Rationale and Design of a Phase III Single-Arm Multicenter Study of Dabigatran Etexilate for the Secondary Prevention of Venous Thromboembolism in Children
Notice bibliographique
Résumé
Abstract Background: In children, the incidence of venous thromboembolism (VTE) is increasing and is often associated with underlying diseases such as cancer, or risk factors such as thrombophilia. Following treatment for acute VTE, thrombosis or thromboembolic events can recur particularly if a clinical risk factor for VTE persists. The efficacy and safety of the oral anticoagulant dabigatran etexilate (DE) have been demonstrated in a number of thrombosis-related indications in adults, including for secondary VTE-prevention. There are, however, potential differences between adults and children related to developmental physiology and pharmacology and therefore trials to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of DE in children are required. To date, all pediatric phase IIa studies conducted have shown a similar PK and PK/PD relationship of DE in comparison to adult studies. Objective: To describe the design of a study to evaluate the safety and PK-PD of DE for secondary prevention of VTE in children aged 0-<18 years. Methods: This phase III, open-label, single-arm, multicenter study will be conducted at ~100 sites worldwide (NCT02197416). Eligible patients will have completed a course of initial treatment for confirmed acute VTE (for ≥ 3 months) and be considered at high risk for VTE recurrence due to the remaining presence of a clinical risk factor. Approximately 100 subjects between 0-<18 years of age will be included. Treatment with DE will extend up to 12 months, or less if the clinical risk factor resolves, with a follow-up visit 28 days after the last dose. DE will be administered twice daily as capsules, pellets or oral liquid formulation, depending on subject age and their ability to swallow capsules or pellets. A dosing nomogram will be used to scale down an adult dose based on the child's age and weight. Initial doses calculated using the nomogram should achieve steady-state trough concentrations of DE of between 50 and < 250 ng/ml, a range which is assumed to result in safe and effective use of DE in this pediatric population; after about 3 days, trough dabigatran plasma concentration will be measured and DE may be titrated up or down to achieve the target steady-state trough plasma concentration. Results: Demographic and medical history data will be collected for all participants. The primary outcomes to be evaluated are instances at 6 and 12 months of image-proven VTE recurrence; major and minor bleeding, including clinically relevant non-major bleeding; and overall and thrombotic/thromboembolic mortality. All elements of the primary endpoints will be evaluated by an independent adjudication committee that will confirm or refute outcome events. The secondary outcomes are rates of post-thrombotic syndrome at 6 and 12 months; PK and PD (e.g., activated partial thromboplastin time and ecarin clotting time); and the number of DE dose adjustments required during the treatment period. Data on the acceptability of the age-appropriate drug formulation, the tolerability of the study medication, adverse events, treatment discontinuations due to an adverse event, and laboratory and clinical parameters will also be collected during the study. Safety and tolerability will be monitored by the independent Data Monitoring Committee. Conclusion: This phase III study has been designed to provide data on the safety and PK-PD of DE for the secondary prevention of VTE in children aged 0-<18 years. Disclosures Luciani: Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Mitchell:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Huang:Boehringer Ingelheim: Employment. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».