E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lymphoma, Acute Lymphoblastic Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma, Acute Lymphoblastic Leukemia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025310 |
E.1.2 | Term | Lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 compare the effect of prophylactic oral or enteric apixaban vs no administration of systemic prophylactic anticoagulant during induction chemotherapy, on the composite endpoint of adjudicated non-fatal DVT (including symptomatic and asymptomatic), PE, and CVST; and VTE-related-death during
approximately 28 days of open-label treatment in pediatric subjects (1 to < 18 years) with newly diagnosed ALL or lymphoma (T or B cell), a functioning central venous access device (CVAD) and receiving asparaginase during chemotherapy induction.
- To assess the effect of prophylactic oral or enteric apixaban versus no administration of systemic prophylactic
anticoagulant during induction chemotherapy, on adjudicated major bleeding events during approximately 28 days of open-label treatment in pediatric subjects (1 to < 18 years) with newly diagnosed ALL or lymphoma (T or B cell), a functioning CVAD and receiving asparaginase during chemotherapy induction |
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E.2.2 | Secondary objectives of the trial |
- To assess the effect of prophylactic oral or enteric apixaban versus no administration of systemic prophylactic
anticoagulant during induction chemotherapy, on single adjudicated endpoints of non-fatal DVT (including symptomatic and asymptomatic), PE, and CVST; and VTE-related-death during approximately 28 days of open-label treatment in pediatric subjects (1 to < 18 Y) with newly diagnosed ALL or lymphoma (T or B cell), a functioning CVAD and receiving asparaginase during chemotherapy induction.
- To assess the effect of prophylactic oral or enteric apixaban versus no administration of systemic prophylactic
anticoagulant during induction chemotherapy, on the composite endpoint of adjudicated major and clinically relevant non-major (CRNM) bleeding events during approximately 28 days of open-label treatment in pediatricsubjects (1 to < 18 Y) with newly diagnosed acute ALL or lymphoma (T or B cell), a functioning CVAD and receiving asparaginase during chemotherapy induction. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
See Appendix 9 in the protocol |
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E.3 | Principal inclusion criteria |
•New diagnosis of de novo ALL, lymphomas (T or B cell), or mixed-phenotype acute leukemia
•Planned 3-4 drug systemic induction chemotherapy with a corticosteroid, vincristine and a single dose or multiple doses of asparaginase, with or without daunorubicin
•Functioning Central Venous Access Device
•Must be able to tolerate oral medication or have it administered via an Nasogastric tube (NGT) or GT tube
•Males and females,age 1 year(365 days) to < 18 (17 years and 364 days) years
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E.4 | Principal exclusion criteria |
•Subjects scheduled to have > 3 Lumbar Punctures over the course of the study treatment period
•Prior history of documented DVT or PE in the past 3 months
•Known inherited bleeding disorder or coagulopathy
•Major surgery [excluding Central Venous Access Device (CVAD) replacement and bone marrow aspiration and non-open biopsy] within the last 7 days prior to enrollment that may be associated with a risk of bleeding. Open biopsy is considered a major surgery.
•Uncontrolled severe hypertension at enrollment. Severe hypertension is defined as a systolic or diastolic blood pressure (BP) > 5 mm Hg above the 95th percentile as defined by the National High Blood Pressure Education Program Working Group (NHBPEP) established guidelines for the definition of normal and elevated blood pressure in children
•Extreme hyperleukocytosis, white blood cell (WBC) counts over 200 x 109/L (200,000/microL) at the time of enrollment
•Liver dysfunction manifested by SGTP (ALT) > 5X Upper limit of normal (ULN) and/or Aspartate aminotransferase (AST) >5 X ULN and/or direct (conjugated) bilirubin > 2X ULN
•Renal function < 30% of normal for age and size as determined by the Schwartz formula
•International normalized ratio (INR) > 1.4 and activated partial thromboplastin time (aPTT) > 3 seconds above the upper limit of normal for age, within 1 week prior to enrollment.
•History of allergy to apixaban or Factor Xa inhibitors
•History of significant adverse reaction or major bleeding related adverse reaction to other anticoagulant or antiplatelet agents
•History of any significant drug allergy (such as anaphylaxis or hepatotoxicity
•Any investigational drug being administered during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
•Efficacy: The primary efficacy endpoint is a composite of adjudicated non-fatal DVT (including asymptomatic and symptomatic), PE, and CSVT and VTE-related-death objectively confirmed by independent adjudication
•Safety: The primary safety endpoint will be adjudicated major bleeding using the International Society on Thrombosis and Haemostasis (ISTH) definition for children |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Efficacy: Up to 1 month
•Safety: Up to 1 month |
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E.5.2 | Secondary end point(s) |
•Efficacy: a) Non-fatal asymptomatic DVT
•Efficacy: b) Non-fatal symptomatic DVT
•Efficacy: c) Non-fatal PE
•Efficacy: d) CSVT
•Efficacy: e) VTE-related-death
•Safety: Composite of major and clinically relevant non major bleeding (CRNMB) using the ISTH definition for children
•Pharmacodynamics: Anti-FXa Activity measured by plasma concentration assay
•Pharmacokinetics: Measured by maximum observed concentration (Cmax)
•Pharmacokinetics: Measured by trough observed concentration (Cmin)
•Pharmacokinetics: Measured by area under the concentration-time curve in one dosing interval [AUC(TAU)] |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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.8.3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Belgium |
Brazil |
Canada |
Croatia |
Czech Republic |
Hungary |
Korea, Republic of |
Mexico |
New Zealand |
Poland |
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.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 4 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 21 |