9%) and 5.25 mg/kg (89.0%) treatment groups completed the full 96 weeks of the study.
Patients were required to have at least 1 relapse in the previous 12 months. In the overall study population, the median age was 39 years (range 18 to 65), and the female to male ratio was approximately 2:1. The mean duration of MS prior to study enrolment was 8.7 years, and the median baseline neurological disability based on Kurtzke Expanded Disability Status Scale (EDSS) score across all treatment groups was 3.0 (range 0 to 6.0). Over two thirds of the study patients were treatment-naive for MS disease-modifying drugs (DMDs). The remaining patients were pre-treated with either interferon beta-1a, interferon beta-1b, glatiramer acetate or natalizumab.
Patients with relapsing-remitting MS receiving cladribine 3.5 mg/kg showed statistically significantly improvements in the annualised relapse rate, proportion of patients relapse-free over 96 weeks, proportion of patients free of sustained disability over 96 weeks and time to 3-month EDSS progression compared to patients on placebo (see Table 3).
Table 3 Clinical outcomes in the CLARITY study (96 weeks)
Parameter
Placebo
(n = 437)
Cladribine cumulative dose
3.5 mg/kg
(n = 433)
5.25 mg/kg
(n = 456)
Annualised relapse rate (95% CI)
0.33 (0.29, 0.38)
0.14* (0.12, 0.17)
0.15* (0.12, 0.17)
Relative reduction (cladribine vs. placebo)
57.6%
54.5%
Proportion of patients relapse-free over 96 weeks
60.9%
79.7%
78.9%
Time to 3-month EDSS progression, 10th percentile (months)
10.8
13.6
13.6
Hazard ratio (95% CI)
0.67* (0.48, 0.93)
0.69* (0.49, 0.96)
* p <0.001 compared to placebo
In addition, the cladribine 3.5 mg/kg treatment group was statistically significantly superior to placebo with regard to number and relative reduction of T1 Gd+ lesions, active T2 lesions and combined unique lesions as demonstrated in brain MRI over the entire 96 weeks of the study. Patients taking cladribine compared to the placebo treatment group had 86% relative reduction in the mean number of T1 Gd+ lesions (adjusted mean number for cladribine 3.5 mg/kg, and placebo groups were 0.12 and 0.91, respectively), 73% relative reduction in the mean number of active T2 lesions (adjusted mean number for cladribine 3.5 mg/kg, and placebo groups were 0.38 and 1.43, respectively) and 74% relative reduction in the mean number of combined unique lesions per patient per scan (adjusted mean number for cladribine 3.5 mg/kg, and placebo groups were 0.43 and 1.72, respectively) (p <0.001 across all 3 MRI outcomes).
Post-hoc analysis of time to 6-month confirmed EDSS progression resulted in a 47% reduction of the risk of disability progression in the cladribine 3.5 mg/kg compared to placebo (hazard ratio = 0.53, 95% CI [0.36, 0.79], p <0.05); in the placebo group the 10th percentile was reached at 245 days, and not reached at all during the study period in the cladribine 3.5 mg/kg group.
As shown in Table 3 above, higher cumulative doses did not add any clinically meaningful benefit, but were associated with a higher incidence in ≥grade 3 lymphopenia (44.9% in the 5.25 mg/kg group vs. 25.6 % in the 3.5 mg/kg group).
Patients who had completed the CLARITY study could be enrolled in CLARITY Extension. In this extension study, 806 patients received either placebo or a cumulative dose of cladribine 3.5 mg/kg (in a regimen similar to that used in CLARITY) over the 96-week study period. The primary objective of this study was safety, whi |
