| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute treatment and secondary prophylaxis of recurrent VTE (venous thromboembolism) in children with or without cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute treatment and secondary prophylaxis of recurrent VTE (venous thromboembolism) in children with or without cancer. |
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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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066899 |
| E.1.2 | Term | Venous thromboembolism |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 determine the pharmacodynamic (PD) profiles for treatment doses of dalteparin in pediatric subjects of different ages with venous thromboembolism (VTE), and with or without cancer, using anti-Xa (Xa) levels and a population PD analysis methodology.
- To determine the median dose (IU/kg) required to achieve therapeutic anti-Xa levels (0.5 to 1.0 International Units [IU]/mL) based on subject age and weight. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the proportion of major bleeding events during dalteparin treatment.
- To assess the proportion of minor bleeding events during dalteparin treatment.
- To explore the proportion of objectively documented new or progressive symptomatic VTE during dalteparin treatment.
- To explore the relationships of recurrent VTE and major bleeding events with anti-Xa levels if data permits.
- To explore the proportions of subjects with progression, regression, resolution or no change in the qualifying VTE during dalteparin treatment.
- To describe the overall safety profile of dalteparin in pediatric subjects of different ages with or without cancer and VTE.
- To assess proportion of subjects achieving an anti Xa therapeutic range of 0.5 to 1.0 IU/mL during the Dose Adjustment Phase. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects meet inclusion if all of the following are true:
1. Have been objectively diagnosed with a venous thrombotic event documented using one of the following acceptable imaging modalities within 4 days of enrollment:
- Compression ultrasound with Doppler [CUD];
- Computed tomography with/without venography [CT/CTV];
- Magnetic resonance imaging with/without venography [MRI/MRV];
- Conventional venography [CV];
- Ventilation-perfusion scan [V/Q] (for pulmonary artery);
- Spiral CT angiography [SCTA];
- Conventional pulmonary angiogram [CPA].
2. Are judged clinically to require anticoagulation therapy.
3. Are in the age range of ≥36 weeks gestation and <19 years at Screening/Baseline.
4. Have given signed informed consent (and assent, as appropriate) to participate prior to enrollment.
5. For cancer patients, a diagnosis of active malignancy (currently under treatment), other than basal cell or squamous cell carcinoma of the skin.
6. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. |
|
| E.4 | Principal exclusion criteria |
Subjects are excluded if any one of the following apply:
1. Weight ≤3.0 kg or >100 kg at Screening/Baseline.
2. Platelet count ≤ 50,000/mm (despite appropriate medical measures to support platelet count).
3. Received oral anticoagulant (OAC) therapy within 3 days of enrollment.
4. History of administration of therapeutic doses of LMWH (low molecular weight heparin) or unfractionated heparin for a period of > 4 days (or >8 doses of LMWH) for the qualifying VTE.
5. Received unfractionated heparin within 3 hours, or LMWH within 12 hours, of the first dose of dalteparin.
6. Acute VTE intervention which includes thrombolytic therapy.
7. Major bleeding at the time of Screening or enrollment or an unacceptably high risk of bleeding at the discretion of the investigator.
8. Activated partial thromboplastin time (aPTT) ≥5 seconds above upper limit of normal (ULN), and that corrects to within normal limits upon 1:1 mixing with normal plasma.
9. Prothrombin time (PT) ≥2 seconds above ULN, and that corrects to within normal limits upon 1:1 mixing with normal plasma.
10. Creatinine clearance <60mL/min in subjects >1 month of age.
11. Uncontrolled hypertension characterized by a sustained systolic pressure or diastolic pressure >99th percentile of age- and heightrelated
norms.
12. History of heparin-induced thrombocytopenia (HIT).
13. Any condition in which the investigator feels the subject is unsafe or inappropriate for study participation.
14. Insufficient subcutaneous tissue to facilitate subcutaneous drug administration.
15. Pregnant female subjects; breastfeeding female subjects; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of assigned treatment.
16. Refusal by sexually active postmenarche female subjects to adhere to an acceptable form of contraception.
17. Unable or unwilling to comply with scheduled follow-up visits. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacodinamic Endpoints:
- Determine the median dose of dalteparin (IU/kg) associated with the achievement of the therapeutic anti-Xa level (0.5-1.0 IU/mL) among subjects that achieved their therapeutic anti-Xa level during the dose adjustment phase, for each age cohort group;
- Anti-Xa activity versus time profile following dalteparin treatment will be explored using a population PD analysis methodology. Population PD parameters such as clearance, volume of distribution, absorption rate constant will be estimated based on anti-Xa levels collected during dose adjustment phase, PD phase and follow-up phase. Age and other relevant covariates will be explored in the population PD analysis. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Determine the median dose of dalteparin (IU/kg) during the dose adjustment phase.
- Population PD parameters: during dose adjustment phase, PD phase and follow-up phase. |
|
| E.5.2 | Secondary end point(s) |
- Proportion of subjects achieving an anti-Xa therapeutic range of 0.5 to 1.0 IU/mL during the Dose Adjustment Phase (up to 7 days);
- Proportion of subjects with objectively documented, new or progressive symptomatic VTE during dalteparin treatment utilizing the same objective technique performed at Baseline;
- Time to first episode of symptomatic recurrent VTE during dalteparin treatment;
- Proportions of subjects with progression, regression, resolution and no change (in comparison to qualifying VTE) during dalteparin treatment;
- Proportion of subjects with major bleeding during dalteparin treatment;
- Proportion of subjects with minor bleeding during dalteparin treatment;
- Description of subjects' adverse events (AEs) throughout the study period;
- Summary of chemistry, hematology, vital signs and physical examinations.
- Time to first major bleeding events during dalteparin treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See section E.5.2 (depending on the Endpoint the timepoint is during the dose adjustment phase or during dalteparin treatment) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| 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 | Yes |
| 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) | Yes |
| 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
| 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 | 22 |
| 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 |
| Canada |
| Croatia |
| Germany |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Russian Federation |
| Slovenia |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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