E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Venous Thrombosis |
Trombosi venosa |
|
E.1.1.1 | Medical condition in easily understood language |
A blood clot in a vein that is blocking blood flow |
Coagulo venoso che impedisce il flusso sanguigno |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 |
to assess the incidence of major bleeding and clinically
relevant non-major bleeding |
valutare l’incidenza di emorragia maggiore e di emorragia non maggiore clinicamente |
|
E.2.2 | Secondary objectives of the trial |
1) to assess the incidence of recurrent venous thromboembolism
2) to assess asymptomatic deterioration in the thrombotic burden on repeat imaging
3) to characterize the pharmacokinetic/pharmacodynamic profile of a 30-day treatment with oral rivaroxaban. |
• valutare il peggioramento trombotico in assenza di sintomi con la ripetizione dell’imaging
caratterizzare il profilo farmacocinetico/ farmacodinamico di un trattamento per 30 giorni con rivaroxaban orale
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Children aged 6 months to < 6 years who have been treated for at least 2 months or, in case of catheter
related thrombosis, for at least 6 weeks with LMWH, fondaparinux and/or VKA for documented symptomatic or asymptomatic venous thrombosis and who will enter their last month of intended anticoagulant treatment
2. Hemoglobin, platelets, creatinine, alanine aminotransferase (ALT) and bilirubin evaluated within 10 days prior to randomization
3. Informed consent provided |
1.Bambini di età compresa fra 6 mesi e meno di 6 anni che siano stati trattati per almeno 2 mesi oppure, nel caso della trombosi correlata al catetere, per almeno 6 settimane con LMWH, fondaparinux e/o un VKA per trombosi venosa sintomatica od asintomatica documentata e che entreranno nei loro ultimi 30 giorni di trattamento anticoagulante programmato
2.Prima della randomizzazione verranno esaminati i valori di emoglobina, la conta piastrinica, la creatinina, l’alanin-aminotransferasi (ALT) e la bilirubina totale valutata entro 10 giorni prima della randomizzazione
3.Consenso informato rilasciato e, se è il caso, l’assenso del bambino |
|
E.4 | Principal exclusion criteria |
1. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy
2. Symptomatic progression of venous thrombosis during preceding anticoagulant treatment
3. Planned invasive procedures, including lumbar puncture and removal of non-peripherally placed central lines during study treatment
4. An estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
5. Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or ALT > 5x upper level of normal (ULN) or total bilirubin > 2x ULN with direct bilirubin > 20% of the total
6. Platelet count < 100 x 109/L
7. Hypertension defined as > 95th age percentile a
8. Life expectancy < 3 months
9. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically
10. Concomitant use of strong inducers of CYP3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine
11. Hypersensitivity or any other contraindication listed in the local labeling for the comparator treatment or
experimental treatment
12. Inability to cooperate with the study procedures
13. Previous randomization to this study
14. Participation in a study with an investigational drug or medical device within 30 days prior to randomization. |
1. Emorragia in atto o rischio elevato di emorragia che controindichi una terapia anticoagulante
2. Progressione sintomatica della trombosi venosa durante il precedente trattamento anticoagulante
3. Procedure invasive programmate, comprese la puntura lombare e la rimozione delle linee centrali inserite non perifericamente durante il trattamento dello studio
4. Filtrazione glomerulare stimata (eGFR) < 30 mL/min/1,73 m2
5. Malattia epatica che sia associata a coagulopatia che comporti un rischio di emorragia clinicamente rilevante od un livello di ALT >5 volte il limite superiore della norma (ULN) o di bilirubina totale >2 volte l’ULN con bilirubina diretta >20 del totale
6. Conta piastrinica < 100 x 109/L
7. Ipertensione definita come > 95° percentile dell’età
8. Aspettativa di vita < 3 mesi
9. Impiego concomitante di forti inibitori dell’isoenzima del citocromo P450 3A4 (CYP3A4) e della glicoproteina P (P-gp), cioè tutti gli inibitori della proteasi del virus dell’immunodeficienza umana e dei seguenti antimicotici azolici: ketoconazolo, itraconazolo, voriconazolo, posaconazolo, se usati in via sistemica
10. Impiego concomitante di forti induttori di CYP3A4, cioè rifampicina, rifabutina, fenobarbitale, fenitoina e carbamazepina
11. Qualsiasi altra controindicazione elencata nel foglio illustrativo locale per il trattamento di confronto od il trattamento sperimentale
12. Incapacità a collaborare con le procedure dello studio
13. Precedente randomizzazione a questo studio
14. Partecipazione ad uno studio con un farmaco od un dispositivo medico sperimentale entro 30 giorni prima della randomizzazione
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Composite of major and clinically relevant non-major bleeding |
Insieme di emorragia maggiore e di emorragia non maggiore clinicamente rilevante |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During or within 2 days after stop of study treatment |
Durante o entro 2 giorni dopo la fine del trattamento sperimentale |
|
E.5.2 | Secondary end point(s) |
1. Composite of all recurrent venous thromboembolism and asymptomatic deterioration on repeat imaging; results of pharmacokinetics (PK) / pharmacodynamics (PD).
2. Prothrombin time
3. Activated partial thromboplastin time |
Insieme di tromboembolismo venoso ricorrente e di peggioramento asintomatico all’imaging ripetuto; risultati della farmacocinetica (PK) / pharmacodinamica (PD
2. Tempo di protrombina
3. tempo di tromboplastina parziale attivata
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At 31 Days
2. Day1 (post dose at.5-1.5h, 2.5-4h),day 15 (post dose at 2-8h) and day 30 (post dose at 10-16)
3. Day1 (post dose at.5-1.5h, 2.5-4h),day 15 (post dose at 2-8h) and day 30 (post dose at 10-16) |
1. A 31 giorni
2. Giorno 1 (dopo la dose di farmaco somministrata eseguire il prelievo a 0.5 – 1.5 ore e a 2,5 – 4 ore), il giorno 15 (dopo la dose somministrata prelievo a 2-8 ore) il giorno 30 (dopo la dose somministrata prelievo a 10-16 ore)
3. Giorno 1 (dopo la dose di farmaco somministrata eseguire il prelievo a 0.5 – 1.5 ore e a 2,5 – 4 ore), il giorno 15 (dopo la dose somministrata prelievo a 2-8 ore) il giorno 30 (dopo la dose somministrata prelievo a 10-16 ore)
|
|
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 | Yes |
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Australia |
Austria |
Belgium |
Brazil |
Canada |
France |
Germany |
Ireland |
Israel |
Italy |
Japan |
Netherlands |
Poland |
Russian Federation |
Spain |
Switzerland |
United Kingdom |
United States |
|
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |