Double-blind, placebo-controlled, randomized, parallel-group Phase II study in subjects with relapsing forms of multiple sclerosis (MS) to evaluate the safety, tolerability, and effects of two doses of CDP323 over 24 weeks with a rater-blind MRI follow-up over 12 weeks

INTERVENTION: Product Name: CDP323 Product Code: CDP323 Pharmaceutical Form: Capsule, hard CAS Number: 455264‐30‐9 Current Sponsor code: CDP323 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 250‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: Relapsing forms of multiple slerosis ; MedDRA version: 9.1 Level: LLT Classification code 10048393 Term: Multiple sclerosis relapse PRIMARY OUTCOME: Main Objective: Compare the effects of 500 mg CDP323 twice daily on MS‐related imaging parameters in subjects with relapsing MS (RMS) with the effects seen under placebo treatment in that population over a period of 24 weeks Primary end point(s): Primary Efficacy Variable; Cumulative number of newly active lesions over 24 weeks as seen on standardized brain MRI; scans. The following lesions are considered newly active:; • new gadolinium (Gd) enhancement on T1‐weighted images;; • non‐enhancing on T1‐weighted images but new on T2‐weighted images;; • new enlargement on T2‐weighted images but non‐enhancing on T1‐weighted images.; ; Pharmacokinetic and Pharmacodynamic Variables; • for all subjects, plasma concentrations of CDP323, CT7758, and CT533652‐00 will be determined from samples taken during specified time points; a 'sparse' sampling; schedule will be followed; • population‐kinetic methods may be used to describe derived pharmacokinetic; parameters for CDP323, CT7758, and CT533652‐00; • in a subset of centers suitable to set up the logistics for pharmacodynamic tests markers, such markers including VCAM1 binding may be determined; in addition, subjects participating in this pharmacodynamic sub‐study will be asked to also undergo a more intense pharmacokinetic sampling schedule to allow an investigation of a kineticdynamic relationship. Some pharmacokinetic parameters will be computed from this subgroup.; ; Safety Variables; Standard and disease‐related safety variables:; • adverse events (AEs); • vital sign parameters (heart rate, blood pressure, body temperature, body weight); • blood chemistry: sodium, potassium, chloride, calcium, magnesium, urea, creatinine,; SGOT, SGPT, GGT, AP, uric acid, bilirubin (total, conjugated and unconjugated), total; serum protein, albumin, total cholesterol and glucose; • hematology: erythrocytes, leukocytesa, differential leukocyte count including immature formsa, thrombocytes, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC); • thyroid function tests: TSH; • clotting tests: partial thromboplastin time and prothrombin time; • urinalysis: pH, protein, glucose, erythrocytes, leukocytes; • 12‐lead ECG: centrally measured or calculated variables: heart rate, PQ time, QRS; time, and QT time in lead II; QTcB (corrected QT time calculated according to Bazett's; formula); QTcF (corrected QT time calculated according to Fridericia's formula);; ?QTcBV4‐QTcB3, ?QTcBV5‐QTcBV3, ?QTcFV4‐QTcFV3, and ?QTcFV5‐QTcFV3 (i.e.,; differences between QTcB/QTcF calculated at V4 and V5 to the respective values; calculated for Baseline (V3); central overall assessment of normal/abnormal findings; with/without clinical relevance; • proportion of subjects who have worsened by 1.0 EDSS point between the; measurements at 'Start of treatment' (SoT) and EoT (EDSS = Expanded Disability; Status Scale); Class‐related; • pre‐post status for markers for infectious diseases:; • Tuberculosis; • Toxoplasmosis (IgG antibody to Toxoplasma gondii); • time‐course of lymphocyte phenotyping (CD3, CD4, CD8, CD19, and CD25)a; • presence of JC virus DNA in serum and/or PBMCs; • presence of potential signs of progressive multifocal leukencephalopathy (PML)in MRI; • presence of potential clinical signs and/or symptoms of PML; Safety variables related to study drug withdrawal:; • cumulative number of newly active lesions on the two T1/T2 post‐withdrawal scans; • cumulative volume of Gd‐enhancing lesions (new or persisting) on the two T1 postwithdrawal scans; •volume of hyperintense lesions (BOD) on T2 at wk40 or 'End of Study' (EoS); • 'scan activity' on each post‐withdrawal scan; • proportion of 'active' post‐withdrawal scans per subject; • 'subject activity' throughout the drug‐free follow‐up period; • variables related to MS relapses (all at wk40 or EoS); • total number of relapses; • number of relapses confirmed by the investigator; • number of relapses documented otherwise; • number of relapses treated with steroids; • need for hospitalization due to relapses; • proportion of relapse‐free subjects; • proportion of subjects who have worsened by 1.0 EDSS point between the; measurements at EoT and 'End of study' (EoS); • number of 'activity‐free' subjects at wk40 or EoS; ; Secondary Objective: ‐ Compare CDP323's tolerability and safety in RMS subjects with placebo treatment in that population over a period of 24 weeks;; ‐ Compare the effects of CDP323 on the occurrence of relapses in RMS subjects with the effects seen under placebo treatment in that population over a period of 24 weeks;; ‐ Compare the effects of twice daily dosing of CDP323 vs once daily dosing of CDP323 including the related time course of a4/VCAM‐1 binding between the two dosing regimen and placebo;; ‐ Characterize the main pharmacokinetic parameters of CDP323 and its metabolites in subjects suffering from RMS;; ‐ Assess potential withdrawal effects after termination of treatment with CDP323. INCLUSION CRITERIA: • written informed consent; • being of legal capacity and able to understand the nature of the study and its potential risks; • being willing to comply with the study's safety precautions and with the intended drug‐free long‐term follow‐up at the study site 12 months after the last intake of study medication. • diagnosis of MS according to the revised McDonald criteria (Polman et al. Ann Neurol 2005;58:840‐6); • relapsing form of MS, i.e., RRMS or SPMS (with superimposed relapses) according to Lublin and Reingold (Neurology 1996;46:907‐11); • screening EDSS score of 0‐6.0, inclusive; • female and male subjects aged 18‐60 years inclusive at time of informed consent; • clinical relapse activity in the 12 months before screening and documented in the subject's medical records; • active disease, defined by the presence of either, • at least nine lesions on the screening T2 scan or, • Gd enhancement on the scre