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 | 18.0 |
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 extrapolated 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 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 12 to <18 years of age at the time of consent (Age Group 1).
• An approved amended protocol will be implemented prior to enrollment of each subsequent age group (Age Groups 2, 3, and 4).
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, and splanchnic thrombosis.
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 for at least 6 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.Female subjects who, in the opinion of the investigator, are biologically capable of having children and are sexually active and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for 28 days after the last dose of assigned treatment.
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E.4 | Principal exclusion criteria |
1. Anticoagulant treatment for the index VTE for greater than 7 days prior to randomization.
2. Thrombectomy, thrombolytic therapy, or insertion of a caval filter to treat the index VTE
3. A mechanical heart valve
4.Active bleeding or high risk of bleeding (e.g. central nervous system (CNS) tumors) at the time of randomization.
5.Intracranial bleed, including intraventricular hemorrhage, within 3 months prior to randomization.
6.Abnormal baseline liver function (ALT > 3 x upper limit of normal (ULN) or conjugated bilirubin > 2x ULN) at randomization.
7.At the time of randomization, inadequate renal function as defined in Section 7.2.2 Estimated Glomerular Filtration Rate Assessment of the protocol.
8.Platelet count < 50×10^9 per L at randomization.
9.At the time of randomization, uncontrolled severe hypertension as defined in Section 7.1 Physical Examination of the protocol.
10.At the time of randomization, use of prohibited concomitant medication as listed for apixaban in Section 5.5 Concomitant Medication of the protocol.
11.Known allergy to apixaban.
12.Female subjects who are either pregnant or breastfeeding a child.
13.Geographically unavailable for follow-up.
14.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.
15.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.
16.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.
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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 DVT, PE and paradoxical embolism and (ii) VTE-related mortality.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• All cause death
• Index VTE status (e.g. progression, regression, or resolution)
• Stroke
• New symptomatic or asymptomatic DVT
• New symptomatic PE
• Apixaban concentrations
• Anti-FXa activity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Austria |
Canada |
Germany |
Italy |
Russian Federation |
Ukraine |
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.8.9.2 | In all countries concerned by the trial years | 6 |
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 |