase	MSBase	MSBase	MSBase

Abbreviations. Danish MS, Danish Multiple Sclerosis Registry; Finnish MS, Finnish Multiple Sclerosis Registry; MSBase, Multiple Sclerosis database; MSDS 3D, Multiple Sclerosis Management System 3 Dimension; Nor MS, Norwegian Multiple Sclerosis Registry and Biobank; NTD, NeuroTransData; Swedish MS, Swedish Multiple Sclerosis Registry; Swiss MS, Swiss Multiple Sclerosis Cohort-Study.

Table 6. Demographics and disease characteristics of patients in CLARION (cut-off date: 1 May 2021).

	Cladribine cohort n = 1266	Fingolimod cohort n = 1127
Age at inclusion, years
Mean (SD)	31.5 (9.5)	30.9 (9.8)
Range (min, max)	6.4–68	6–65
Female sex, n (%)	918 (72.5)	766 (68.0)
MS registry/data source (country), n (%)
Danish MS Registry (Denmark)	180 (14.2)	458 (40.6)
Finnish MS Registry (Finland)	128 (10.1)	159 (14.1)
MSBase (Australia, Turkey)	154 (12.2)	68 (6.0)
MSDS 3D (and NTD) (Germany)	294 (23.2)	192 (17.0)
Norwegian MS Registry and Biobank (Norway)	360 (28.4)	159 (14.1)
Swedish MS Registry (Sweden)	137 (10.8)	64 (5.7)
Swiss MS Cohort-Study (Switzerland)	13 (1.0)	27 (2.4)
MS clinical course at inclusion, n (%)
Relapsing remitting MS	1166 (92.1)	1054 (93.5)
Secondary progressive MS	41 (4.5)	46 (4.8)
Primary progressive MS	16 (1.3)	1 (0.1)
Primary relapsing MS	2 (0.2)	0 (0)
Other	1 (0.1)	6 (0.6)
Unknown	40 (3.2)	19 (1.7)
History of DMT use for MS prior to inclusion, n (%)
None	456 (36.0)	267 (23.7)
One DMT	372 (29.4)	409 (36.3)
Two DMT	211 (16.7)	242 (21.5)
≥ 3 DMT	227 (17.9)	209 (18.5)

Note. The Norwegian MS Registry and Biobank categorization does not include secondary progressive MS or primary relapsing MS; instead, they report data on relapsing remitting MS, primary progressive MS, and unknown. Denmark, Finland, and MSBase are able to report patients with “Other” MS course. Percentages are calculated out of 906 for the cladribine cohort and out of 968 for fingolimod.

Abbreviations. DMT, disease-modifying therapy; MS, multiple sclerosis; MSBase, Multiple Sclerosis database; MSDS 3D, Multiple Sclerosis Management System 3 Dimension; NTD, NeuroTransData; SD, standard deviation.

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