| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043565 |
| E.1.2 | Term | Thromboembolic event |
| E.1.2 | System Organ Class | 100000004866 |
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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 |
| To assess the safety and descriptive efficacy of apixaban in pediatric subjects requiring anticoagulation for the treatment of a VTE. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate apixaban pharmacokinetic (PK) and anti-FXa activity in pediatric subjects requiring anticoagulation for the treatment of a VTE. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Children from birth to <18 years of age with a minimum weight of 2.6 kg at the time of randomization. An approved protocol will be implemented prior to enrollment of each subsequent age group.
Neonates are defined as infants from birth up to ≤27 days of life. For pre-term infants born between 34 and <37 weeks gestation, investigators have the option to define the 27 day neonatal period starting from the actual date of birth (post-natal age) or may choose to define the 27 day neonatal period starting when the postmenstrual age (gestational age plus the post-natal age) reaches 37 weeks and enroll the infant no more than 27 days thereafter into Cohort 4. Gestational age is the time elapsed between the first day of the last normal menstrual period and the day of delivery. Neonates or infants born prematurely at <34 weeks' gestation are excluded from this study until the age of ≥ 6 months of life. Gestational age will only be taken into consideration for eligibility up to 6 months of age.
2.Presence of an index VTE which is confirmed by imaging. Index VTE include, but are not limited to, deep vein thrombosis, pulmonary embolus, cerebral sinovenous thrombosis, renal vein thrombosis, portal vein thrombosis, catheter-related thrombosis and splanchnic thrombosis. In Germany only, cerebral sinovenous thrombosis will be excluded.
3.Intention to manage the index VTE with anticoagulation treatment for at least 12 weeks or intention to manage the index VTE with anticoagulation treatment in neonates (birth to 27 days) and children 28 days to <2 years of age for 6-12 weeks.
4.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. Depending on local regulations, whenever the minor is able to give assent, the minor’s assent must also be obtained.
5.Subjects/legally acceptable representatives who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
6.For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective method of contraception throughout the study and for at least 33 days (5 half-lives plus 30 days) after the last dose of assigned treatment.
7. Subjects able to tolerate oral feeding, nasogastric (NG), gastric (G) feeding for at least 5 days. |
|
| E.4 | Principal exclusion criteria |
1. Anticoagulant treatment for the index VTE for greater than 14 days prior to randomization. Neonates that are enrolled into the PK cohort must be on a minimum of 5 days and a maximum of 14 days SOC anticoagulation prior to randomization. Neonates that are enrolled into the post PK cohort may receive SOC anticoagulation for up to 14 days prior to randomization.
2. Cerebral sinovenous thrombosis (in Germany only).
3. Thrombectomy, thrombolytic therapy, or insertion of a caval filter to treat the index VTE
4. A mechanical heart valve
5.Active bleeding or high risk of bleeding (e.g. central nervous system (CNS) tumors) at the time of randomization.
6.Intracranial bleed, including intraventricular hemorrhage, within 3 months prior to randomization.
7.Abnormal baseline liver function (ALT > 3 x upper limit of normal (ULN) or conjugated bilirubin > 2x ULN) at randomization.
8.At the time of randomization, inadequate renal function as defined in Section 7.2.2 Estimated Glomerular Filtration Rate Assessment of the protocol.
9.Platelet count < 50×109 per L at randomization.
10.At the time of randomization, uncontrolled severe hypertension as defined in Section 7.1 Physical Examination of the protocol.
11.At the time of randomization, use of prohibited concomitant medication as listed for apixaban in Section 5.5 Concomitant Medication of the protocol.
12.Known allergy to apixaban or any of the other ingredients in the apixaban formulation, or hypersensitivity to any of the components of the comparators.
13.Female subjects who are either pregnant or breastfeeding a child.
14.Geographically unavailable for follow-up.
15.Family members who are either investigational site staff members directly involved in the conduct of this trial or site staff members otherwise supervised by the Investigator. Family members who are Pfizer or Bristol Myers Squibb (BMS) employees directly involved in the conduct of this trial.
16.Taking an investigational drug in other studies within 30 days before the first dose of apixaban and/or during study participation. N.B. using marketed medications commonly used in usual and customary practice, though not labeled for use in children, is acceptable.
17.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
18. Use of aggressive life-saving therapies such as ventricular assist
devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the
time of enrollment.
19. Unable to take oral or enteric medication via the NG or G tube.
20. Known inherited or acquired antiphospholipid syndrome (APS).
21. Known inherited bleeding disorder or coagulopathy with increased
bleeding risk (eg, hemophilia, von Willebrand disease, etc.) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Safety: The composite of major and clinically relevant non-major bleeding.
Primary Efficacy: A composite of: (i) all image-confirmed and adjudicated symptomatic and asymptomatic recurrent VTE defined as either contiguous progression or non-contiguous new thrombus and including but not limited to, DVT, PE and paradoxical embolism and (ii) VTE-related mortality.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• All cause death
• VTE related mortality
• Index VTE status (e.g. unchanged, regression, or resolution)
• Stroke
• New or recurrent symptomatic or asymptomatic DVT .
• New or recurrent symptomatic or asymptomatic PE.
• VTEs, other than DVT or PE (i.e. cerebral sinovenous thrombosis, renal vein thrombosis, portal vein thrombosis, catheter-related VTE, and splanchnic thrombosis).
• Major bleeding
• Clinically relevant non-major bleeding
• Minor bleeding
• Apixaban concentrations
• Anti-FXa activity |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Mexico |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Turkey |
| Ukraine |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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