E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Venous or arterial thrombosis |
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E.1.1.1 | Medical condition in easily understood language |
Blood clot in a vein or artery. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066899 |
E.1.2 | Term | Venous thromboembolism |
E.1.2 | System Organ Class | 100000004866 |
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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 |
• to characterize the pharmacokinetic/pharmacodynamic profile of a 7-day treatment with oral rivaroxaban |
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E.2.2 | Secondary objectives of the trial |
• to assess the incidence of major bleeding and clinically relevant non-major bleeding
• to assess the incidence of symptomatic recurrent thromboembolism and
• to assess asymptomatic deterioration in the thrombotic burden on repeat imaging
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Children from birth to less than 6 months with documented symptomatic or asymptomatic venous or arterial thrombosis who have been treated with anticoagulant therapy for at least 5 days.
2. Gestational age at birth of at least 37 weeks.
3. Hemoglobin, platelets, creatinine, alanine aminotransferase (ALT) and total and direct bilirubin assessed within 10 days prior to enrollment.
4. Oral feeding/nasogastric/gastric feeding for at least 10 days.
5. Informed consent provided.
6. Body weight >2600 g. |
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E.4 | Principal exclusion criteria |
1. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy, including history of intra-ventricular bleeding
2. Symptomatic progression of thrombosis during preceding anticoagulant treatment
3. Planned invasive procedures, including lumbar puncture and removal of non-peripherally placed central lines during study treatment
4. Hepatic disease which is associated with either: coagulopathy leading to a clinically relevant bleeding risk, or alanine aminotransferase (ALT) > 5x upper level of normal (ULN) or total bilirubin (TB) > 2x ULN with direct bilirubin > 20% of the total
5. Creatinine > 1.5 times of normal
6. Uncontrolled hypertension defined as > 95th percentile.
7. History of gastrointestinal disease or surgery associated with impaired absorption
8. Platelet count <100 x 109/L
9. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), e.g. all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically (fluconazole is allowed)
10. Concomitant use of strong inducers of CYP3A4, e.g. rifampicin, rifabutin, phenobarbital, phenytoin and carbamazepine
11. Indication for anticoagulant therapy other than current thrombosis
12. Indication for antiplatelet therapy or non-steroid anti-inflammatory drug (NSAID) therapy. Incidental use is allowed.
13. Hypersensitivity to rivaroxaban or its excipients
14. Participation in a study with an investigational drug or medical device within 30 days prior to enrollment.
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E.5 End points |
E.5.1 | Primary end point(s) |
PK/PD modeling, using population approaches will be used to describe the pharmacokinetics of rivaroxaban, and to relate anticoagulant parameters of rivaroxaban with plasma concentrations. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After last patient. last visit |
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E.5.2 | Secondary end point(s) |
1. The occurrence of recurrent venous or arterial thromboembolism and asymptomatic deterioration in thrombotic burden will be summarized.
2. All safety analyses will be performed on the safety population. Bleeding events observed later will be described separately. Individual listings of major and clinically relevant non-major bleeding will be provided.
3. The occurrence of recurrent venous or arterial thromboembolism and asymptomatic deterioration in thrombotic burden |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. After last patient,ast visit
2.The analysis will primarily focus on bleeding that occurred during or within 2 days after stop of rivaroxaban
3. After last patient, last visit |
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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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
pharmacokinetics and pharmacodymamics study |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Canada |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Spain |
Switzerland |
Turkey |
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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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 | 3 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 14 |