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

Abstract

Background: The 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.

Methods: Patients 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.

Results: At 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.

Conclusion: A 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.

Keywords: cladribine; extension study; magnetic resonance imaging; relapsing–remitting multiple sclerosis.

Conflict of interest statement

Conflict of interest statement: GC has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, Receptos, Biogen Idec, Genentech-Roche, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Receptos, Biogen Idec, Genentech-Roche, Merck, Biogen Dompè, and Bayer Schering. SC has received honoraria for lectures/consultations from Merck, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals and Actinobac Biomed Inc.; has served on advisory boards for Bayer HealthCare, Merck, Actinobac Biomed, Teva Pharmaceuticals, and Biogen Idec; and received grant support from Bayer HealthCare. KR has received honoraria for lectures and steering committee meetings from EMD Serono, Biogen Idec, Sanofi-Aventis, Genzyme, Novartis, Teva Neurosciences, Acorda and Roche/Genentech. PS-S has served on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck, Teva, Novartis, Roche, and Genzyme. PV has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Merck, Celgen, Roche and Almirall; and research support from Biogen, Sanofi-Genzyme, Bayer, and Merck. AA and FD are employees of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. GG has received speaker honoraria and consulting fees from Abbvie, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec FivePrime, GlaxoSmithKline, GW Pharma, Merck, Pfizer Inc., Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd., Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck, Novartis and Ironwood.

Figures

Figure 1.

CLARITY and CLARITY Extension study plan. Assessments of MRI activity were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96 of double-blind treatment, and at the start and end of a 6-month supplemental follow-up period (unless the final double-blind period assessment was within 4 weeks of the start of the supplemental follow up). †patients who received placebo in CLARITY were assigned to treatment with cladribine 3.5 mg/kg in CLARITY Extension. ‡patients who received cladribine 3.5 mg/kg or 5.25 mg/kg in CLARITY were rerandomized to receive placebo or cladribine 3.5 mg/kg in CLARITY Extension. PC 3.5 mg/kg, placebo in CLARITY/cladribine 3.5 mg/kg in CLARITY Extension; CP 3.5 mg/kg, cladribine 3.5 mg/kg in CLARITY/placebo in CLARITY Extension; CC 7.0 mg/kg, cladribine 3.5 mg/kg in CLARITY/cladribine 3.5 mg/kg in CLARITY Extension; CC 8.75 mg/kg, cladribine 5.25 mg/kg in CLARITY/cladribine 3.5 mg/kg CLARITY Extension; CP 5.25 mg/kg, cladribine 5.25 mg/kg in CLARITY/placebo in CLARITY Extension; SUPF, supplemental follow up; MRI, magnetic resonance imaging; RRMS, relapsing–remitting multiple sclerosis.

Figure 2.

Mean number of T1 gadolinium-enhanced lesions in all patients at CLARITY baseline and in the cladribine tablet 3.5 mg/kg in CLARITY/placebo in CLARITY Extension and 5.25 mg/kg groups during CLARITY Extension, according to gap duration. Error bars indicate standard deviation. CP, cladribine tablet in CLARITY/placebo in CLARITY Extension; Gd+, gadolinium enhanced.

Figure 3.

Proportion of patients with no T1 gadolinium-enhanced lesions in the cladribine tablet 3.5 mg/kg in CLARITY/placebo in CLARITY Extension and 5.25 mg/kg groups during CLARITY Extension according to gap duration. Error bars indicate 95% confidence intervals. CP, cladribine tablet in CLARITY/placebo in CLARITY Extension; Gd+, gadolinium enhanced.