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    Summary
    EudraCT Number:2009-017978-21
    Sponsor's Protocol Code Number:EMR700568-012
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-01-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2009-017978-21
    A.3Full title of the trial
    Prospective observational long-term safety registry of Multiple Sclerosis patients who have participated in cladribine clinical trials (PREMIERE).
    Registro prospettico osservazionale sulla sicurezza a lungo termine di pazienti affetti da sclerosi multipla che hanno preso parte agli studi clinici sulla cladribina (PREMIERE).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-term safety registry of Multiple Sclerosis patients who have participated in cladribine clinical trials
    Studio per raccogliere dati sulla sicurezza a lungo termine di Cladribina in pazienti che hanno partecipato a precedenti studi clinici con Cladribina.
    A.3.2Name or abbreviated title of the trial where available
    PREMIERE
    PREMIERE
    A.4.1Sponsor's protocol code numberEMR700568-012
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01013350
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMERCK SERONO SA
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Serono S.A. - Geneva
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center Merck KGaA
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 6151 72 5200
    B.5.5Fax number+ 49 6151 72 2000
    B.5.6E-mailservice@merck.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCladribine Tablet
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCLADRIBINE
    D.3.9.1CAS number 4291-63-8
    D.3.9.2Current sponsor codeEMD280922
    D.3.9.3Other descriptive name2-CdA, 2-chloro-2'-deoxy-ß-D-adenosine
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number.875
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis patients who have participated in cladribine tablets clinical trials
    Pazienti con Sclerosi Multipla che abbiano partecipato a precedenti studi sulla Cladribina orale.
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    Sclerosi Multipla
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level SOC
    E.1.2Classification code 10029205
    E.1.2Term Nervous system disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    Lo scopo principale del registro è fornire dati sulla sicurezza a lungo termine della cladribina orale nel trattamento della sclerosi multipla (SM), stimando la frequenza e i fattori di rischio degli eventi definiti per lo studio per un periodo protratto, che vada oltre il periodo di esposizione alla cladribina, in una popolazione di soggetti esposti alla cladribina orale in studi clinici selezionati condotti dallo sponsor e nelle relative estensioni.
    E.2.2Secondary 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
    •Valutare la sicurezza a lungo termine di cladribina misurando la frequenza di sindromi mielodisplastiche (MDS),tossicità ematologiche, considerando i potenziali fattori di rischio •Descrivere dati demografici e caratteristiche della SM di soggetti che manifestano e di quelli che non manifestano gli eventi specificati per lo studio •Esplorare il verificarsi di infezioni gravi, neoplasie, decessi, MDS, tossicità ematologica ed esiti di gravidanza nei soggetti esposti alla cladribina rispetto ai soggetti non esposti o ai gruppi a bassa esposizione cumulativa •Riportare in maniera prospettica le osservazioni del registro confrontando gli eventi dello studio nella popolazione trattata con cladribina verso un gruppo di confronto interno o popolazioni esterne disponibili •Descrivere il altri eventi clinici rilevanti
    E.2.3Trial contains a sub-study No
    E.3Principal 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. XML File Identifier: 2r7kDP+G9TszIeNWeAN1vV8IpU8= Page 11/22 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
    Tutti i soggetti arruolati in uno degli studi clinici selezionati del programma di sviluppo della cladribina orale saranno idonei a essere arruolati nel registro quando avranno terminato la partecipazione allo studio clinico. Dovranno però essere soddisfatti entrambi i seguenti criteri di inclusione: • Precedente arruolamento negli studi clinici selezionati del programma di sviluppo della cladribina orale, a prescindere dalla randomizzazione al farmaco sperimentale (IMP, Investigational Medicinal Product) o al placebo, una volta terminate la partecipazione allo studio clinico o all’estensione dello studio clinico • Firma del consenso informato scritto
    E.4Principal 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
    Saranno esclusi dalla partecipazione allo studio: • Soggetti che non possono essere contattati per telefono, oppure; • Soggetti che non sono in grado di rispondere ai questionari del registro e che non dispongono di un parente o caregiver che possa rispondere alle domande dei questionari del registro
    E.5 End points
    E.5.1Primary 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.
    • Incidenza cumulativa di infezioni gravi e selezionate, neoplasie e decessi; • Valutazione dell’andamento dell’incidenza cumulativa nel tempo, a partire dalla prima esposizione a cladribina orale/placebo; • Tempo alla risoluzione della linfopenia, tra i partecipanti al registro affetti da linfopenia persistente; • Frequenza delle gravidanze ed esiti delle gravidanze (aborto spontaneo, aborto volontario, nati morti e nati vivi — a termine, prematuri, oltre il termine e presenza di anomalie congenite) tra le donne esposte alla cladribina, nonché tra le partner dei soggetti di sesso maschile arruolati nel programma, e disabilità dello sviluppo, malformazioni strutturali o altre importanti problematiche di salute nella prole. Tempo intercorso tra la ricerca di una gravidanza e l’avvio della gravidanza tra le partecipanti (o le partner dei partecipanti) che desideravano una gravidanza.
    E.5.1.1Timepoint(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.
    Le analisi preliminari degli obiettivi primari e secondari saranno condotte quando si renderanno disponibili i dati di follow-up di 2 anni per 1000 pazienti. Successivamente le analisi saranno condotte ogni due anni.
    E.5.2Secondary 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.
    • Incidenza cumulativa di sindromi mielodisplastiche (MDS) e tossicità ematologiche; • Analisi descrittive dei dati demografici e delle caratteristiche della SM di soggetti che manifestano e di quelli che non manifestano gli eventi specificati per lo studio; • Valori di hazard ratio per infezioni gravi e selezionate, neoplasie e decessi nei soggetti esposti alla cladribina rispetto ai soggetti non esposti o ai gruppi a bassa esposizione cumulativa; • Tasso di recidiva degli eventi specificati per lo studio nei soggetti che hanno avuto un evento incidente, giustificante il tempo-persona totale di follow-up; • Frequenza di eventi clinicamente rilevanti diversi da quelli selezionati e di infezioni gravi, neoplasie, decessi, MDS e tossicità ematologiche
    E.5.2.1Timepoint(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.
    Le analisi preliminari degli obiettivi primari e secondari saranno condotte quando si renderanno disponibili i dati di follow-up di 2 anni per 1000 pazienti. Successivamente le analisi saranno condotte ogni due anni.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Prospective observational safety registry with no IMP administration
    Registro prospettico osservazionale sulla sicurezza senza somministrazione di IMP
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial0
    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.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA130
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Bosnia and Herzegovina
    Brazil
    Canada
    Georgia
    India
    Korea, Democratic People's Republic of
    Korea, Republic of
    Lebanon
    Macedonia, the former Yugoslav Republic of
    Russian Federation
    Saudi Arabia
    Singapore
    Taiwan
    Thailand
    Tunisia
    Turkey
    Ukraine
    United Arab Emirates
    United States Minor Outlying Islands
    E.8.7Trial 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
    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.
    La durata del periodo di follow-up per tutti i soggetti sarà estesa fino alla fine del registro - pianificato per il 2018 - o 8 anni dopo l’arruolamento nel primo studio clinico sulla cladribina a seconda di quale dei due eventi si verifica prima.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2175
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-01-05. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women Yes
    F.3.3.4Nursing women Yes
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 976
    F.4.2.2In the whole clinical trial 2175
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not defined in the protocol
    Non definito nel protocollo
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-05-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-05-12
    P. End of Trial
    P.End of Trial StatusCompleted
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