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A Pilot Feasibility And Safety Multicenter Trial Of Administering Weight FiXET Study

Information source: Hamilton Health Sciences Corporation
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Venous Thromboembolism

Intervention: Enoxaparin (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: Hamilton Health Sciences Corporation

Summary

Background Enoxaparin is a commonly used low molecular weight heparin (LMWH) for the treatment of neonatal 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 a evidence-based review to assess the utility of monitoring LMWH therapy with anti-Xa levels. Here the investigators describe the FiXET trial. Methods/Design This is a prospective pilot, feasibility and safety multicenter, randomized controlled trial to compare the approach of treating thrombosis in neonates 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). The investigators plan to recruit 20 neonates over a 6 month period, who will be randomized prior to their first anti-Xa level being resulted. Key feasibility outcomes include screening/:recruitment ratio, monthly recruitment rate, and completeness of data collection. The investigators 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 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 without monitoring to the current conventional approach of routine monitoring with anti-Xa levels.

Clinical Details

Official title: A Pilot Feasibility And Safety Multicenter Trial Of Administering Weight Adjusted Fixed Dose Of Low Molecular Weight Heparin (Enoxaparin) To Neonates With Thrombosis (Fixet): Study Protocol

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label

Primary outcome:

Feasibility (At least 10 subjects can be recruited in each of the 4 participating centers over a 6 month period)

Safety (No more than 20% of subjects are removed from the study due to low or high anti Xa levels or major bleeding)

Feasibility (At least 50% of all approached patients can be recruited)

Feasibility (Complete data collection and follow-up of at least 90% of all recruited subjects)

Secondary outcome:

efficacy of resolution of thrombosis

mean anti-Xa levels

number of enoxaparin dose adjustments required in the control arm

number of venipuncture attempts for blood sampling in patients

Detailed description: BACKGROUND The use of low molecular weight heparin (LMWH) for the treatment of neonatal and pediatric thrombosis was first reported in 1996. They conducted a dose finding study using the LMWH enoxaparin in 25 children aged newborn to 17 years. Their work provided preliminary data on the excellent safety and efficacy profile of enoxaparin in the treatment of thrombosis in pediatric population. They discovered two important concepts in relation to dosing and monitoring of enoxaparin in neonates. First, neonates required a higher dose of enoxaparin (1. 64 mg/kg/dose twice daily) compared to older children (1 mg/kg/dose twice daily) to achieve therapeutic anticoagulation, evaluated by anti-Xa levels. Second, enoxaparin therapy must be monitored with anti-factor Xa (anti-Xa) levels and not activated partial thromboplastin time (APTT). In the therapeutic range of 0. 5-1. 0 u/ml, enoxaparin has minimal effect on APTT. Subsequent to the above work, many investigators have studied the use of enoxaparin and other LMWHs, including dalteparin, tinzaparin and nadroparin, prospectively. The common emerging theme in all of the studies was that neonates required higher dosing to maintain therapeutic anti-Xa levels compared to older children. These papers form the basis of the most current dosing guidelines. Enoxaparin is dosed at 1. 5 mg/kg for treatment and 0. 75 mg/kg for prophylaxis in neonates. Subsequent to the initial studies, there have been more reports suggesting that neonates may require even higher enoxaparin doses to attain and maintain therapeutic anti-Xa levels. A literature review in 2008 suggested to increase enoxaparin doses to 1. 7 mg/kg for term and 2. 0 mg/kg for premature neonates. Since 2008, few studies have replicated this finding. Of note a group compared 75 neonates treated with an initial enoxaparin dose of 1. 5 mg/kg or 1. 7 mg/kg. They found that those neonates treated with 1. 7 mg/kg dose had a therapeutic anti-Xa level of 0. 57 units/mL (u/mL), with no patients being supratherapeutic. And it took only 1 day versus 2 days for those treated at the lower dose to reach the therapeutic range. Others have had similar findings in their cohort. These two studies also included premature neonates and found that these patients required an even higher enoxaparin dose of 2. 0-2. 2 mg/kg to maintain therapeutic anti-Xa levels. There is substantial evidence in the literature to suggest that premature and term neonates require higher dosing of enoxaparin in order to achieve therapeutic anti-Xa levels. Monitoring of LMWH therapy in neonates has been an ongoing challenge. The therapeutic range of anti-Xa (0. 50-1. 0 u/mL) was extrapolated from adult studies. These parameters have since been adopted in consensus guidelines and used by other research studies. There is limited evidence correlating anti-Xa levels with resolution of thrombosis or incidence of hemorrhage. Additionally, there is significant variability among commonly used anti-Xa assays in clinical practice. There are two types of anti-Xa assay: 1) with exogenous AT added and 2) without exogenous AT. The addition of exogenous AT allows measurement of the LMWH effect without the influence of AT deficiency (if present), whereas the anti-Xa assay without exogenous AT allows measurement of the in vivo LMWH effect. Studies comparing different anti-Xa assays found a lack of correlation. In a recent study, the authors showed that changing anti-Xa assays resulted in an average 33% change in the anti-Xa values, which significantly affected the dosing of enoxaparin for the treated patients. For patients aged <3 months, there was a 0. 35 mg/kg change in the mean enoxaparin dosing to maintain therapeutic anti-Xa levels before and after the anti-Xa assay change at the author's institution. Along with methodical issues surrounding the use of anti-Xa assays, there are important clinical and resource issues to consider. The need for multiple venipunctures for blood sampling required to monitor anti-Xa levels is a significant cause for pain in neonates and a frustration for health care professionals charged with finding accessible veins frequently. Also, many centers who treat neonates with thrombosis do not have the finances to afford resources, such as equipment, anti-Xa assays, and personnel, required for the testing. These centers routinely treat patients with a weight-adjusted fixed dose of enoxaparin. There is no evidence at present to suggest that this is an effective or safe approach. There is, hence, the need to systematically study the utility of anti-Xa monitoring in the neonatal population. Aims 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 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). METHODS/DESIGN Recruitment will start in July, 2015. This will occur over 6 months per center and may take up to 1 year. Analysis and dissemination will occur after this period of time. The study is expected to be completed by October, 2016. Study design The FiXET trial is a prospective pilot, feasibility and safety multicenter, randomized controlled trial. Study setting and participants The neonatal intensive care units of four or more tertiary hospitals in Canada will participate in this trial. The investigators plan to recruit a total 20 patients based on the following protocol-defined inclusion and exclusion criteria. Sample size The purpose of the larger randomized controlled trial (RCT) will be to establish non-inferiority of administering weight adjusted fixed dose of enoxaparin in comparison to variable dose titrated to maintain anti-Xa levels of 0. 5-1. 0 u/mL. Considering a difference of less than 10% of no clinical importance and using 80% as the estimated complete/partial response rate for both groups, the sample size required to achieve an 80% power at an alpha of 0. 05 would be 396 subjects. In order to conduct the RCT among 10-12 centers over 3 years, the expected accrual would be 0. 9-1. 1 subjects per month per center, depending on the size of the center. In this trial, the investigators plan to assess feasibility of recruiting at least 5 subjects over a 6 month period per center. The overall sample size among 4 centers would be 20 subjects. Randomization All patients will begin treatment with enoxaparin as per the treatment protocol. Patients will be enrolled and randomized prior to their 1st anti-Xa level being resulted. The randomization sequence will be generated by a computer program at a ratio of 1: 1 among the two arms using the minimization method. Allocation concealment and blinding The current pilot study will be open label and there will not be concealment of allocation. The larger RCT will be blinded and allocation concealed in most appropriate manner as deemed by the study team and statistician. Treatment protocol The enoxaparin dose for patients will be based on current available evidence as discussed in the background section. Premature neonates will receive 2. 0 mg/kg/dose rounded to nearest whole mg twice daily, while term neonates will receive 1. 7 mg/kg/dose rounded to nearest whole mg twice daily. Patients will have blood sampling for anti-Xa levels drawn after the 3rd or 4th dose from starting or adjustment, followed by once weekly while admitted in hospital and once monthly once discharged. Patients will have appropriate imaging according to institutional guidelines, which must include at least end of treatment imaging. The duration of enoxaparin therapy will be 6 weeks to 6 months at the discretion of the treating physician. Interventions This trial will have two arms as below. 1. Experimental Arm: in the experimental arm patients will not have any dose titration regardless of anti-Xa level. An outline of the steps that will be taken should a patient have an anti-Xa level outside the therapeutic range are included in the protocol. 2. 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. Primary Outcome 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 with thrombosis. Feasibility criteria

- At least 10 subjects can be recruited in each of the 4 participating centers over a 6

month 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

- Low or high anti-Xa levels

- 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; (ii) bleeding into a critical organ (intracranial, pulmonary or retroperitoneal); or bleeding requiring surgical intervention. Minor bleeding will be defined as any overt or macroscopic evidence of bleeding that does not fulfill criteria for major bleeding. Secondary outcome 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. Statistical Analysis The safety and efficacy of the intervention will be evaluated on an intention-to-treat basis for all eligible patients randomized to the trial. Demographic parameters, if normally distributed, will be reported as mean with standard deviation and compared using Student's t test or analysis of variance (ANOVA). Non-normally distributed data will be reported as median with interquartile range and compared with appropriate non-parametric tests (Kruskal-Wallis one way ANOVA). Categorical data will be reported as number and percentage and compared using a chi-square or Fisher exact tests where indicated. A two-sided P value of 0. 05 will be used to indicate statistical significance. Ethics approval and trial registration The trial has been approved by Hamilton Integrated Research Ethics Board. All participating trial sites will be required to obtain ethics approval from their local research ethics board. Clinical trials application has been submitted to Health Canada and recruitment will only begin upon approval. Funding This trial is not funded. 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 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. 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 without monitoring to the current conventional approach of routine monitoring with anti-Xa levels. Trial status Awaiting Health Canada approval to begin recruitment.

Eligibility

Minimum age: N/A. Maximum age: 60 Days. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Premature (<36 completed weeks gestational age (GA), 0-60 days of corrected age) and

term (≥37 completed weeks GA, 0-60 days of corrected age) neonates;

- 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, or cardiac thrombosis diagnosed by echocardiogram. Exclusion Criteria:

- Cerebral sinovenous thrombosis;

- 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

Locations and Contacts

Additional Information

Starting date: July 2015
Last updated: June 30, 2015

Page last updated: August 23, 2015

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