Merck KGaA announced results of the two-year ( 96-week ) placebo-controlled CLARITY Phase III trial using Cladribine tablets to treat patients with relapsing-remitting multiple sclerosis.
The results of the pivotal trial have shown that annual short-course treatment with Cladribine tablets led to a significant reduction in the rate of clinical relapses, disability progression and brain lesions, as well as a significant increase in the proportion of patients who remained relapse-free.

The data were presented today for the first time at the 61st Annual Meeting of the American Academy of Neurology in Seattle.

The results from both Cladribine tablets treatment groups in the study demonstrated a statistically significant reduction in the annualized rate of relapses compared to placebo ( primary endpoint ). Patients treated with the low-dose regimen of Cladribine tablets experienced a 58% relative reduction in annualized relapse rates with respect to placebo ( 0.14 versus 0.33 for the placebo group; p<0.001 ). Patients in the high-dose regimen group experienced a 55% relative reduction in annualized relapse rates with respect to placebo ( 0.15 versus 0.33; p<0.001 ).

The proportion of patients who remained relapse-free ( one secondary endpoint of the trial ) was significantly higher in the Cladribine tablets treatment groups than in the placebo group. Over the two-year period of the study, 80% of the patients treated with the low dose regimen of Cladribine tablets and 79% of the patients treated with the high-dose regimen experienced no clinical relapse, compared with 61% of the patients from the placebo group ( p<0.001 for both dose regimens ). Therefore, the relative risk to relapse in patients treated with Cladribine tablets was approximately half of that seen in patients on placebo.

Treatment with Cladribine tablets led to a more than 30% reduction in the risk of disability progression ( another secondary endpoint ) relative to placebo over the two-year period of the study ( low-dose regimen: hazard ratio=0.67; p=0.018 – high-dose regimen: hazard ratio=0.69; p=0.026 ). Progression of disability was measured by a 1-point or greater increase in the Expanded Disability Status Scale ( EDSS ) sustained for at least three months ( or at least a 1.5 point increase if baseline EDSS was 0; or 0.5 point increase if baseline EDSS was 5.0 and above ).

Sustained and statistically significant reductions in different types of brain lesions as measured by each of the pre-specified key magnetic resonance imaging ( MRI ) secondary endpoints were shown and were consistent with clinical outcomes. Over the two year period of the study, both dose regimens of Cladribine tablets demonstrated a statistically significant reduction of at least 70% in the mean number of active T1 gadolinium-enhanced lesions per subject per scan, the mean number of active T2 lesions per subject per scan, as well as the mean number of combined unique lesions per subject per scan, compared to placebo ( reductions ranging from 73% to 88% depending on MRI measure and dose group; p<0.001 for each of these MRI measures and for both dose regimens ).

Overall, the frequencies of adverse events by MedDRA System Organ Class in both Cladribine treatment groups were comparable to those observed in the placebo group. The most commonly reported adverse events were headaches, nasopharyngitis, upper respiratory tract infections and nausea. Lymphopenia, an expected event based on the presumed mechanism of action of Cladribine, occurred more frequently in the Cladribine tablets treatment groups ( low-dose regimen: 22%; high-dose regimen: 31%; placebo: 2% ).

The overall rate and incidence of infections in patients treated with Cladribine tablets and placebo were similar. Herpes zoster infections were reported in 2.3% of patients treated with Cladribine tablets. These herpes infections were localized to the skin and responded appropriately to treatment.

In patients treated with Cladribine tablets, four malignancies were reported during the study ( cervical stage 0, melanoma, ovarian and pancreatic ), and a case of choriocarcinoma was reported at week 14 of gestation in a Cladribine-treated patient who became pregnant six months after completion of the study. Observed malignancies were isolated cases across different organ systems. The current ongoing clinical studies with Cladribine tablets will provide data on a larger patient population and a longer duration of treatment to collect more conclusive information on this safety aspect.

Source: Merck KgaA, 2009

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