E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nephrotic syndrome is defined as severe proteinuria (> 3.5 g / day), edema and hypoalbuminemia. It is conditioned by a defect in the kidney's glomerular filtration barrier, resulting in the loss of a large number of plasma proteins including coagulation factors and consequently a increased risk of thromboembolic complications. The most frequent cause of nephrotic syndrome is the renal disease membranous nephropathy, which is associated with the greatest risk of thromboembolic complications. |
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E.1.1.1 | Medical condition in easily understood language |
In nephrotic syndrome, the kidney's filtering function is damaged and causes proteins to be lost in the urine, which increases the risk of forming blood clots in eg. legs and lungs. |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029167 |
E.1.2 | Term | Nephrotic syndrome with lesion of membranous glomerulonephritis |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029165 |
E.1.2 | Term | Nephrotic syndrome in diseases classified elsewhere |
E.1.2 | System Organ Class | 100000004857 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This study aims to describe the biochemical coagulation profile and investigate the effect of dalteparin and apixaban on this profile in patients with nephrotic syndrom. More specifically, we will: 1 Identify abnormalities in the coagulation profile in nephrotic syndrom promoting a prothrombotic state. 2 Describe the effects of dalteparin on the biochemical coagulation profile in nephrotic syndrom. 3 Determine the levels of plasma apixaban and its effect on the biochemical coagulation profile in nephrotic syndrom compared with healthy controls.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Substudy 1: To identify abnormalities in the coagulation profile in nephrotic syndrome 60 patients will be included in substudy 1.
Inclusion criteria: • Age > 18 • eGFR > 30 mL/min/1,73 m2 • P-albumin < 30 g/L • Stabilized diabetes with hemoglobinA1c < 65 mmol/mol • U-albumin excretion > 2.2 g/day • Known glomerular disease including membranous nephropathy, which may cause nephroticy syndrom or diagnostically unresolved nephrotic syndrome with a planed kidney biopsy.
Substudy 2: Up to 50 patients from substudy 1 will be treated with dalteparin to describe the effects on the biochemical coagulation profile.
Inclusion criteria: • Age > 18 years • eGFR > 30 mL/min/1,73 m2 • P-albumin < 25 g/L • Stabilized diabetes with hemoglobinA1c < 65 mmol/mol • U-albumin excretion > 2.2 g/day • Known glomerular disease including membranous nephropathy, which may cause nephroticy syndrom or diagnostically unresolved nephrotic syndrome with a planed kidney biopsy.
Substudy 3: To determine the levels of plasma apixaban and its effect on the biochemical coagulation profile in nephrotic syndrome compared to atrial fibrillation patients, 10 patients with nephrotic syndrome and membranous nephropathy will be treated with apixaban and compared to 10 patients with atrial fibrillation.
Patiens with nephrotic syndrome. Inclusion criteria: • Age > 18 years • eGFR > 30 mL/min/1,73 m2 • P-albumin < 25 g/L • U-albumin excretion > 2.2 g/day • One of the following conditions based on a kidney biopsy: - Membranous nephropathy - Minimal change disease - Focal segmental glomerulosclerosis • Stabilized diabetes with hemoglobinA1c < 65 mmol/mol
Healthy controls. Inclusion criteria: • Age > 18-years • eGFR > 30 mL/min/1,73 m2 • P-albumin > 36 g/lL • Stabilized diabetes with hemoglobinA1c < 65 mmol/mol • Patients exhibiting indications of infection must have CRP concentration < 30 mg/l • U-albumin excretion < 300 mg/day
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E.4 | Principal exclusion criteria |
Exclusion criteria: • Kontraindikation to apixaban. • Kontraindikation to dalteparin. • Known allergy or intolerance to apixaban. • Known allergy or intolerance to dalteparin. • Treatment with anticoagulation for other reasons. • Treatment with COX-1 inhibitors or ADP receptor inhibitors. • Known acquired or congenital coagulation defect not related to nephrotic syndrome or thromboembolic disease within 3 months. • Lack of compliance, comorbidity or other conditions that, in the eyes of the inclusive physician, make the patient unfit to participate in the trial. • Pregnancy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Description of the coagulation profile 1 In patients with nephrotic syndrom, thromboxane B2 (marker of the primary hemostasis) as well as thrombin generation and prothrombin Fragment 1+2 (markers of the secondary hemostasis) are increased compared to healthy controls. 2 In patients with nephrotic syndrom, the natural anticoagulants are decreased compared to healthy controls. 3 In patients with nephrotic syndrom, clot lysis and plasminogen activator inhibitor-1 (markers of fibrinolysis) are decreased compared to healthy controls.
The effects of dalteparin on the biochemical coagulation profile: 1 In patients with nephrotic syndrom, treatment with dalteparin leads to a decrease in thrombin generation compared with baseline.
The effects of apixaban on the biochemical coagulation profile: 1 In patients with nephrotic syndrom, apixaban leads to a decrease in thrombin generation compared with baseline. 2 The decrease in thrombin generation following apixaban is similar in patients with nephrotic syndrom and healthy controls. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When the last patient is included and has completed the study, the biochemical samples will be analyzed and data will be compiled. Inclusion of patientes is expected to begin September 2020 and end in september 2023. |
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E.5.2 | Secondary end point(s) |
Apixaban: 1 The plasma and urine concentrations of apixaban in patients with nephrotic syndrom is comparable to the plasma and urine concentration of apixaban in healthy controls. 2 In patients with nephrotic syndrome the decreases in thrombin generation following dalteparin or apixaban are similar. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
When the last patient is included and has completed the study, the biochemical samples will be analyzed and data will be compiled. Inclusion of patientes is expected to begin September 2020 and end in september 2023. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Pharmacokinetic trial |
Farmakokinetisk studie |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Blood and urine samples are compared to healthy controls |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The project is expected to extend over 36 months. Inclusion of patients comences 01.09.2020 with expected completion 01.09.2023.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |