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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040729 |
E.1.2 | Term | Single ventricle |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A
To characterize the single- and multiple-dose PK and PK/ PD profiles after oral rivaroxaban therapy administered to pediatric subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment.
Part B
To evaluate the safety and efficacy of rivaroxaban, administered twice daily (exposure matched to rivaroxaban 10 mg once daily in adults) compared to ASA, given once daily (approximately 5 mg/kg) for thromboprophylaxis in pediatric subjects 2 to 8 years of age with single ventricle physiology who have completed the Fontan procedure within 4 months prior to enrollment. |
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E.2.2 | Secondary objectives of the trial |
Part A
To assess the safety and tolerability of rivaroxaban treatment.
Part B
To further characterize the PK and PK/PD profiles of rivaroxaban. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Boys or girls 2 to 8 years of age with single ventricle physiology and who have completed the initial Fontan procedure within 4 months prior to enrollment
2. Considered to be clinically stable by the investigator and able to tolerate oral or enteral administration of a suspension formulation and oral/enteral feedings
3. Satisfactory initial post-Fontan transthoracic echocardiographic screening as defined in the Post-Fontan Echocardiographic Examination Research Protocol
4. Parent/legally acceptable representative must sign an informed consent form (ICF) and child assent will also be provided, if applicable, according to local requirements. |
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E.4 | Principal exclusion criteria |
1. Evidence of thrombosis, including those that are asymptomatic confirmed by post-Fontan procedure transthoracic echocardiogram, or other imaging techniques, during the screening period of the study
2. History of gastrointestinal disease or surgery associated with clinically relevant impaired absorption
3. History of or signs/symptoms suggestive of protein-losing enteropathy
4. Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant therapy, including a history of intracranial bleeding
5. Indication for anticoagulant or antiplatelet therapy other than current study, however:
- A subject who has received VKA after the Fontan procedure may be eligible provided that the subject has discontinued VKA before the screening visit. Baseline laboratory samples must be obtained at least 7 days after the last dose of VKA.
- A subject who is receiving ASA at the time of the screening visit may be eligible and may continue on ASA provided the last dose is taken at least 24 hours prior to the first dose of study drug.
6. Platelet count <50 x 10^9/L at screening.
7. Creatinine clearance (CrCl) <30 mL/min/1.73m2.
8. Known clinically significant liver disease. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A:
PK and PD Parameters: PT, aPTT and anti-FXa activity against Rivaroxaban plasma concentration.
PK: AUC (O-24), Cmax after single dose and AUC (0-24), Cmax and Cmin at steady state
Part B:
Efficacy: Thrombotic events (venous or arterial), defined as:
- The appearance of a new thrombotic burden within the cardiovascular system on either routine surveillance or clinically indicated imaging, or
- The occurrence of a clinical event known to be strongly associated with thrombus (such as cardioembolic stroke, pulmonary embolism).
Safety: major bleeding events as defined by ISTH
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
Day 1, 4, Month 3, 12
Part B:
Ongoing throughout the study as well as at pre-defined time points (Day 12, Months 3, 6 and 12) from enrollment until final follow-up phone call
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E.5.2 | Secondary end point(s) |
Part A:
Efficacy: Thrombotic events (venous or arterial), defined as:
- The appearance of a new thrombotic burden within the cardiovascular system on either routine surveillance or clinically indicated imaging, or
- The occurrence of a clinical event known to be strongly associated with thrombus (such as cardioembolic stroke, pulmonary embolism).
Any death
Safety: major bleeding events, Clinically relevant non-major bleeding events and trivial (minimal) bleeding as defined by ISTH; other adverse events and clinical laboratory test values (CBC, CrCl, liver function tests, and PT and aPTT).
Part B:
PK/PD Parameters: PT, aPTT and anti-FXa activity against Rivaroxaban plasma concentration.
PK: AUC (O-24), Cmax after single dose and AUC (0-24), Cmax and Cmin at steady state
Safety: Clinically relevant non-major bleeding events and trivial (minimal) bleeding as defined by ISTH; any death, other adverse events and clinical laboratory test values(CBC, CrCl, liver function tests, and PT and aPTT) .
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
Ongoing throughout the study as well as at pre-defined time points (Day 12, Months 3, 6 and 12) from enrollment until final follow-up examination
Part B:
Day 1, Month 3, Month 12
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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) | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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) | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
China |
France |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
Spain |
Thailand |
United Kingdom |
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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The study is considered completed with the last scheduled study contact shown in the Time and Events Schedule for the last subject participating in the study. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 | 6 |