CLARITY
Cladribine
CLARITY showed that two short annual courses of oral cladribine produced sustained reductions in relapses, disability progression, and MRI activity.
- Phase
- Phase III
- Population
- Relapsing-remitting multiple sclerosis (RRMS)
- Controlled period
- Apr 2005 — Nov 2008
What was compared
Cladribine 3.5 mg/kg
Cumulative oral dose delivered in short treatment courses
Placebo
Matching short oral courses
Additional randomized arm
Cladribine 5.25 mg/kg
Higher cumulative oral dose in short treatment coursesPrimary endpoint
Annualized relapse rate
96 weeks
Primary endpoint results
Annualized relapse rate
Relapses per participant-year
Both cumulative doses reduced relapse rate versus placebo (P<0.001).
Selected secondary outcomes
HR 0.67 for 3.5 mg/kg and 0.69 for 5.25 mg/kg versus placebo.
79.7% and 78.9% versus 60.9% with placebo.
Who was studied
Key inclusion criteria
- Age 18–65 years
- RRMS diagnosis based on McDonald criteria 2001
- Baseline EDSS 0–5.5; body weight 40–120 kg
- At least 1 relapse in the previous 12 months
- MRI lesions consistent with MS
Key exclusion criteria
- Failure of at least 2 previous DMTs
- Previous immunosuppressive therapy
- Cytokine therapy, intravenous immunoglobulin, or plasmapheresis within 3 months
- Prespecified abnormal blood counts or a disorder compromising immune function
- Relapse within 28 days before entry
Participants at baseline
| Characteristic | Cladribine 3.5 mg/kgN=433 | Cladribine 5.25 mg/kgN=456 | PlaceboN=437 |
|---|---|---|---|
| Age, years — mean ± SD | 37.9 ± 10.3 | 39.1 ± 9.9 | 38.7 ± 9.9 |
| Female sex — n (%) | 298 (68.8%) | 312 (68.4%) | 288 (65.9%) |
| Time since MS symptom onset, years — mean ± SD | 7.9 ± 7.2 | 9.3 ± 7.6 | 8.9 ± 7.4 |
| EDSS — mean ± SD | 2.8 ± 1.2 | 3.0 ± 1.4 | 2.9 ± 1.3 |
| Previous DMT use — n (%) | 113 (26.1%) | 147 (32.2%) | 142 (32.5%) |
| Gadolinium-enhancing T1 lesions present — n (%) | 138 (31.9%) | 147 (32.2%) | 128 (29.3%) |
SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy.
Source: Giovannoni et al., NEJM 2010, Table 1
Safety signal
- Lymphocytopenia occurred in 21.6% and 31.5% of the cladribine groups versus 1.8% with placebo.
- Herpes zoster occurred in 8 and 12 cladribine-treated participants and none receiving placebo.
Why it mattered
CLARITY showed that brief annual courses of oral cladribine could produce sustained relapse and MRI effects across a 96-week study. It established an immune-reconstitution approach in which the treatment schedule differed from continuous daily maintenance therapy.
Important limitation
The 96-week trial could not settle long-latency safety questions; benefit–risk interpretation depends on careful attention to lymphocyte suppression and longer follow-up.