E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10043607 |
E.1.2 | Term | Thrombosis |
E.1.2 | System Organ Class | 10047065 - Vascular 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 |
• To characterize the pharmacokinetic profile of rivaroxaban
administered as granules for oral suspension |
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E.2.2 | Secondary objectives of the trial |
• To document safety and tolerability in terms of AEs observed
after administration of the rivaroxaban granules for oral
suspension formulation |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. For group A and B:
Children with an age between 6 months and <12 years who have completed
anticoagulant treatment at least 10 days prior to the planned study drug
administration
For Group C:
Children with an age ≥2 months and weight between 3 and <12 kg, who have
completed anticoagulant treatment at least 10 days prior to the planned study
drug administration.
Gestational age at birth of at least 37 weeks
Oral feeding/ nasogastric/ gastric feeding for at least 10 days 29
For Groups A, B and C:
2. Normal PT and aPTT within 10 days prior to planned study drug administration
3. Written informed consent provided and, if applicable, child assent provided |
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E.4 | Principal exclusion criteria |
For Groups A, B and C:
1. Active bleeding or high risk for bleeding, contraindicating anticoagulant therapy
2. Planned invasive procedures, including removal of central lines, within 24 hours before and after single dose intake
3. An estimate glomerular filtration rate (eGFR) < 30 mL/min/1.73m2
4. Hepatic disease which is associated either with:
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.
5. Platelet count < 50 x 109/L
6. Hypertension (defined as systolic and/or diastolic blood pressure >95th percentile for age)
7. Concomitant use of strong inhibitors of both CYP3A4 and P-glycoprotein, e.g.,
all human immunodeficiency virus protease inhibitors and the following azoleantimycotic agents: ketoconazole, itraconazole, voriconazole, and posaconazole, if used systemically (fluconazole is allowed)
8. Concomitant use of strong inducers of CYP3A4, e.g., rifampicin, rifabutin,
phenobarbital, phenytoin and carbamazepine
9. Inability to cooperate with the study procedures
10. Hypersensitivity to rivaroxaban
11. Participation in a study with an investigational drug other than rivaroxaban or a medical device within 30 days prior to treatment
For Group C only:
12. History of gastrointestinal disease or surgery associated with impaired absorption |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variables for pharmacokinetics will be the standard pharmacokinetic (PK) parameters for exposure, area under the curve (AUC) and Cmax, derived via population PK approaches. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Group A and B
Depending on age, PK samples are collected at several time points within 24 hours after drug administration
For Group C
PK samples are collected at several time points within 28 hours after drug administration |
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E.5.2 | Secondary end point(s) |
The principal safety outcome is the composite of major bleeding and clinically relevant non-major bleeding. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 24 hrs after drug administration with additional followup on day 8 (+3) days. |
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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 | 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 |
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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.8.3 |
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 | 20 |
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 |
Canada |
Finland |
France |
Hungary |
Ireland |
Italy |
Spain |
Sweden |
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 | 4 |
E.8.9.1 | In the Member State concerned days | 27 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 27 |