A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects with Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY).

INTERVENTION: Product Name: cladribine Product Code: Not Applicable Pharmaceutical Form: Tablet INN or Proposed INN: CLADRIBINE CAS Number: 4291638 Other descriptive name: 2‐chloro‐2’‐deoxyadenosine (2‐CdA) Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Relapsing Remitting Multiple Sclerosis (RRMS) ; MedDRA version: 9.1 Level: PT Classification code 10028245 Term: Multiple sclerosis INCLUSION CRITERIA: ° Were randomised in Trial 25643 and satisfy one of the following: ‐ Completed their randomised treatment course and scheduled visits for the full 96 weeks (a)(b); or ‐ Did not complete the randomized treatment course in Trial 25643, but who elected to receive rescue treatment with Rebif or another DMD, and who completed scheduled clinic visits for the full 96 weeks (a)(b); or ‐ Did not complete the randomised treatment course in Trial 25643, declined rescue with Rebif or another DMD, and still completed scheduled clinic visits for the full 96 weeks (a)(b); or ‐ Did not complete the randomised treatment course in Trial 25643, were not eligible for rescue option with Rebif, and still completed scheduled clinic visits for the full 96 weeks (a)(b). ° Be male or female and between 18 and 65 years of age (inclusive, at time of informed consent prior to entry into Trial 25643) ° Have no medical history or evidence of latent tuberculosis infec PRIMARY OUTCOME: Main Objective: Safety objectives:; • Evaluate the safety of extended treatment with oral cladribine when administered according to a fixed annual dosing schedule to subjects who completed Trial 25643 (CLARITY); • Determine the effect of oral cladribine on QTc interval. Primary end point(s): Note that the safety endpoints and some other endpoints of this trial will utilise observations from the antecedent Trial 25643 and this extension Trial 27820 (if data are available). The specific time points or the following endpoints will be detailed in the statistical analysis section.; ; ° Proportion of subjects with at least one grade 4 CTCAE toxicity on the following parameters of hematologic and hepatic function: absolute lymphocyte count (ALC),; hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin; ; ° Proportion of subjects with grades 3 or 4 adverse events (AEs) for hematologic and hepatic indices; ; ° Mean change in absolute lymphocyte count, hemoglobin level, WBC, ANC, platelets, ALT, AST, and bilirubin; ; ° Incidence of all treatment emergent AEs and SAEs; ; ° Proportion of subjects developing infections, infection‐related AEs and malignancies; ; ° Time to first grade 3 and 4 hematological toxicity or liver toxicity; ; ° Median time to recovery from hemtological and liver toxicity; ; ° Median time to nadir of absolute lymphocyte count and mean time to recovery to normal values; ; ° Mean change in QTc interval from baseline; ; ; Secondary Objective: • Explore the long‐term benefit (rate of disease progression as reflected by rate of change in Expanded Disability Status Score [EDSS] score) of treatment with oral cladribine vs. placebo; • Explore the relationship between oral cladribine treatments and various immunologic parameters, MRI measures of disease activity, clinical relapses and disease progression in subjects previously randomised in Trial 25643; • Determine the benefit of continued oral cladribine treatment on health‐related quality of life and economic outcome measures; • Explore the association between genetic variants, clinical efficacy, MRI endpoints and groups of subject with adverse events (grade 3 and 4 toxicity); • Explore the effect of oral cladribine on gene expression profiles