E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing Remitting Multiple Sclerosis (RRMS) |
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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 | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
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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 |
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. |
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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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray; NOTE: For subjects 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 scheduled 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 NOTE: For subjects with abnormal laboratory hematological parameters, please refer to section 6.2.1 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.
° 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 90 days following completion of the last dose of study medication or following early termination or early withdrawal. 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.
° Subject must be willing and able to participate in the trial and have provided written, informed consent
° Voluntarily provide written informed consent, and for USA sites only, a subject authorization under Health Insurance Portability and Accountability 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.”
(a) - For subjects who had to delay entry into the CLARITY Extension study whereby there was a gap interval of varying duration, who subsequently, during the gap interval were treated with a DMD or Rebif should discontinue the DMD or Rebif for a period of at least 3 months prior to Study Day 1. For those subjects who are unable or are unwilling to discontinue their DMD, they may not be re- randomized to receive study medication. These subjects are encouraged to enter the study but will be followed for safety only. (b) - For subjects who had to delay entry into the CLARITY Extension study, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria) are not able to be re-randomized to receive study medication in the CLARITY Extension study. These subjects are encouraged to enter the study, but will be followed for safety only. |
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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); NOTE: For subjects with positive heme-occult test, please refer to section 6.2.1 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.
° 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 DMD 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
NOTE: For subjects who had to delay entry into the CLARITY Extension study whereby there was a gap interval of varying duration, who subsequently, during the gap interval were treated with a DMD or Rebif should discontinue the DMD or Rebif for a period of at least 3 months prior to Study Day 1. For those subjects who are unable or are unwilling to discontinue their DMD, they may not be re- randomized to receive study medication. These subjects are encouraged to enter the study but will be followed for safety only.
NOTE: For subjects who had to delay entry into the CLARITY Extension study, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria section 5.2.2.) are not able to be re-randomized to receive study medication in the CLARITY Extension study. These subjects are encouraged to enter the study, but will be followed for safety only.
° 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 |
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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 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
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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 | 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 | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
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 | 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
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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 |