E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing forms of multiple slerosis
Esclerosis multiple (EM) con recaidas |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048393 |
E.1.2 | Term | Multiple sclerosis relapse |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
- 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 α4/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. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub-study is included in this protocol. It's a pharmacodynamic sub-study with in addition an investigation of a kinetic-dynamic relationship. |
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E.3 | Principal inclusion criteria |
• written informed consent; • able to understand the nature of the study and its potential risks; • willing to comply with the study's safety precautions and with the intended drug-free long-term follow-up over the telephone; • 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 0-5.5, inclusive; • female and male subjects aged 18-55 years inclusive at time of informed consent; • at least one clinical relapse 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 screening T1 scan or, • Gd enhancement on an MRI scan during the past 12 months or, • at least two new T2 lesions during the past 12 months; • failed prior treatment with beta-interferons due to lack of efficacy or tolerability; • female subjects of childbearing potential must agree to practice one of the following contraception method: • double-barrier contraception (i.e., using a male or female condom with spermicide, or diaphragm or cervical cap with spermicide) or • any contraceptives containing estrogens plus one of the following: diaphragm or cervical cap with spermicide, male or female condom with spermicide or • intrauterine devices or • contraceptives containing progestins only, e.g., etonogestrel or levonorgestrel or medroxyprogesterone or norethindrone or • monogamous relationship with vasectomized partner or, • sexual abstinence. Note: Lack of childbearing potential will be considered under these circumstances: • post-menopausal for at least two years, • bilateral oophorectomy, ovariectomy, salpingectomy, or tubal ligation, • hysterectomy; • congenital sterility. • negative pregnancy tests at screening and at baseline for female subjects of childbearing potential; • full immunocompetency: CD4+ lymphocyte count within reference range; • JC viral DNA particles undetectable in blood at two separate measurements. |
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E.4 | Principal exclusion criteria |
• type of MS other than relapsing; • any disease other than MS that could better explain the subject's signs and symptoms; • any conditions that could interfere with the MRI or any other evaluation in the study; • any clinically significant disease state or findings other than MS, in particular neoplastic disease or organ transplantation (in case of doubt, UCB's responsible medical officer will be consulted and a joint documented decision will be made between investigator and UCB's medical officer); • any clinically significant deviation from reference ranges in laboratory tests or any abnormal, clinically significant ECG findings, in particular any marked pre-study prolongation of the QTcB interval, i.e., if both, the Screening (V1) and the Baseline (V3) ECG demonstrate a QTcB interval >450 ms (in case of doubt, UCB's responsible medical officer will be consulted and a joint documented decision will be made between investigator and UCB's medical officer); • any significant deviation from reference ranges for hepatic function as defined by either SGOT, SGPT, GGT, or AP elevated 3-fold or higher beyond the upper limit of the reference range or total bilirubin elevated 2-fold or higher beyond the upper limit of the reference range; • signs of silent infections, including positive tests for HIV1, HIV2, or Hepatitis B or Hepatitis C, or tuberculosis; • any condition possibly interfering with drug absorption; • known allergy to gadolinium-DTPA, and/or ingredients of the study drug formulation; • history of severe AEs to any drug; • participation in any clinical drug trial within 30 days prior to screening; • concomitant treatment with theophylline or warfarin or the following drugs known for their potential to interfere with cardiac repolarization: amiodarone, arsenic trioxide, bepredil, budipine, cisapride, chinidine (quinidine), chloroquine, chlorpromazine, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, sotalol, sparfloxacin, thioridazine • pre-treatment with the following substances prior to screening within the following time frames: • at any time: natalizumab, mitoxantrone or cyclophosphamide; total lymphoid irradiation; anti-lymphocyte monoclonal antibody treatment (e.g., anti-CD4, Campath-1H); • up to 30 days prior to screening: any interferons, glatiramer acetate, corticosteroids and ACTH, IvIg, cyclosporine A, human antibodies, any other immunomodulating or immunosuppressive drugs including recombinant cytokines, any other putative or experimental MS treatment; • six month prior to screening: azathioprine • pregnancy or lactation; • history of alcohol or drug abuse within the year before screening; • medical, psychiatric or other conditions that compromise the subject's ability to understand the subject information, to give informed consent, to comply with the trial protocol, or to complete the study; • any reason why, in the investigator's opinion, the subject should not participate.
If a subject suffers a relapse during the screening phase, he/she may not be randomized on the planned SoT visit. He/she may be randomized 30 days ± 3 days after the end of the last relapse. |
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E.5 End points |
E.5.1 | 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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |