Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing–remitting multiple sclerosis: the CLARITY Extension study

Abstract

BackgroundThe CLARITY and CLARITY Extension studies demonstrated that treatment of relapsing–remitting multiple sclerosis (RRMS) with cladribine tablets (CT) results in significant clinical improvements, compared with placebo. This paper presents the key magnetic resonance imaging (MRI) findings from the CLARITY Extension study.MethodsPatients who received a cumulative dose of either CT 3.5 or 5.25 mg/kg in CLARITY were rerandomized to either placebo or CT 3.5 mg/kg in CLARITY Extension. Patients from the arm that received placebo in CLARITY were assigned to CT 3.5 mg/kg. MRI assessments were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96, and in a supplemental follow-up period.ResultsAt CLARITY Extension baseline, patients who received placebo during CLARITY had more T1 gadolinium-enhanced (Gd+) lesions than patients who received CT during CLARITY. These patients, who were then exposed to cladribine 3.5 mg/kg during the extension, experienced a 90.4% relative reduction (median difference −0.33, 97.5% confidence interval −0.33–0.00; p < 0.001) in T1 Gd+ lesions at the end of the extension compared with the end of CLARITY. Overall, the majority of patients in each treatment group remained free from T1 Gd+ lesions throughout CLARITY Extension. However, a small proportion of patients who were treated with cladribine in CLARITY and received placebo in CLARITY Extension showed evidence of increased MRI activity, and this was associated with a prolonged treatment gap between CLARITY and CLARITY Extension.ConclusionA 2-year treatment with CT 3.5 mg/kg has a durable effect on MRI outcomes in the majority of patients, an effect that was sustained in patients who were not retreated in the subsequent 2 years after initial treatment. ClinicalTrials.gov identifier: NCT00641537

Cladribine Tablets and Relapsing–Remitting Multiple Sclerosis: A Pragmatic, Narrative Review of What Physicians Need to Know

“…the majority of patients for at least a further 2 years, without further treatment and despite recovery of median total lymphocyte counts to within the normal range. There was some increase in lesion activity on the MRI scans in patients in CLARITY Extension who received cladribine tablets 3.5 mg/kg in the initial (2-year) phase and then received placebo in the extension phase [16]. This increased lesion activity was mainly in patients who entered the extension phase more than 43 weeks after the end of the randomised phase [16].…”

“…The clinical efficacy of cladribine tablets 3.5 mg/kg was evaluated in 1326 patients with RRMS in the CLAdRIbine Tablets treating multiple sclerosis orallY (CLARITY) study, a randomised, placebo-controlled, 96-week clinical trial (Table 1) [10]. Briefly, compared to placebo, cladribine tablets 3.5 mg/kg was associated with 47% reduction in the risk of 6-month EDSS progression in a subgroup with high disease activity at baseline lower relapse rates, a higher proportion of patients with no evidence of disease activity, less progression of disability and a reduction in disease activity as measured by magnetic resonance imaging (MRI) [10][11][12][13][14][15][16]. The reduction in disability progression was greater in patients with higher indices of disease activity at baseline than in those without higher baseline indices of disease activity [13].…”

“…Treatment with cladribine tablets 5.25 mg/kg was also evaluated in the CLARITY study, where it demonstrated a similar efficacy in MS but a greater potential for lymphopenia; accordingly, this dose is not used clinically and is not described in this article. CLARITY Extension was a 2-year extension to CLARITY (n = 806) [15,16]. The annualised relapse rate was 0.10 (95% confidence interval [CI] 0.06-0.13) for 186 patients who received cladribine tablets 3.5 mg/kg in both CLARITY and CLARITY Extension and 0.15 (95% CI 0.09-0.21) for 98 patients who received cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY Extension; 81.2 and 75.6% of patients, respectively, remained relapse-free over 4 years [15].…”

Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing–Remitting Multiple Sclerosis Patients? A Narrative Review

“…Clinical trials have demonstrated the efficacy of Cladribine Tablets 3.5 mg/kg over 2 years of follow-up in patients with RMS, including reductions in relapse rates, magnetic resonance imaging (MRI)-based disease activity and progression of disability [46][47][48]. Longer-term efficacy was observed in an extension to a clinical trial in RMS patients that involved a total of 4 years of follow-up [49,50]. Importantly, in this extension study, relapse rates were similar for patients who continued to receive Cladribine Tablets 3.5 mg/kg and those who were re-randomized to placebo [49].…”

An Overview of High-Efficacy Drugs for Multiple Sclerosis: Gulf Region Expert Opinion

“…Cladribine tablets are indicated for adults with highly active RMS as defined by clinical and radiological features [ 30 ]. In clinical trials, cladribine tablets significantly reduced the ARR, probability of disability progression, and brain lesions as compared to placebo over 96 weeks in patients with RRMS [ 11 , 16 , 17 ]. The most common adverse event associated with cladribine tablets is lymphopenia [ 30 ].…”