E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Sclerosis patients who have participated in cladribine tablets clinical trials |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.0 |
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 |
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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 |
The main purpose of the registry is to produce long-term safety data on oral cladribine in multiple sclerosis (MS) by estimating the frequency and risk factors for defined study events over a long period extending beyond cladribine exposure, in a population of subjects who have been exposed to oral cladribine in Sponsor selected clinical studies and their relative extensions. |
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E.2.2 | Secondary objectives of the trial |
•Assess the long-term safety of cladribine by measuring the frequency of MDS, hematological toxicity, taking into account potential risk factors
•Describe the demographic and MS disease characteristics of subjects who experience and those who do not experience study events
•Explore the occurrence of selected and severe infections, malignancies, deaths, MDS, hematological toxicity and pregnancies and pregnancy outcomes in relation to the cumulative dose and length of exposure to cladribine
•Put into perspective the findings in the registry by comparing the study events occurring in the cladribine treated population to an internal comparison group or available external populations
•Describe the rate of recurrence of study events in subjects who have had an incident event accounting for the total person-time of follow-up
•Describe the occurrence of other clinically relevant events not included as primary objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The registry target population includes all subjects who participated in Sponsor oral cladribine phase I to III clinical trials in MS associated with a protocol approved prior to the time of submission of the marketing application and completed (last patient, last visit) after November 2008.
All subjects in the target population will be eligible for enrollment in the registry once their participation in the clinical trial has ended. Both the following inclusion criteria must be fulfilled:
• Prior enrollment into selected clinical trials of the cladribine development program as described in section 5.1 regardless of randomization to either IMP or placebo, once participation in the clinical trial or in the clinical trial extension has ended
• Written informed consent was given
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E.4 | Principal exclusion criteria |
The following two reasons will exclude subjects from registry participation:
• Subjects who cannot be reached by phone, or;
• Subjects unable to answer the registry questionnaires and who do not have a next of kin or caregiver able to answer the registry questionnaires
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E.5 End points |
E.5.1 | Primary end point(s) |
• Cumulative incidence of severe and selected infections, malignancies, and deaths
• Assessment of cumulative incidence patterns over time since first exposure to cladribine/placebo;
• Time to resolution of lymphopenia, among registry participants with persistent lymphopenia;
• Frequency of pregnancies and pregnancy outcomes (spontaneous abortion, elected abortion, stillbirth, and live birth—full term, premature, overdue, and presence of congenital anomalies) occurring among female subjects exposed to cladribine, as well as among female partners of male subjects in the program, and developmental disabilities, structural malformations, or other important health conditions in the offspring. Time between seeking pregnancy and becoming pregnant among participants (or partners) seeking pregnancy. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Preliminary analyses of the primary and secondary endpoints will be conducted when 2 years of follow-up data are available for 1000 subjects after registry enrollment. Thereafter these analyses will be conducted every 2 years. |
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E.5.2 | Secondary end point(s) |
• Cumulative incidence of MDS, and hematological toxicity;
• Descriptive analyses of demographic and MS disease characteristics of subjects who experience and those who do not experience study events;
• Hazard ratios for severe and selected infections, malignancies, and deaths in cladribine exposed subjects compared with cladribine unexposed subjects or low cumulative cladribine exposure groups;
• Rate of recurrence of study events in subjects who have had an incident events, accounting for the total person-time of follow-up;
• Frequency of clinically relevant events other than selected and severe infections, malignancies, deaths, MDS, and hematological toxicity. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Preliminary analyses of the primary and secondary endpoints will be conducted when 2 years of follow-up data are available for 1000 subjects after registry enrollment. Thereafter these analyses will be conducted every 2 years. |
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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 | No |
E.6.6 | Pharmacokinetic | No |
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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Prospective observational safety registry with no IMP administration |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 | No |
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 |
Argentina |
Australia |
Austria |
Belgium |
Bosnia and Herzegovina |
Brazil |
Bulgaria |
Canada |
Croatia |
Czech Republic |
Denmark |
Estonia |
Finland |
France |
Georgia |
Germany |
Greece |
India |
Italy |
Korea, Republic of |
Latvia |
Lebanon |
Lithuania |
Macedonia, the former Yugoslav Republic of |
Morocco |
Netherlands |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Saudi Arabia |
Serbia |
Singapore |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Tunisia |
Turkey |
Ukraine |
United Arab Emirates |
United Kingdom |
United States |
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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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The duration of follow-up for all subjects will extend to the end of the registry - which is planned for 2018 - or 8 years after enrollment into the first cladribine clinical trial (first visit), whichever occurs first. |
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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 | 7 |
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 | 8 |
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 |