Dose-adjustment of Enoxaparin by a Bayesian Pharmacological Approach in Pediatric Kidney Transplant Recipients (OPTI-TREX)

Assistance Publique - Hôpitaux de Paris

Status and phase: Enrolling; Phase 4

Conditions: Pediatric Kidney Transplant Recipients

Treatments: Drug: Bayesian based dose adjustment of enoxaparin; Drug: Usual dose adjustment of enoxaparin

Study type: Interventional

Funder types: Other

Identifiers

NCT05672550

APHP180617

2021-000099-12 (EudraCT Number)

Details and patient eligibility

About

Allograft vascular thrombosis is a devastating complication in kidney transplantation in adults and older children. Though uncommon, it is often irreversible and represents the main cause of graft loss within after kidney transplantation in adults and in the first post-operative year in children. Since allograft thrombosis is usually observed in the first 48h post-operatively, the need to promptly achieve appropriate anticoagulation in at-risk patients is of utmost importance.

However, no consensus exists regarding the optimal prophylaxis in the peri-transplant period and the following dose-adjustment, and practices are highly heterogeneous among centers. Moreover, the therapeutic target is very narrow and antithrombotic agents may conversely increase the risk of allograft hematoma. Enoxaparin is a low molecular weight heparin commonly used in this context, but off-label in children. Therapeutic ranges are based on anti-Xa levels 4 to 6 hours following injection and extrapolated from adults although evidences suggest that such extrapolation may be inappropriate in many circumstances. The current pediatric practice of dose adjustment to achieve and maintain a target anti-Xa range is empirical and dependent on the physician.

The aim of the proposed clinical trial is to assess the efficacy/safety profile of this bayesian-based dose optimization in the clinical setting, as compared to the current practices of empirical adjustment. This should greatly improve the personalized management of renal transplanted children, a subset of patients with singular renal function and little-investigated pharmacokinetics and help standardizing and rationalizing practices.

Full description

The investigators will compare the efficacy of the Bayesian based dose versus the dose determined in a usual empirical way based on each physician's experience.

The primary endpoint is the Anti-Xa activity within the target range 28 to 30 hours after initiation of the treatment.

This is an open labelled randomized clinical trial. The randomization will proceed during the inclusion visit by the local pediatric nephrologist or intensivist just before the first enoxaparin injection, administered within 24 hours post-transplantation.

The investigators will conduct a national multicentric study with 9 inclusion centers which are all nephrology units specialized in renal transplantation.

Enrollment: 50 estimated patients

Sex: All

Ages: 2 to 20 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

1. Pediatric renal transplant recipients
2. Aged ≥ 2 years and ≤18 years
3. With an indication for enoxaparin treatment in the first post-transplant week according to the local transplant team such as inherited or acquired thrombotic disorders (eg. but not exclusive protein C, protein S, and antithrombin III deficiency; factor V Leiden mutation (FV506Q), prothrombin mutation (G20210A), mutation in the MTHFR (methyl Tetra hydro folate reductase) gene (C677T), and antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulants), history of thrombosis, donor age < 2 years, recipient age < 5 years, cold ischemia time >24h, multiple renal vessels.
4. Informed consent form signed by the legal guardian(s)
5. Affiliated to a health insurance system, including AME

Exclusion Criteria

1. Per-transplant technical surgical problems
2. Pre-inclusion allograft thrombosis (before randomization and enoxaparin administration)
3. Peri-operative thrombosis or uncontrolled bleeding (before randomization and enoxaparin administration)
4. Peri-operative hemodynamic instability
5. Medical history of heparin-induced thrombocytopenia
6. Allergic reaction to enoxaparin or excipients
7. Pregnancy
8. LMWH (Low molecular weight heparins) prophylactic before transplant
9. UFH (unfractionated heparin) treatment during renal transplantation with an anti-Xa level detectable 4-6h post administration

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

50 participants in 2 patient groups

Bayesian based dose adjustment

Experimental group

Description:

Optimization of the enoxaparin dose using a bayesian program in order to prevent patients from complications due to the renal transplantation. A first recommended dose of enoxaparin (50 IU/kg) is administered subcutaneously during transplantation or within the first 24 hours. Then, in the experimental group, the dose is adjusted following a bayesian program integrated in the electronic Case Report Form which is based on each patient's data as the Anti-Xa activity

Treatment:

Drug: Bayesian based dose adjustment of enoxaparin

Treatment as usual (empirical dose adjustment)

Active Comparator group

Description:

Anti-Xa activity is measured and twice-daily enoxaparin empirical dose-adjustment is performed according to the usual practices in the investigating centers

Treatment:

Drug: Usual dose adjustment of enoxaparin