CLASSIC-MS (CLARITY/CLARITY Extension Cohort)
(2023)Objective
To evaluate the long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension in patients with relapsing multiple sclerosis treated with cladribine tablets.
Study Summary
• 90.0% of patients exposed to cladribine tablets were not using a wheelchair and not bedridden at any time since LPSD (EDSS <7), compared with 77.8% of never-exposed patients (OR=0.39, 95% CI=0.17-0.93, p=0.034), demonstrating sustained long-term mobility benefits
• Patients exposed to cladribine had lower annualized relapse rates (ARR 0.12 vs 0.23), were more likely to remain on no subsequent DMT (55.8% vs 26.8%), and had higher employment rates (51.0% vs 27.5%) compared to never-exposed patients over the median 10.9-year follow-up
Intervention
Cladribine tablets (3.5 mg/kg cumulative dose over 2 years) as administered during the CLARITY and CLARITY Extension parent studies, with long-term follow-up in CLASSIC-MS
Inclusion Criteria
Patients who participated in CLARITY with or without subsequent enrollment in CLARITY Extension, received at least 1 course of cladribine tablets or placebo during the parent studies, and were able to provide informed consent at the time of enrollment in CLASSIC-MS.
Study Design
Arms: Exposed to cladribine tablets (all exposed), Subgroup exposed to cladribine tablets 3.5 mg/kg cumulative dose over 2 years, Never exposed to cladribine tablets (placebo)
Patients per Arm: All exposed: N=394, Subgroup exposed to 3.5 mg/kg dose: N=160, Never exposed (placebo): N=41
Outcome
• Secondary endpoint: 81.2% (320/394) of exposed vs 75.6% (31/41) of never-exposed patients did not use an ambulatory device at any time since LPSD (EDSS <6); for the 3.5 mg/kg subgroup, 78.8% (126/160) met the endpoint
• Annualized relapse rate since LPSD was 0.12 (95% CI=0.11-0.14) for exposed patients vs 0.23 (95% CI=0.19-0.27) for never-exposed patients; 55.8% of exposed patients required no subsequent DMTs vs only 26.8% of never-exposed patients over the median 10.9-year follow-up
Bottom Line
With a median 10.9 years of follow-up after CLARITY/CLARITY Extension, patients exposed to cladribine tablets demonstrated sustained long-term mobility benefits: 90.0% were not wheelchair-bound or bedridden (vs 77.8% never-exposed, p=0.034), had lower annualized relapse rates (0.12 vs 0.23), less need for subsequent DMTs (55.8% needed no further DMTs vs 26.8%), and higher employment rates (51.0% vs 27.5%), supporting the durable efficacy of cladribine tablets beyond the treatment period.
Major Points
- 90.0% of cladribine-exposed patients maintained long-term mobility (not using wheelchair, not bedridden, EDSS <7) at any time since LPSD over a median 10.9 years, significantly higher than 77.8% of never-exposed patients (OR=0.39, p=0.034).
- 81.2% of exposed patients did not use an ambulatory device at any time since LPSD (EDSS <6), compared with 75.6% of never-exposed patients, with similar results in the 3.5 mg/kg subgroup (78.8%).
- The annualized relapse rate (ARR) since LPSD was approximately half in the exposed cohort (0.12, 95% CI=0.11-0.14) compared to the never-exposed cohort (0.23, 95% CI=0.19-0.27), with 48.0% of exposed patients remaining relapse-free vs 26.8% never-exposed.
- 55.8% of cladribine-exposed patients required no subsequent DMTs after LPSD, compared to only 26.8% of never-exposed patients; time-to-event analysis showed estimated median time to first subsequent DMT of 12.0 years for exposed vs 2.8 years for never-exposed.
- At the 4-year responder analysis, 34.5% of exposed patients were both not using further DMTs and had no evidence of disease reactivation, compared with 14.6% of never-exposed patients.
- Median EDSS score increased by 1.0 point in cladribine-exposed patients (from 2.50 to 3.50) over the follow-up period, compared with a 1.5-point increase in never-exposed patients (from 3.00 to 4.50).
- Employment rates at Study Visit 1 were notably higher in the exposed cohort (51.0%, 201/394) compared to the never-exposed cohort (27.5%, 11/40).
- These findings demonstrate that the benefits of short-course cladribine treatment are sustained long-term without requiring continuous immunosuppression, contrasting with maintenance therapies like natalizumab and fingolimod.
Study Design
- Study Type
- Exploratory, low-interventional, multicenter, ambispective, Phase IV study
- Randomization
- Yes
- Blinding
- Not applicable (open-label observational follow-up; original parent studies were double-blind placebo-controlled)
- Sample Size
- 435
- Follow-up
- Median 10.9 years since last parent study dose (range 9.3-14.9 years)
- Centers
- 98
- Countries
- 29 countries
Primary Outcome
Definition: Long-term mobility: Proportion of patients not using a wheelchair in the 3 months prior to Study Visit 1 and not bedridden at any time since LPSD (EDSS <7)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 77.8% (28/36) of never-exposed patients met the primary endpoint | 90.0% (341/379) of exposed patients met the primary endpoint; 88.2% (134/152) in 3.5 mg/kg subgroup | - (OR=0.39 (0.17-0.93) for all exposed vs never-exposed; OR=0.52 (0.20-1.33) for 3.5 mg/kg subgroup vs never-exposed) | p=0.034 for all exposed vs never-exposed; p=0.173 for 3.5 mg/kg subgroup |
Limitations & Criticisms
- No formal sample size calculations were conducted due to the exploratory nature; the study planned to enroll 788 patients but only achieved 662, and only 435 from the CLARITY/CLARITY Extension cohort were analyzed.
- Significant imbalance between exposure groups (394 exposed vs 41 never-exposed) limits the statistical power of between-group comparisons and increases uncertainty of estimates.
- The ambispective design introduces potential recall and ascertainment biases, particularly for the retrospective component (EDSS scores, wheelchair use, relapse history between parent study end and CLASSIC-MS enrollment).
- Lack of randomization in the follow-up phase means observed differences may be confounded by factors not controlled for, including subsequent DMT use patterns and other treatment decisions.
- Employment status at parent study baseline was not collected, limiting interpretation of employment-related results at Study Visit 1.
- MRI data collected during CLASSIC-MS were limited and could not be used to calculate responder rates based on imaging findings.
- Safety data were not evaluated, having been reported separately in parent studies, preventing assessment of long-term safety alongside efficacy.
- Selection bias is possible since it is unknown what happened to patients from the parent studies who did not enroll in CLASSIC-MS, though baseline characteristics of enrolled vs non-enrolled patients were reportedly similar.
Citation
Multiple Sclerosis Journal 2023; 29(6): 719-730