Study of the Bioaccumulation of Tinzaparin in Renally Impaired Patients When Given at Prophylactic Doses

Study Overview
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Brief Summary
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The purpose of this study is to assess if accumulation of anti-Xa activity occurs after repeated daily administration of prophylactic doses of tinzaparin in patients with severe chronic kidney disease (CKD) requiring thromboprophylaxis for non-surgical conditions. It is anticipated that tinzaparin used at a fixed dose for thromboprophylaxis in severe CKD patients (eGFR ≤ 30 ml/min /1.73 m2) at risk for venous thromboembolism (VTE) will not bioaccumulate at a significant level, meaning an increase of ≥ 20% of the anti-Xa mean level between day 2 or 3 and day 5.

Detailed Description
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STUDY DESIGN : Prospective, monocentric, open-label, single-arm, observational cohort study Subjects hospitalized for non-surgical reasons by medical departments (ie Nephrology, Pneumology, Cardiology and Internal medicine) with chronic kidney disease (baseline eGFR ≤30 ml/min/1.73 m2) receiving tinzaparin prophylaxis at a dose of 3500 IU (or 4500 IU if BMI > 30kg/m2) once-daily. Pharmacokinetic parameters: Peak anti-Xa analyses done after 2 (or 3), 5, and 8 days of treatment, and one trough anti-Xa analysis on day 5. The bioaccumulation of tinzaparin will be assessed by determining whether this dosing regimen is associated with an excessive increase in anti-Xa levels over the course of the treatment (see below for statistical analysis). RECRUITMENT PROCESS: A systematic screening for potential study subjects will be made by the research coordinators based on key computer searches fields throughout four different softwares. Through these databases, researchers will be able to perform a preliminary selection of any of the eligible subjects by identifying hospitalized patients that will ultimately be treated. The pharmacists responsible for validation of tinzaparin prescriptions at the pharmacy department will work with the research team at the initial screening by identifying eligible candidates. Since the choice of prescribed agents is to the prescriber's discretion, the recruitment procedures will be triggered mainly as soon as a prescription of tinzaparin at thromboprophylaxic dose is written.Subjects who meet the inclusion criteria and do not meet any exclusion criteria will be considered eligible candidates and additional baseline information will be collected at that point, such as ethnicity and sex. The eligible participant will be addressed directly by a member of the research team. Informed consent will be sought and documented through the Information Form and Informed Consent (FIC) already approved by the ethics committee the hospital. DATA COLLECTION: Four blood samples, three of which will be collected 4±1 hours after the injection of tinzaparin at days 2 (or 3), at day 5 and at day 8, and one trough that will be collected at day 5. Pre-identified tubes (encoded) will be provided to the nursing and the sample shipping staff with specific instructions for manipulation of the blood sample and shipping to the laboratory. STUDY SAMPLE: In this study, it is considered that bioaccumulation should be statistically significant if Cmax of anti-Xa are increased by at least 20%. Estimation of the population size was performed using information obtained from Mahé et al. due to the similar nature of the population studied. As for mean plasma anti-Xa peak levels, a study done by Bara L et al. showed that 431 patients receiving 3 500 IU of tinzaparin for thromboprophylaxis had a mean of 0.15 IU/ml, which is the dose that will be given to most of the subjects in the present study. Based on the coefficient variation of Mahé et al. of 0.36 and the mean plasma anti-Xa level found by Bara L. et al, a standard deviation of 0.05 IU/ml was established, considering that the same coefficient of variation should be maintained across the dose administered. For the purpose of this study, researchers presumed an identical variance between all anti-Xa levels regardless of the day of blood sample collection. According to the null hypothesis, the mean of the distribution is 0.15 IU/ml while for the alternative hypothesis; the average would be 0.18 IU/ml (since established cut-off is a 20% increase). With a paired one-tailed t test, an alpha error of 0.05, a power of 0.90, and a strong correlation between measurements (r=0.7) , 25 participants are required to detect an increase ≥ 20% in anti-Xa activity between sampling on day 2 or 3 and at maximum of 8 days.

Official Title
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Study of the Bioaccumulation of Tinzaparin in Renally Impaired Patients When Given at Prophylactic Doses

Conditions
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Renal Insufficiency, Chronic, Deep Venous Thrombosis, Protection Against

Intervention / Treatment
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* Drug: Tinzaparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old A prescription of prophylactic tinzaparin (3500 IU or 4500 IU) has been initiated by order of the treating physician Patient admitted for medical reasons by one (but not limited to) of the following wards: nephrology, internal medicine, cardiology or pneumology Chronic severe renal impairment defined as an eGFR ≤ 30 mL/min/1.73 m2 at the moment of prescription and when available, eGFR at baseline, ie ≤ 30 ml/min/1.73 m2 for the last 3 months Estimated length of stay ≥ 5 days Written informed consent obtained within at most 3 ± 1 hours after the second or third dose of tinzaparin. Exclusion Criteria: Super obese (Body-mass Index (BMI) > 50kg/m2) Treatment with UFH, LMWH or oral factor Xa inhibitors <48h prior starting the first dose of tinzaparin Prophylaxis with LMWH other than tinzaparin < 48h prior starting the first dose of tinzaparin Prophylaxis with heparin < 12h prior starting the first dose of tinzaparin Treatment with argatroban, bivalirudin < 24 hours prior starting the first dose of tinzaparin Treatment with oral direct thrombin inhibitors, danaparoid, fondaparinux, or anti-vitamin K agents for < 7 days prior to starting the first dose of tinzaparin Acute renal failure in an individual with baseline eGFR > 30 ml/min/1.73 m2 Prophylactic tinzaparin in use for more than 72h before inclusion Severe liver insufficiency (Child- Pugh C) Anuria or chronically dialysed patients (or eGFR < 5 ml/min/1.73 m2) Participation in another study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tinzaparin<br>Hospitalized patients with chronic renal insufficiency (eGFR ≤ 30 mL/min/1.73 m2) at risk of VTE secondary to non-surgical reasons and receiving thromboprophylactic doses of tinzaparin 3500 or 4500 unit sub-cutaneous once daily. | Drug: Tinzaparin<br>* 3500 Unit or 4500 Unit subcutaneous once daily<br>* Other names: Innohep;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak anti-Xa levels in patients with eGFR ≤ 30 mL/min/1.73 m2 receiving repeated daily doses of tinzaparin for VTE prophylaxis | To compare the anti-Xa levels between day 2 (or 3) and day 5 in order to assess if bioaccumulation occurs at a significant level, meaning an increase of ≥ 20% of the anti-Xa mean level.The anti-Xa levels will be measured 4±1 hours after administration, which corresponds to the maximal concentration (Cmax) of tinzaparin anti-Xa activity. | 4±1 hours after administration of tinzaparin on days 2 or 3, and 5. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak anti-Xa levels in patients with eGFR ≤ 20 mL/min/1.73 m2 receiving repeated daily doses of tinzaparin for VTE prophylaxis | To compare the anti-Xa levels between day 2 (or 3) and day 5 in order to assess if bioaccumulation occurs at a significant level, meaning an increase of ≥ 20% of the anti-Xa mean level. The anti-Xa levels will be measured 4±1 hours after administration, which corresponds to the Cmax of tinzaparin of the anti-Xa activity. | 4±1 hours after administration of tinzaparin on days 2 or 3, and 5. | 
| Peak anti-Xa levels in patients with eGFR ≤ 30 mL/min/1.73 m2 receiving repeated daily doses of tinzaparin for VTE prophylaxis | To compare the anti-Xa levels between day 2 (or 3) and day 8 in order to assess if bioaccumulation occurs at a significant level, meaning an increase of ≥ 20% of the anti-Xa mean level. The anti-Xa levels will be measured 4±1 hours after administration, which corresponds to the Cmax of tinzaparin anti-Xa activity. | 4±1 hours after administration of tinzaparin on days 2 or 3, and 8. | 
| Anti-Xa trough level | To explore the safety of tinzaparin at daily prophylactic doses for VTE in renally impaired patients by measuring the trough anti-Xa level (Cmin) on day 5, and to assess the proportion of participants with a trough above 0.40 IU/mL. A level of just above 0.50 IU/ml anti-Xa activity (close to 0.4 IU/ml) is within the range of therapeutic anticoagulation for the treatment of VTE with tinzaparin and, therefore, is considered excessive anticoagulation for VTE prophylaxis. | On day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thromboembolism, Venous Thrombosis, Embolism and Thrombosis, Chronic Renal Diseases, Kidney Failure, Chronic, Renal Failure, Chronic, Venous Thromboembolism, Tinzaparin, Innohep, Heparin, Low-Molecular-Weight