Pilot Feasibility and Safety of Administering Weight Adjusted Fixed LMWH Dose (FiXET)

A Pilot Feasibility And Safety Multicenter Trial Of Administering Weight Adjusted Fixed Dose Of Low Molecular Weight Heparin (Enoxaparin) To Neonates and Children With Thrombosis (FiXET)

Background Enoxaparin is a commonly used low molecular weight heparin (LMWH) for the treatment of neonatal and children thrombosis that is monitored with anti-factor Xa (anti-Xa) levels. However, this therapeutic range of anti-Xa (0.5 - 1.0 u/ml) was extrapolated from adult studies. The burden of pain to neonates due to venipunctures and of resources to the health care system also warrants an evidence-based review to assess the utility of monitoring LMWH therapy with anti-Xa levels.

Methods/Design This is a prospective pilot, feasibility and safety multicenter, randomized controlled trial to compare the approach of treating thrombosis in neonates and children with enoxaparin using weight adjusted fixed dose to variable dose titrated to maintain a pre-determined anti-Xa range (0.5-1.0 u/mL). We plan to recruit 20 neonates and children over the study period, who will be randomized within their first week of anti-coagulation treatment. Key feasibility outcomes include screening/recruitment ratio, monthly recruitment rate, and completeness of data collection. We will also measure the safety outcome of bleeding as well as comment on efficacy of resolution of thrombosis as a secondary outcome.

Discussion The administration of weight adjusted fixed dose of enoxaparin without anti-Xa monitoring has the potential to reduce pain from multiple venipunctures in neonates and children as well as resources used in their already complex care. The results of the FiXET trial will set the framework for a larger multicenter randomized controlled trial to compare the efficacy of administering enoxaparin to neonates and children without monitoring to the current conventional approach of routine monitoring with anti-Xa levels.

Study Overview

• Status: Recruiting
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Enoxaparin

Detailed Description

1. Scientific Rationale Enoxaparin is a commonly used low molecular weight heparin (LMWH) for the treatment of neonatal and children thrombosis that is monitored with anti-factor Xa (anti-Xa) levels. However, this therapeutic range of anti-Xa (0.5 - 1.0 u/ml) was extrapolated from adult studies. The burden of pain to neonates and children due to venipunctures and of resources to the health care system also warrants an evidence-based review to assess the utility of monitoring LMWH therapy with anti-Xa levels. This FiXET trial is to compare the approach of treating thrombosis in neonates and children with enoxaparin using weight adjusted fixed dose to variable dose titrated to maintain a pre-determined anti-Xa range (0.5-1.0 u/mL). We plan to recruit 20 neonates and children over the study period, who will be randomized within their first week of anti-coagulation treatment. Key feasibility outcomes include screening/recruitment ratio, monthly recruitment rate, and completeness of data collection. We will also measure the safety outcome of bleeding as well as comment on efficacy of resolution of thrombosis as a secondary outcome.

   1.1 Potential Risk and Benefits The administration of weight adjusted fixed dose of enoxaparin without anti-Xa monitoring has the potential to reduce pain from multiple venipunctures in neonates and children as well as resources used in their care. The results of the FiXET trial will provide preliminary clinical data regarding the feasibility and safety of this approach to anticoagulation treatment in neonates and children. It will also provide a preliminary idea about the efficacy of such an approach. This trial, if successful, will set groundwork for a larger multicenter randomized controlled trial to compare the efficacy of administering enoxaparin to neonates and children without monitoring to the current conventional approach of routine monitoring with anti-Xa levels.

2. Study Objectives The aim of this trial is to determine the feasibility and safety of doing a randomized control trial to compare the approach of treating thrombosis in neonates and children with enoxaparin using weight adjusted fixed dose to variable dose titrated to maintain a pre-determined anti-Xa range (0.5-1.0 u/mL).
3. Eligibility Criteria Four or more tertiary hospitals will participate in this trial. We plan to recruit a total of 20 patients based on the following protocol-defined inclusion and exclusion criteria.

4. Study Design FiXET trial is a prospective pilot, feasibility and safety multicenter, randomized controlled trial. Recruitment will start following institutional REB approval. This will occur over 1year per centre and may take up to 2 years. Analysis and dissemination will occur after this period of time.

   4.1 Study Endpoints

   Primary Objective The primary outcome of this trial is to assess feasibility and safety, as defined below, of administering a weight adjusted fixed dose of enoxaparin to neonates and children with thrombosis.

   Feasibility criteria

   • At least 5 subjects can be recruited in each participating centre over the study period
   • At least 50% of all approached patients can be recruited
   • Complete data collection and follow-up of at least 90% of all recruited subjects

   Safety criteria

   - No more than 20% of subjects are removed from the study due to 1) low or high anti-Xa levels, or 2) major bleeding

   Major bleeding will be defined as (i) fatal bleeding; (ii) clinically overt bleeding resulting associated with a decrease in hemoglobin of 20 g/L (2 g/dL) in a 24 hour period; (iii) bleeding into a critical organ (intracranial, pulmonary or retroperitoneal); or bleeding requiring surgical intervention [17].

   Minor bleeding will be defined as any overt or macroscopic evidence of bleeding that does not fulfill criteria for major bleeding [17].

   Secondary Objective Secondary outcome measures include 1) efficacy in resolution of thrombosis; 2) mean anti-Xa levels; 3) number of enoxaparin dose adjustments required in the control arm; and 4) number of venipuncture attempts for blood sampling in patients.

5. Expected Duration of Participant Participation The duration of enoxaparin therapy will be 6 weeks to 6 months at the discretion of the treating physician.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Wenli Xie, MSc, CCRC; Phone Number: 76054 905-521-2100; Email: xiew@mcmaster.ca

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • Recruiting
      • IWK Health Center
      • Contact: Zara Forbrigger; Email: zara.forbrigger@iwk.nshealth.ca
      • Principal Investigator: Ketan Kulkarni, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8N3Z5
      • Recruiting
      • HHSC/McMaster Children's Hospital
      • Contact: Wenli Xie, MSc; Phone Number: 76054 905-521-2100; Email: xiew@mcmaster.ca
      • Principal Investigator: Mihir Bhatt, MD
      • Sub-Investigator: Anthony Chan, MD
    • Ottawa, Ontario, Canada, K1H 8L1
      • Not yet recruiting
      • Children's Hospital of Eastern Ontario
      • Contact: Tracy Jackson, CCRP; Phone Number: 3101 (613) 737-7600; Email: TJackson@cheo.on.ca
      • Principal Investigator: Ewurabena Simpson, MD
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Principal Investigator: Leslie Raffini, MD
      • Contact: Isabella Mccary; Phone Number: 40431 215-590-0431; Email: MCCARYI@email.chop.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Birth to under 18 years of age at the diagnosis of thrombosis event
• Diagnosis of deep vein thrombosis confirmed by either venography or ultrasound, pulmonary embolism confirmed by ventilation perfusion scan or spiral CT scan or pulmonary angiogram, clinically stable cerebral sinovenous thrombosis confirmed with magnetic resonance imaging, or cardiac thrombosis diagnosed by echocardiogram.
• The treating team has decided to initiate anti-coagulation therapy

Exclusion Criteria

• Platelet count < 50x109/L;
• Hemorrhage or high risk of bleeding with the use of anticoagulation therapy;
• Creatinine > 1.5x upper limit of normal;
• Liver dysfunction associated with coagulopathy leading to a clinically relevant bleeding risk;
• Documented history of heparin induced thrombocytopenia;
• Known contraindication to heparin

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Experimental Arm:patients will not have any dose titration regardless of anti-Xa level. Premature neonates will receive enoxaparin 2.0 mg/kg/dose rounded to nearest whole mg twice daily, while term neonates will receive enoxaparin 1.7 mg/kg/dose rounded to nearest whole mg twice daily. Children≥1 month corrected age will receive 1.5 mg/kg/dose twice daily (maybe rounded +/- 10% for convenience of dosing) while children≥2 month corrected age will receive 1.0 mg/kg/dose twice daily (maybe rounded +/- 10% for convenience of dosing).	Drug: Enoxaparin; WEIGHT ADJUSTED FiXED DOSE OF LOW MOLECULAR WEIGHT HEPARIN (ENOXAPARIN) TO NEONATES AND CHILDREN WITH THROMBOSIS (FiXET); Other Names: Enoxaparin sodium
Other: Control Arm; Control Arm: patients who will have dose titration based on anti-Xa levels to maintain a therapeutic range of 0.5-1.0 u/mL (standard of care).	Drug: Enoxaparin; WEIGHT ADJUSTED FiXED DOSE OF LOW MOLECULAR WEIGHT HEPARIN (ENOXAPARIN) TO NEONATES AND CHILDREN WITH THROMBOSIS (FiXET); Other Names: Enoxaparin sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of recruiting at least 5 subjects over the study period per center	Number of Participants from each participating center; Rate of recruitment per approaching; Rate of completed data collection and follow-up per all recruited subjects These variables will be combined to reflect the feasibility of trial recruitment	12 - 24 months
Safety of administering a weight adjusted fixed dose of enoxaparin to neonates and children with thrombosis	- Percentage of subjects removed from the study due to 1) low or high anti Xa levels or 2) major bleeding	12 - 24months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy in resolution of thrombosis	-Rate of thrombosis resolution	12-24 months
Safety of anticoagulation	Mean anti-Xa levels; Number of Enoxaparin dose adjustments in the control arm; Number of venipuncture attempts for blood sampling These Categorical variables will be combined to analyze the safety of this FiXET dose anticoagulation therapy on patients	12-24 months

Collaborators and Investigators

• Sponsor: Hamilton Health Sciences Corporation
• Collaborators: Children's Hospital of Philadelphia; Children's Hospital of Eastern Ontario; IWK Health Centre
• Investigators: Principal Investigator: Mihir Bhatt, MD, HHSC/McMaster Children's Hospital

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: May 14, 2015
• First Submitted That Met QC Criteria: June 30, 2015
• First Posted (Estimate): July 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 14, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: children; RCT; Enoxaparin; neonate; thrombosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: HamiltonHSC

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No