Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

Study Overview
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Brief Summary
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The study aims to describe the biochemical coagulation profile and investigate the effect of Low molecular weight heparin and Apixaban on this profile in patients with nephrotic syndrome.

Detailed Description
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The initial part of the study is a prospective cross-sectional study which will describe the biochemical coagulation profile in nephrotic patients. It will include 60 patients with nephrotic syndrome and data from 50 anonymous blood donors matched in age and gender for comparison. The second part of the study is an open-label, controlled, non-randomized, interventional clinical trial consisting of 3 groups of patients with nephrotic syndrome or atrial fibrillation treated with either Dalteparin or Apixaban. The study participant is expected to be in stable condition after 4 full days of treatment. For administrative reasons, the final biochemical tests are performed on day 4, 5, 6 or 7 described as day 4 in this protocol. Group A: Up to 50 patients with nephrotic syndrome treated with injection Dalteparin 200 Units/kg subcutaneous once a day for 4 days Group B: 10 patients with nephrotic syndrome and membranous nephropathy treated with Apixaban 5 mg twice daily for 4 days. Group C: 10 patients with atrial fibrillation and no kidney disease treated with Apixaban 5 mg twice daily for 4 days. Patients participating in the initial part of the study will be included in det second part (Group A) if they meet the inclusion criteria. If the patient is diagnosed with membranous nephropathy it is possible to be included in the initial part as well as the second part (Group A and B).

Official Title
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Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

Conditions
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Nephrotic Syndrome, Thromboembolic Disease

Intervention / Treatment
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* Drug: Dalteparin
* Drug: Apixaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Nephrotic patients - no intervention Age 18-79 years Estimated Glomerular Filtration Rate (eGFR) > 49 mL/min/1.73 m2 P-albumin < 30 g/L U-Albumin excretion > 2.2 g/day Known glomerular disease including membranous nephropathy, which may cause nephrotic syndrome or diagnostically unresolved nephrotic syndrome with a planed kidney biopsy. Inclusion Criteria: Nephrotic patients treated with Dalteparin Age 18-79 years eGFR > 49 mL/min/1.73 m2 P-albumin < 25 g/L U-Albumin excretion > 2.2 g/day Known glomerular disease including membranous nephropathy, which may cause nephrotic syndrome or diagnostically unresolved nephrotic syndrome with a planed kidney biopsy. Inclusion Criteria: Nephrotic patients treated with Apixaban Age 18-79 years eGFR > 49 mL/min/1.73 m2 P-albumin < 25 g/L U-Albumin excretion > 2.2 g/day Membranous Nephropathy Inclusion Criteria: Patients with atrial fibrillation treated with Apixaban Age 18-79 years eGFR > 49 mL/min/1.73 m2 P-albumin > 36 g/L U-Albumin excretion < 300 mg/day Atrial Fibrillation Exclusion Criteria: Contraindication to Apixaban Contraindication to Dalteparin Known allergy or intolerance to Apixaban Known allergy or intolerance to Dalteparin Treatment with anticoagulation for other reasons. Treatment with cyclooxygenase-1-inhibitors or Adenosine Diphosphate (ADP) receptor inhibitors. Known acquired or congenital coagulation defect non related to nephrotic syndrome or thromboembolic disease within 3 months. Known diabetes mellitus. Lack of compliance, comorbidity or other conditions that, in the patients unfit to participate in the trial. Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An open-label, controlled, non-randomized, interventional clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Coagulation profile in Nephrotic syndrome<br>Investigation of the biochemical coagulation profile in patients with nephrotic syndrome. | |
| Experimental: Nephrotic syndrome<br>Nephrotic patients without diabetes. | Drug: Dalteparin<br>* Drug: Dalteparin 200 units/kg once a day for 4-7 days.<br>* Other names: Fragmin;|
| Experimental: Membranous nephropathy and nephrotic syndrome<br>Membranous nephropathy and nephrotic syndrome. | Drug: Apixaban<br>* Drug: Apixaban 5 mg twice a day for 4-7 days.<br>* Other names: Eliquis;|
| Active Comparator: Atrial fibrillation<br>Atrial fibrillation with no kidney disease. | Drug: Apixaban<br>* Drug: Apixaban 5 mg twice a day for 4-7 days.<br>* Other names: Eliquis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Thrombin Generation Assay in nephrotic patients treated with Dalteparin | Thrombin Generation Assay is used to monitor the anticoagulation therapy | Predose on Day 1 | 
| Steady state Thrombin Generation Assay (TGA) in nephrotic patients treated with Dalteparin (Nadir TGA value) | Thrombin Generation Assay is used to monitor the anticoagulation therapy | Predose day 4 | 
| Steady state Thrombin Generation Assay (TGA) in nephrotic patients treated with Dalteparin (4 hours TGA value) | Thrombin Generation Assay is used to monitor the anticoagulation therapy | 4 hours postdose on Day 4 | 
| Initial Thrombin Generation Assay in nephrotic patients treated with Apixaban | Thrombin Generation Assay is used to monitor the anticoagulation therapy. | Predose on Day 1 | 
| Thrombin Generation Assay in nephrotic patients treated with Apixaban over the first 24 hours. | Thrombin Generation Assay is used to monitor the anticoagulation therapy with blood samples at 2.5, 8, 24 hours. | 24 hours | 
| Steady state Thrombin Generation Assay in nephrotic patients treated with Apixaban. | Thrombin Generation Assay is used to monitor the anticoagulation therapy. | Predose day 4 | 
| Initial Thrombin Generation Assay in patients with atrial fibrillation and no kidney disease treated with Apixaban | Thrombin Generation Assay is used to monitor the anticoagulation therapy. | Predose on Day 1 | 
| Thrombin Generation Assay in patients with atrial fibrillation and no kidney disease treated with Apixaban over the first 24 hours. | Thrombin Generation Assay is used to monitor the anticoagulation therapy with blood samples at 2.5, 8, 24 hours. | 24 hours | 
| Steady state Thrombin Generation Assay in patients with atrial fibrillation and no kidney disease treated with Apixaban. | Thrombin Generation Assay is used to monitor the anticoagulation therapy. | Predose day 4 | 
| Comparing Thrombin Generation Assay between group B and C. | Comparing Thrombin Generation Assay in nephrotic patients treated with Apixaban and patients with atrial fibrillation treated with Apixaban. | Predose, 2.5, 8, 24 hours and predose Day 4 | 
| Comparing Thrombin Generation Assay between group A and C. | Comparing Thrombin Generation Assay in nephrotic patients treated with Dalteparin and patients with atrial fibrillation treated with Apixaban. | Baseline and predose Day 4 | 
| Comparing Thrombin Generation Assay between group A and B. | Comparing Thrombin Generation Assay in nephrotic patients treated with Dalteparin and nephrotic patients treated with Apixaban. | Baseline and predose Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of bleeding-events durin the study. | Number of cases with bleeding-events. | Predose until 7 days after last dose of apixaban. | 
| Evaluation of thromboembolic complications during the study. | Number of cases with thromboembolic complications | Predose until 7 days after last dose of apixaban. | 
| Comparing plasma concentration of Apixaban between group B and C | Comparing plasma-Apixaban in nephrotic patients and patients with atrial fibrillation. | Day 4 | 
| Comparing urine concentration of Apixaban between group B and C | Comparing urine-Apixaban in nephrotic patients and patients with atrial fibrillation. | Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nephrotic Syndrome, Glomerulonephritis, Hypoalbuminemia, Proteinuria, Thromboembolic Disease, Membranous Nephropathy