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    Summary
    EudraCT Number:2012-001309-26
    Sponsor's Protocol Code Number:CSL689_20'01
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-21
    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 number2012-001309-26
    A.3Full title of the trial
    A multicenter, open-label, multiple-dose, dose escalation study to investigate the pharmacokinetics, efficacy, and safety of rVIIa-FP (CSL689) in subjects with hemophilia (A or B) and inhibitors.
    Studio di intensificazione della dose, multicentrico, in aperto, a dosi multiple teso a valutare la farmacocinetica, l¿efficacia e la sicurezza di rVIIa-FP (CSL689) in soggetti con emofilia (A o B) e produzione di inibitori
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of recombinant factor VIIa fusion protein (rVIIa-FP, CSL689) for ondemand treatment of bleeding episodes in patients with hemophilia A or B with inhibitors
    Studio sul fattore ricombinante VIIa-FP per il trattamento degli episodi di sanguinamento nei pazienti con emofilia A o B
    A.3.2Name or abbreviated title of the trial where available
    CSL689_2001
    CSL689_2001
    A.4.1Sponsor's protocol code numberCSL689_20'01
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/342/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCSL BEHRING GMBH
    B.1.3.4CountryGermany
    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 supportCSL Behring GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCSL Behring GmbH
    B.5.2Functional name of contact pointTrial Registration Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressEmil-von-Behring Stra¿e 76
    B.5.3.2Town/ cityMarburg
    B.5.3.3Post code35041
    B.5.3.4CountryGermany
    B.5.4Telephone number+49 6421 393092
    B.5.5Fax number+49 6421 393092
    B.5.6E-mailclinicaltrials@cslbehring.com
    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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/133/10 e EMA/OD/132/10
    D.3 Description of the IMP
    D.3.1Product nameRecombinant fusion protein, linking activated coagulation factor VII with albumin
    D.3.2Product code CSL689
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name NOVOSEVEN - 2MG (100KUI)-POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE-USO ENDOVENOSO-POLV:FLAC(VETRO) SOLV:SIRINGA(VETRO)-POLV:2MG (100KUI) (50KUI/ML) SOLV:2ML-1 FLAC+1SIRINGA+1ADATTATORE PER FLAC
    D.2.1.1.2Name of the Marketing Authorisation holderNOVO NORDISK A/S
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameNovoSeven
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    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
    Hemophilia A or B
    Emofilia A o B
    E.1.1.1Medical condition in easily understood language
    Hemophilia
    Emofilia
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10053752
    E.1.2Term Hemophilia B with anti factor IX
    E.1.2System Organ Class 100000004850
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10053751
    E.1.2Term Hemophilia A with anti factor VIII
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    PK Module: To evaluate the PK of CSL689 (0.75 and 1.5 mg/kg) in subjects with hemophilia (A or B) and inhibitors and to compare the PK of 1.5 mg/kg CSL689 with the labeled doses of NovoSeven rFVIIa (0.09 and 0.27 mg/kg).
    Dose-evaluation Module: To determine the best dose (population-based best dose) of the 2 CSL689 doses evaluated (0.75 and 1.5 mg/kg).
    Repeated-dose Module: To evaluate the clinical efficacy of the population-based best dose of CSL689 for on-demand therapy of bleeding events in subjects with hemophilia (A or B) and inhibitors.
    Modulo PK: valutare PK di CSL689 (0,75 e 1,5 mg/kg) in soggetti con emofilia (A o B) e produzione di inibitori e confrontare PK di CSL689 alla dose di 1,5 mg/kg con le dosi approvate di NovoSeven rFVIIa (0,09 e 0,27 mg/kg).
    Modulo di valutazione della dose: determinare la dose migliore (migliore dose basata sulla popolazione) tra le 2 dosi di CSL689 valutate (0,75 e 1,5 mg/kg).
    Modulo a dose ripetuta: valutare l¿efficacia clinica della migliore dose basata sulla popolazione di CSL689 per la terapia al bisogno di episodi emorragici in soggetti con emofilia (A o B) e produzione di inibitori.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of intravenous (IV) administration of CSL689
    Valutare la sicurezza e la tollerabilit¿ della somministrazione endovenosa (EV) di CSL689.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male subjects with hemophilia A or B and inhibitors.
    2. Age =12 and =65 years.
    3. High responding inhibitor with documented historical inhibitor titer >5 Bethesda Units (BU)/mL.
    4. Body weight =100 kg.
    5. Written informed consent for study participation obtained from the subject or the subject’s legally acceptable representative (as appropriate) before undergoing any study-specific procedures.
    1. Soggetti maschi con emofilia A o B e produzione di inibitori.
    2. Età =12 anni e =65 anni.
    3. Inibitore ad alta risposta con titolazione dell’inibitore storica documentata >5 unità Bethesda (UB)/mL.
    4. Peso corporeo =100 kg.
    5. Consenso informato scritto per la partecipazione allo studio ottenuto dal soggetto o dal Suo rappresentante legale autorizzato (quando appropriato) prima che il soggetto sia sottoposto alle procedure specifiche dello studio.
    E.4Principal exclusion criteria
    1. Congenital or acquired coagulation disorders other than hemophilia A or B.
    2. Ongoing immune tolerance induction therapy or planned immune tolerance induction therapy during the study period until the last follow-up visit.
    3. Known or suspected hypersensitivity to any excipient of CSL689.
    4. Known or clinically suspected allergy to activated recombinant human FVII.
    5. Known active pseudotumors.
    6. Body mass index >30 kg/m².
    7. Platelet count <50,000 platelets/µL.
    8. Major surgery within 28 days before screening (catheter, stents, dental procedures, and port insertion are acceptable).
    9. Scheduled major and / or orthopedic surgery during the study period through follow-up visit.
    1. Disturbo della coagulazione congenito o acquisito diverso dall’emofilia A o B.
    2. Terapia di induzione della tolleranza immunologica in corso o pianificata durante il periodo dello studio fino all’ultima visita di follow-up.
    3. Ipersensibilità nota o sospetta a qualsiasi eccipiente di CSL689.
    4. Allergia nota o sospetta su base clinica in grado di attivare FVII ricombinante umano.
    5. Pseudotumori attivi noti.
    6. Indice di massa corporea >30 kg/m².
    7. Conta piastrinica <50.000 piastrine/µl.
    8. Intervento di chirurgia maggiore entro 28 giorni dallo screening (sono accettabili catetere, stent, procedure odontoiatriche e inserimento di porta).
    9. Intervento di chirurgia maggiore e/o ortopedico programmato durante la durata dello studio fino alla visita di follow-up.
    E.5 End points
    E.5.1Primary end point(s)
    PK of CSL689 and NovoSeven rFVIIa will be assessed based on plasma FVIIa activity with and without baseline correction. The following primary PK endpoints will be evaluated:• Area under the FVIIa activity versus time curve from time zero to the last sample with quantifiable FVIIa activity (AUC0-t).• Incremental recovery.• t1/2.• Total CL.
    Sarà Valutata PK di CSL689 e NovoSeven rFVIIa in base all’attività plasmatica di FVIIa con e senza correzione iniziale. Saranno valutati i seguenti endpoint primari di PK:• area sotto la curva dell’attività di FVIIa nel tempo dal momento zero all’ultimo campione con attività quantificabile di FVIIa (AUC0-t);• recupero incrementale;• t1/2;• CL totale
    E.5.1.1Timepoint(s) of evaluation of this end point
    Before injection and/or at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and/or at up to 11 time points until 120 hours after injection for CSL689. Elimination half-life: Up to 24 hours after injectionfor Eptacog alfa; up to 48 hours after injection for CSL689
    Prima dell'iniezione e/o in fino a 6 punti di tempo fino a 24 ore dopo l'iniezione per Eptacog alfa; prima dell'iniezione e/o in fino a 11 punti di tempo fino a 120 ore dopo l'iniezione per CSL689. Emivita di eliminazione: fino a 24 ore dopo l’iniezione per Eptacog alfa; fino a 48 ore dopo l'iniezione per CSL689
    E.5.2Secondary end point(s)
    Percentage of bleeding events successfully treated with 1 or 2 injections of CSL689 at each dose level.
    ¿ Number and proportion of bleeding events requiring >1 injection of CSL689 in Blocks A and B.
    ¿ Number of CSL689 injections per bleeding episode.
    ¿ Total dose of CSL689 required per bleeding episode
    Percentuale degli episodi emorragici trattati con successo con 1 o 2 iniezioni di CSL689 a ogni livello di dose.
    ¿ Numero e proporzione di episodi emorragici che richiedono >1 iniezione di CSL689 nei blocchi A e B.
    ¿ Numero di iniezioni di CSL689 per episodio emorragico.
    ¿ Dose totale di CSL689 necessaria per episodio emorragico
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to 24 hours after the relevant CSL689 injection for the relevant bleeding event for the first eight endpoints; Up to 9 month for the last five endpoints
    Fino a 24 ore dopo l'iniezione di CSL689 per l'evento di sanguinamento rilevante per i primi otto punti finali; Fino a 9 mesi per gli ultimi cinque endpoint
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    Qualit¿ della Vita
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Georgia
    Japan
    Korea, Democratic People's Republic of
    Malaysia
    Russian Federation
    Serbia
    South Africa
    Thailand
    Turkey
    Ukraine
    United States
    European Union
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 53
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 54
    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)
    Subjects completing study CSL689_2001 will be invited to partecipate in a prophylaxis study
    I soggetti che completano lo stduio CSL689_2001 saranno invitati a partecipare a una terapia profilattica
    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 Decision2015-07-13
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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