| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | SCLEROSI MULTIPLA A RICADUTE E REMISSIONI | | SCLEROSI MULTIPLA | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10028245 | | E.1.2 | Term | Multiple sclerosis | | E.1.2 | System Organ Class | 10029205 - Nervous system disorders | |
| 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 | | 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). To assess the safety of clardribine with emphasis on cardiac repolaritation as measured by changes in QT interval (in a subset of patients also partipating in the PK sampling and analysis) | | VEDERE INGLESE | |
| E.2.2 | Secondary objectives of the trial | | 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. Assess population pharmacokinetics (The analysis pertaining to this objective will be provided as an independent report) | | VEDERE INGLESE | |
| 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 | PHARMACOGENETIC:
Vers:
Date:
Title:
Objectives:
| FARMACOGENETICA:
Vers:
Data:
Titolo:
Obiettivi:
ALTRI SOTTOSTUDI:
FARMACOGENOMICA
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| E.3 | Principal inclusion criteria | | Were randomised in Trial 25643 and satisfy one of the following: Completed their randomised treat course and visits for the full 96 weeks (a)(b)or Did not complete the randomized treat course in Trial 25643 but who elected to receive rescue treat with Rebif or another beta-interferon or glatiramer acetate and who completed clinic visits for full 96 weeks or Did not complete the randomised treat course in Trial 25643 declined rescue with Rebif or another betainterferon or glatiramer acetate and still completed clinic visits for the full 96 weeks or Did not complete the randomised treat course in Trial 25643 were not eligible for rescue option with Rebif and still completed clinic visits for the full 96 weeks. 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 infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray; NOTE: For subj with medical history or LTBI ot TB, please refer to Appendices L, M, N. Subjects who should be excluded from blinded medication could be proposed to be followed for safety according to the same visits. All of the following laboratory hematologic parameters must be normal (as defined below inclusively) within 28 days of first dosing of blinded study medication at SD1: - Hemoglobin = 11.6 16.2 G/DL - Leukocyctes (total white blood cells [WBC]) = 4.1 12.3 x 10E3/UL - Absolute lymphocytes = 1.02 3.36 x 10E3/UL - Absolute neutrophil count (ANC) = 2.03 8.36 x10E3/UL - Platelet count = 140-450 x 10E3/UL . Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either: - Be post-menopausal or surgically sterilized; or - Using a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstural cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as those which result in a low failure rate (i.e. less that 1% per year) when used consistently and correctly such as implants, injectables, comined with oral contraceptives, IUSs, sexual abstinence or vasectomised partner. [Note: for Danish sites only, subjects should use a hormonal contraceptive or intrauterine device for the duration of the trial]Treatment of pregnant and nursing women with cladribine is prohibited. If male, he must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication or following early termination or early withdrawal. Voluntarily provide written informed consent, and for USA sites only, a subject authorization under Health Insurance Portability and Accountab Act (HIPAA) Females of childbearing potential, who are either subjects in the trial or who are partners to male subjects in the trial, must use one of the above means of contraception for the entire trial period and for at least 12 weeks after the last dose of trial medication. For the purposes of this trial, women of childbearing potential is defined as:All female subjects after puberty unless they are postmenopausal for at least two years, are surgically sterile or are sexually inactive .... VEDI PROTOCOLLO | | VEDERE INGLESE | |
| E.4 | Principal exclusion criteria | | Have prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening; Have a history of chronic or clinically significant hematological abnormalities; Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values; Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine. Suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/ or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol; History of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease); Have an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-b or any of its excipient(s);Have any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR < 30mL/min/1.73m2); Have a positive stool heme-occult test at Pre-Study Evaluation (PSE); Subject has a history of seizures not adequately controlled by treatment. Concurrent enrolment in any other investigational drug trial with the exception of any Sponsor sub-trial of this protocol that is approved by the Medical Director Any other reason(s) that, in the opinion of the Investigator and/or the Sponsor, would indicate that the subject is unsuitable for inclusion in this extension trial ° Treatment with a beta-interferon or glatiramer acetate less than 3 months prior to Study Day 1 during any gap between completion of CLARITY Trial 25643 and CLARITY Extension Trial 27820 Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at anytime during and since Study 25643. Use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIG) or plasmapheresis since their completion of Trial 25643. Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days before Study Day 1 | | VEDERE INGLESE | |
| E.5 End points |
| E.5.1 | 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 and mean time to recovery from hemtological and liver toxicity ° Median and mean time to nadir of absolute lymphocyte count and mean time to recovery to normal values ° Mean change in QTc interval from baseline | | VEDERE INGLESE | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description | | - Stesso farmaco ad altro dosaggio | | - same IMP used at different dosage | |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | | PRIMA DELLA FINE DELLO STUDIO, LO SPONSOR DETERMINERA' SE CI SARANNO ULTERIORI ESTENSIONI. NEL CASO, IL PROMOTORE NOTIFICHERA' A TUTTI I CENTRI L'IMPLEMENTAZIONE ED I TEMPI DI ATTUAZIONE E SOTTOMETTERA' LA DOCUMENTAZIONE AI CE ED AC PER APPROVAZIONE | |
| 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 |
