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

Dose-adjustment of Enoxaparin by a Bayesian Pharmacological Approach in Pediatric Kidney Transplant Recipients

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.

Study Overview

• Status: Recruiting
• Conditions: Pediatric Kidney Transplant Recipients
• Intervention / Treatment: Drug: Bayesian based dose adjustment of enoxaparin; Drug: Usual dose adjustment of enoxaparin

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Olivia BOYER, Pr; Phone Number: +33 1 42 19 26 48; Email: olivia.boyer@aphp.fr
• Study Contact Backup: Name: Laure CHOUPEAUX, Master; Phone Number: +33 1 44 38 17 11; Email: laure.choupeaux@aphp.fr

Study Locations

• France
  • Ile-de-France
    • Paris, Ile-de-France, France, 75015
      • Recruiting
      • Hôpital Necker - Enfants Malades
      • Contact: Olivia BOYER, Pr; Phone Number: +33 1 42 19 26 48; Email: olivia.boyer@aphp.fr
      • Contact: Laure CHOUPEAUX, Master; Phone Number: +33 1 44 38 17 11; Email: laure.choupeaux@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Exclusion Criteria

1. Per-transplant technical surgical problems
2. Pre-inclusion allograft thrombosis (before randomization and enoxaparin administration)
3. Peri-operative thrombosis or 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment as usual (empirical dose adjustment); Anti-Xa activity is measured and twice-daily enoxaparin empirical dose-adjustment is performed according to the usual practices in the investigating centers	Drug: Usual dose adjustment of enoxaparin; A first recommended dose of enoxaparin 50 IU/kg is administered during transplantation or within the first 24 hours. Then anti-Xa activity is measured and twice-daily (hour 12 ; hour 24) enoxaparin empirical dose-adjustment is performed according to the usual practices in the investigating centers to target.
Experimental: Bayesian based dose adjustment; 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	Drug: Bayesian based dose adjustment of enoxaparin; A first recommended dose of enoxaparin 50 IU/kg subcutaneously is administered during transplantation or within the first 24 hours. Then a Bayesian estimate of individual pharmacokinetics is performed to adapt the next twice daily (Hour 12;Hour 24) enoxaparin dose until achievement of the target on two consecutive measurements. Then anti-Xa activity will be evaluated once a day until day 7.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-Xa activity in target range	Anti-Xa activity within the target range (i.e., success defined by an anti-Xa activity ≥0.3 IU/mL and ≤0.5 IU/mL). (i.e., success defined by an anti-Xa activity ≥0.3 IU/mL and ≤0.5 IU/mL).	At 28-30 hours after initiation of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to achieve target Anti-Xa activity	Success target is defined between 0.3-0.5 IU/mL Time will be defined by the delay between date and time of treatment initiation and date and time of anti-Xa activity measurement in the target range.	Up to 30 days
Graft thrombosis	Graft thrombosis : assessed by allograft ultrasound	Up to 30 days
Enoxaparin-related side effects	Enoxaparin-related side effects during the first postoperative month: bleeding (all localisations), graft hematoma (presence/absence): assessed by ultrasound	Up to 30 days
Allograft bleeding	Allograft bleeding: bleeding with post-operative transfusion	Up to 30 days
Anti-Xa activity in target range	Anti-Xa activity within the target range (i.e., success defined by an anti-Xa activity ≥0.3 IU/mL and ≤0.5 IU/mL). (i.e., success defined by an anti-Xa activity ≥0.3 IU/mL and ≤0.5 IU/mL).	From 28-30 hours to 7 days after initiation of treatment
Enoxaparin induced thrombopenia	Thrombopenia	Up to 30 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Olivia BOYER, Pr, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2023
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: January 3, 2023
• First Submitted That Met QC Criteria: January 3, 2023
• First Posted (Actual): January 5, 2023

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Children; Enoxaparin; Kidney transplantation; Anti-Xa activity; Bayesian based dose; allograft thrombosis
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: APHP180617; 2021-000099-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No