Cost-effectiveness of cladribine tablets versus fingolimod in patients with highly active relapsing multiple sclerosis in Portugal

Figures & data

Figure 1. Markov model.

Table 1. Initial HDA patient distribution, by EDSS state.

EDSS state
0	1	2	3	4	5	6	7	8	9
2.8%	2.8%	32.5%	21.5%	23.4%	11.1%	5.9%	0%	0%	0%

Abbreviations. HDA, high-disease activity; EDSS, expanded disability status scale.

Source: EMD Serono, data on file.

Table 2. Annual transition probability matrix by EDSS state (MS age of onset ≥28 years), after adjustment for HDA-RRMS.

EDSS from/to	0 (%)	1 (%)	2 (%)	3 (%)	4 (%)	5 (%)	6 (%)	7 (%)	8 (%)	9 (%)
0	60.5	26.3	9.4	2.8	0.5	0.2	0.2	0.0	0.0	0.0
1	5.8	61.8	20.7	8.0	2.2	0.6	0.8	0.1	0.0	0.0
2	1.6	12.1	52.9	22.0	5.8	2.4	2.8	0.2	0.1	0.0
3	0.6	5.0	12.0	45.9	11.9	7.6	15.2	1.3	0.5	0.0
4	0.2	2.2	6.7	11.5	39.9	13.5	21.8	3.3	0.9	0.1
5	0.1	0.5	2.9	5.9	8.7	39.2	35.2	5.0	2.4	0.1
6	0.0	0.1	0.4	2.5	3.1	4.1	68.8	14.6	5.9	0.6
7	0.0	0.0	0.1	0.2	0.7	0.4	11.7	69.3	16.1	1.6
8	0.0	0.0	0.0	0.0	0.1	0.1	1.9	5.6	90.3	2.1
9	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.6	17.4	81.8

Abbreviations. EDSS, expanded disability status scale; HDA-RRMS, high disease activity- relapsing remitting multiple sclerosis. Source: Palace et al.²² and CLARITY trial.

Table 3. SPMS conversion probabilities, by EDSS state.

EDSS state	Median time to SPMS conversion (years)	Transition probability (%)
0	0	0.0
1	15	4.5
2	11	6.1
3	7	9.4
4	6	10.9
5	4	15.9
6	3	20.6
7–9	2	29.3

Abbreviations. EDSS, expanded disability status scale; SPMS, secondary progressive multiple sclerosis. Source: Ebers²³.

Table 4. Annual transition probability matrix by EDSS state for SPMS.

EDSS from/to	2 (%)	3 (%)	4 (%)	5 (%)	6 (%)	7 (%)	8 (%)	9 (%)
2	74.4	18.7	2.1	2.8	1.8	0.1	0.1	0.0
3	0.0	70.4	15.9	3.1	9.6	0.5	0.4	0.0
4	0.0	0.0	66.4	13.8	18.1	0.9	0.9	0.0
5	0.0	0.0	0.0	57.4	37.4	2.6	2.6	0.0
6	0.0	0.0	0.0	0.0	87.4	4.8	7.7	0.0
7	0.0	0.0	0.0	0.0	0.0	76.1	23.5	0.4
8	0.0	0.0	0.0	0.0	0.0	0.0	99.6	0.4
9	0.0	0.0	0.0	0.0	0.0	0.0	0.0	100.0

Abbreviations. EDSS, expanded disability status scale; SPMS, secondary progressive multiple sclerosis. Source: Ebers²³.

Table 5. Annualized relapse rate by EDSS state and MS classification.

EDSS state	RRMS	SPMS
0	0.890	0.000
1	0.789	0.000
2	0.648	0.605
3	0.616	0.515
4	0.553	0.487
5	0.525	0.423
6	0.515	0.360
7	0.448	0.303
8	0.367	0.251
9	0.296	0.217

Abbreviations. EDSS, expanded disability status scale; MS, multiple sclerosis; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. Source: UK MS Trust³⁰.

Table 6. MS standardised mortality ratios by EDSS state.

EDSS state	Mortality multiplier
0	1.000
1	1.430
2	1.600
3	1.637
4	1.674
5	1.842
6	2.273
7	3.097
8	4.447
9	6.454

Abbreviation. EDSS, expanded disability status scale. Source: Sadovnick et al.²⁶.

Table 7. Relative clinical efficacy of cladribine tablets and fingolimod, vs. placebo.

Treatment related inputs	Cladribine tablets	Fingolimod
EDSS state progression (HR vs. placebo)	0.281 (0.148–0.532)	0.620 (0.416–1.018)
Annualized relapse rate (RR vs. placebo)	0.356 (0.242–0.506)	0.375 (0.269–0.507)

Abbreviations. EDSS, expanded disability status scale; HR, hazard ratio; RR, rate ratio. 95% credible interval in parenthesis.

Table 8. Mean utility scores.

Event	Patients		Caregivers
	RRMS	SPMS	RRMS/SPMS
EDSS 0	0.870	−0.045	−0.002
EDSS 1	0.799		−0.002
EDSS 2	0.705		−0.002
EDSS 3	0.574		−0.045
EDSS 4	0.610		−0.142
EDSS 5	0.518		−0.160
EDSS 6	0.460		−0.173
EDSS 7	0.297		−0.030
EDSS 8	−0.049		−0.095
EDSS 9	−0.195		−0.095
Relapse	−0.071		0

Abbreviations. EDSS, expanded disability status scale; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Table 9. Estimated annual costs, by EDSS.

EDSS state	Disease management (€)	Relapse (€)
0–3	1,185	1,567
4	5,004	2,347
5	6,781	2,178
6	8,557	2,009
7–9	12,677	1,706

Abbreviation. EDSS, expanded disability status scale.

Table 10. Model inputs related to adverse events.

Event	Probability of event		Desutility per event^27	One-off costs (€)	Source of probabilities
	Cladribine tablets (%)	Fingolimod (%)
Progressive multifocal leukoencephalopathy	0.0	0.001	−0.200	3,233	MS Trust (2016) e EMA^24
Serious infection	2.8	2.2	−0.190	1,917	NMA
Macular oedema	0.0	0.4	−0.400	95	Pooled data
Gastrointestinal disorder	24.5	30.4	−0.240	906	NMA
Thyroid related event	5.1	1.2	−0.110	1,034	NMA
Influenza-like symptoms	1.3	0.5	−0.210	16	NMA
Malignancy	0.6	0.6	−0.116	5,290	Pakpoor et al. (2015)

Abbreviation. NMA, network meta-analysis.

Table 11. Parameters and distributions used in probabilistic sensitivity analysis.

Parameters	Distribution
Mean initial age	Lognormal
Number of relapses on previous year	Lognormal
Weight distribution	Dirichlet
EDSS initial distribution	Dirichlet
Mortality rate	Lognormal
Annualized relapse rate	Lognormal
Proportion of patients with rescue therapy	Beta
Transition probabilities for SPMS	Dirichlet
Transition probabilities for RRMS	Dirichlet
HDA adjustment factor	Lognormal
Progression risk (HR vs. placebo)	Lognormal
Relapse rate (RR vs. placebo)	Lognormal
Rescue therapy risk (OR vs. placebo)	Lognormal
Withdraw risk	Beta
Adverse events risk	Beta
RRMS utility decrements	Lognormal
SPMS utility decrement	Lognormal
Utility decrement for caregivers RRMS/SPMS	Lognormal
Utility decrement by relapse/adverse events	Lognormal
Adverse events costs	Lognormal
Costs by EDSS state/relapse	Gamma
Salvage therapy duration	Normal

Abbreviations. EDSS, expanded disability status scale; HDA, high-disease activity; HR, hazard ratio; RR, rate ratio; OR, odds ratio; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Table 12. Results for estimated costs and consequences (base-case scenario).

	Cladribine tablets	Fingolimod	Incremental
Total costs (€)	190,076€	216,012€	−25,935€
Treatment	49,779€	65,985€	−16,206€
Administration	0€	20€	−20€
Monitoring	244€	478€	−234€
EDSS	129,207€	139,445€	−10,238€
Relapse	9,947€	9,720€	227€
Rescue therapy	536€	0€	536€
Adverse events	363€	364€	0€
QALY	3.42	2.58	0.85
ICUR (€/QALY)			−30,651€/QALY

Abbreviations. QALY, Quality adjusted life years; ICUR, incremental cost-utility ratio.

Table 13. One-way deterministic sensitivity analyses results.

	Incremental values
	Costs (€)	QALY
Base-case	−25,935	0.85
Costs
EDSS state
+20%	−27,983	0.85
−20%	−23,888	0.85
Sá et al.^40	−28,274	0.85
Relapse
+20%	−25,890	0.85
−20%	−25,981	0.85
Sá et al.^40	−25,742	0.85
Unique cost (equal to 1,845 €)	−25.898	0.85
EDSS and relapse
+20%	−27,938	0.85
−20%	−23,933	0.85
Sá et al.^40	−28,081	0.85
Health-related quality of life
Hawton et al.^42	−25,935	0.79
Sá et al.^40 – Portuguese tariffs	−25,935	0.81
Without disutility by adverse events	−25,935	0.85
Without caregivers’ disutility	−25,935	0.80
No adverse events	−25,935	0.85
11-state model structure	−55,006	0.84
Progression based on London Ontario data	−22,343	0.62
Without HDA subgroup adjustment	−28,603	0.74
RRMS transition by disease duration	−47,786	0.85
Relapse rate by disease duration	−26,464	0.85
Fixed mortality (HR =1.68)	−27,303	0.88
Discontinuation
No discontinuation	−36,075	0.81
Same probability of treatment withdrawal for both arms (4.9%)	−31,288	0.79
Waning effect
No cladribine tablets effect after third year	−20,920	0.44
No cladribine tablets effect after second year	−17,485	0.17
Assume the same waning effect of fingolimod for cladribine tablets	−29,079	1.12
Assume the same waning effect of cladribine tablets for fingolimod (full efficacy for 4 years)	−25,749	0.80
No waning effect for both cladribine tablets and fingolimod	−40,966	2.04
Discount rate
7%	−22,065	0.72
3%	−30,361	1.01
0%	−37,973	1.38
Time horizon (years)
30	−26,249	0.84
40	−26,014	0.85

Abbreviations. QALY, Quality adjusted life years; EDSS, expanded disability status scale; HDA, high-disease activity; HR, hazard ratio.

Figure 2. Cost-effectiveness scatter plot.

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