E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing forms of multiple slerosis |
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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; • 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 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 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 or glatiramer acetate due to lack of efficacy or tolerability; • female subjects of childbearing potential must agree to practice one of the following contraception method: • Any of the following systemic hormonal contraceptives having a PEARL index <1% in combination with double-barrier contraception: • combined oral contraceptives; • the "new mini-pill" with high-dose desogestrel (Cerazette); Note: Systemic hormonal contraception with other progestogene- only pills (i.e., the traditional "mini-pill") is not allowed. • implants, patches, or depot injections. Note: double-barrier contraception is defined for this trial as a combination of local mechanical and chemical contraception, i.e., a male or female condom, a diaphragm or cervical cap, all in conjunction with spermicide • intrauterine devices releasing levonorgestrel (Mirena); 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 >500/mm3; • 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 contrast-enhanced MRI, including an estimated glomerular filtration rate (eGFR) <=60ml/min, or with 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 the CYP1A substrates mexiletine, propafenone, theophylline, verapamil or warfarin or statins (e.g., atorvastatin), or rosiglitazone, pioglitazone, repaglinide, amodiaquine and any other compound metabolized primarily through cytochrome P450 2C8, or protease inhibitors (e.g., ritonvavir), systemic triazole antifungals (e.g., ketoconazole) for either their interference with transport protein systems or for their strong inhibition of the P450 cytochrome pathway, or these 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 study participation within the following time frames: • at any time: rituximab, mitoxantrone or cyclophosphamide; total lymphoid irradiation; anti-lymphocyte monoclonal antibody treatment (e.g., anti-CD4, Campath-1H); cladribine, mycophenolate; • up to 30 days prior to baseline: 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; any inoculation with attenuated live vaccines • six month prior to baseline: azathioprine or natalizumab. Treatment with natalizumab must not have been terminated due to lack of efficacy, however subjects with documented natalizumab neutralizing antibodies may be admitted after the wash-out period specified above. • 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 after the last dose of steroid treatment for the relapse. If no steroid treatment was given for the relapse, he/she may be randomized 30 days after the clinical relapse activity has ended or stabilized in the opinion of the investigator. Both screening and re-screening investigations will be documented in two separate CRF’s. |
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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 1. 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), totals serum protein, albumin, total cholesterol and glucose • hematology: erythrocytes, leukocytes, differential leukocyte count including immature forms, 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; QTcF; ∆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) 2. Class-related • pre-post status for markers for infectious diseases: • Tuberculosis • Toxoplasmosis • 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 3. 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 | 9 |
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 | 3 |
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 | 3 |
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 |