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Clinical Trial Results:
Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

Summary
EudraCT number	2019-001212-29
Trial protocol	DK
Global end of trial date	04 Sep 2024

Results information
Results version number	v1(current)
This version publication date	23 Apr 2025
First version publication date	23 Apr 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Prot-0824-2019

ISRCTN number

US NCT number

NCT04850378

WHO universal trial number (UTN)

Sponsor organisation name

Department of Renal Medicine, Aarhus University Hospital, Denmark

Sponsor organisation address

Palle Juul-Jensens Boulevard 35, Aarhus N, Denmark, 8200

Public contact

Sarah Kelddal, Aarhus Universitets Hospital, sarah.kelddal@midt.rm.dk

Scientific contact

Sarah Kelddal, Aarhus Universitets Hospital, sarah.kelddal@midt.rm.dk

Sponsor organisation name

Department of Renal Medicine, Aarhus University Hospital, Denmark

Sponsor organisation address

Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200

Public contact

Department of Renal Medicine, Aarhus University Hospital, Denmark, Department of Renal Medicine, Aarhus University Hospital, Denmark, sarahkelddal@hotmail.com

Scientific contact

Department of Renal Medicine, Aarhus University Hospital, Denmark, Department of Renal Medicine, Aarhus University Hospital, Denmark, sarahkelddal@hotmail.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Apr 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Apr 2024

Global end of trial reached?

Yes

Global end of trial date

04 Sep 2024

Was the trial ended prematurely?

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.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki and GCP guidelines. Ethics committee approval was obtained prior to trial initiation. All participants provided written informed consent. Subjects were covered by the national trial insurance scheme, and data were pseudonymised to ensure confidentiality.

Background therapy

No background therapy was administered across all treatment arms.

Evidence for comparator

Dalteparin is the standard thromboprophylactic treatment in nephrotic syndrome and was chosen as comparator to evaluate the pharmacodynamic profile of apixaban.

Actual start date of recruitment

01 Apr 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 57

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment took place in Denmark from 1 April 2021 to May 1, 2025. Patients with nephrotic syndrome were recruited from both outpatient clinics and during hospital admission. Healthy volunteers were recruited via the national website for research recruitment, Forskning.nu.

Screening details

Screening was done during outpatient visits and pathology conferences using recent p-albumin and ACR values (max one week old). Eligible patients were referred to investigator. Healthy volunteers were recruited via Forskning.nu.

Period 1 title

Coagulation profile

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Blood samples were collected for coagulation profiling prior to any treatment. No investigational product was administered. Some participants ended study participation after this period, while others continued to the dalteparin period.

Apixaban - Nephrotic syndrome

Arm description

This arm includes patients with nephrotic syndrome who underwent baseline blood sampling for coagulation profiling prior to any administration of apixaban. Apixaban is listed as the investigational product due to system requirements, but was not administered during this period.

Arm type

Experimental

Investigational medicinal product name

Apixaban

Investigational medicinal product code

B01AF02

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

No investigational medicinal product was administered during this period. Apixaban is included in the system due to technical requirements, but not given in this phase.

Number of subjects in period 1 ^[1]	Apixaban - Nephrotic syndrome
Started	47
Completed	47

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Healthy volunteers were included only for comparison during the apixaban intervention period, and not for baseline coagulation profiling. Therefore, the number of participants in the baseline period is lower than the total number enrolled.

Period 2 title

Apixaban intervention

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apixaban - Nephrotic syndrome

Arm description

Arm type

Experimental

Investigational medicinal product name

Apixaban

Investigational medicinal product code

B01AF02

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 mg twice daily

Apixaban - Healthy individuals

Arm description

Arm type

Active comparator

Investigational medicinal product name

Apixaban

Investigational medicinal product code

B01AF02

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 mg twice daily

Number of subjects in period 2 ^[2]	Apixaban - Nephrotic syndrome	Apixaban - Healthy individuals
Started	11	10
Completed	11	10

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: A total of 47 patients with nephrotic syndrome were included and completed the baseline period. Of these, 11 continued into the apixaban intervention period. In addition, 10 healthy individuals were included specifically for the apixaban intervention and were not part of the baseline period. Thus, 21 participants in total completed the apixaban intervention period, which explains the discrepancy in subject numbers between the periods.

Baseline characteristics

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Reporting group title

Coagulation profile

Reporting group description

Reporting group values	Coagulation profile	Total
Number of subjects	47	47
Age categorical
Age
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	32	32
From 65-84 years	13	13
85 years and over	2	2
Age continuous
Mean age ± SD at time of inclusion.
Units: years
arithmetic mean (standard deviation)	47 ( 19 )	-
Gender categorical
Sex distribution at baseline.
Units: Subjects
Female	21	21
Male	26	26
Renal diagnosis
Underlying renal diagnosis classified according to kidney biopsy or clinical evaluation at baseline.
Units: Subjects
Membranous nephropathy	15	15
Minimal change disease	17	17
Focal secmental glomerulosclerosis	4	4
Proliferative glomerulonephritis	5	5
Amyloidosis/Myeloma	4	4
Other diagnosis	2	2
Normal kidney	0	0
Comorbidities
Relevant comorbidities at baseline that may influence fluid balance or mimic nephrotic syndrome, including hypertension, heart failure, and liver failure
Units: Subjects
Hypertension	21	21
Heart failure	1	1
Liver failure	0	0
No comorbidities	25	25
eGFR
Kidney function
Units: Subjects
eGFR > 90	15	15
eGFR 60-90	20	20
eGFR 30-59	12	12
Plasma albumin
Measured at baseline prior to any study treatment. Plasma albumin is a key clinical marker of nephrotic syndrome severity.
Units: g/L
arithmetic mean (standard deviation)	22 ( 5 )	-
Urine albumin creatinine ratio
Measured at baseline prior to treatment. uACR is used to quantify proteinuria and assess disease severity in nephrotic syndrome.
Units: mg/g
median (inter-quartile range (Q1-Q3))	4857 (3611 to 6643)	-
D-dimer
D-dimer measured at baseline to assess fibrin turnover and potential prothrombotic state.
Units: mg/L
median (inter-quartile range (Q1-Q3))	0.93 (0.56 to 1.30)	-
Fibrinogen
Fibrinogen measured at baseline as a marker of coagulation activity and inflammation
Units: µmol/L
arithmetic mean (standard deviation)	16.7 ( 4.4 )	-
Median glycated hemoglobin
Glycated hemoglobin (HbA1c) measured at baseline to assess long-term glucose regulation.
Units: mmol/mol
median (inter-quartile range (Q1-Q3))	36 (33 to 38)	-
Hemoblobin
Hemoglobin measured at baseline as part of routine hematological assessment.
Units: mmol/L
arithmetic mean (standard deviation)	8.8 ( 1.1 )	-
White blood cells
Leukocyte count measured at baseline as part of routine hematological assessment.
Units: x 10^9/L
arithmetic mean (standard deviation)	8.3 ( 2.5 )	-
Antithrombin
Antithrombin activity measured at baseline to assess natural anticoagulant capacity
Units: 10^3 IU/L
arithmetic mean (standard deviation)	0.94 ( 0.20 )	-
Protein C
Protein C activity measured at baseline to evaluate natural anticoagulant function.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	1.53 ( 0.30 )	-
Protein S
Protein S activity measured at baseline to assess natural anticoagulant status.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	1.13 ( 0.22 )	-
Coagulation factor VIII
Factor VIII activity measured at baseline to assess procoagulant potential.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	2.23 ( 0.58 )	-
Coagulation factor X
Factor X activity measured at baseline as part of the coagulation profile.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	0.97 ( 0.19 )	-
Platelet count
Platelet count measured at baseline as part of routine hematological and coagulation assessment.
Units: x 10^9/L
arithmetic mean (standard deviation)	296 ( 92 )	-
TRAP
Thrombin receptor-activating peptide (TRAP)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	1231 ( 233 )	-
ADP
Adenosine diphosphate (ADP)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	893 ( 251 )	-
ASPI
Arachidonic acid (ASPI)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	1013 ( 215 )	-
Thrombomodulin
Soluble thrombomodulin measured at baseline as a marker of endothelial cell injury.
Units: ng/mL
arithmetic mean (standard deviation)	30.2 ( 12.6 )	-
Syndecan-1
Syndecan-1 measured at baseline to assess shedding of the endothelial glycocalyx.
Units: ng/mL
median (inter-quartile range (Q1-Q3))	91.9 (58.5 to 152.3)	-
sE-selectin
Soluble E-selectin measured at baseline as a marker of endothelial activation.
Units: ng/mL
arithmetic mean (standard deviation)	39.7 ( 20.9 )	-
Von Willebrand factor antigen
von Willebrand factor measured at baseline as a marker of endothelial activation and prothrombotic potential.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	3.0 ( 1.0 )	-
ETP
Endogenous thrombin potential (ETP) measured at baseline to assess thrombin-generating capacity ex vivo.
Units: nM x min
arithmetic mean (standard deviation)	1398 ( 398 )	-
F1+F2
Prothrombin fragments 1+2 (F1+F2) measured at baseline as markers of in vivo thrombin generation.
Units: pmol/L
arithmetic mean (standard deviation)	509 ( 269 )	-
TAT complex
Thrombin-antithrombin (TAT) complexes measured at baseline to assess in vivo thrombin generation and coagulation activation.
Units: µmol/l
arithmetic mean (standard deviation)	3.5 ( 1.0 )	-
50% clot lysis
Time to 50% clot lysis measured at baseline to evaluate fibrinolytic capacity.
Units: s.
arithmetic mean (standard deviation)	1281 ( 533 )	-
Thromboxane B₂
Thromboxane B₂ (TXB₂) measured at baseline as a marker of platelet activation and thromboxane synthesis.
Units: ng/L
arithmetic mean (standard deviation)	282 ( 159 )	-

Subject analysis set title

Apixaban - Neprhtotic syndrome

Subject analysis set type

Full analysis

Subject analysis set description

Plasma apixaban and its effect on the coagulation profile in patients with nephrotic syndrome

Subject analysis set title

Apixaban - Healthy individuals

Subject analysis set type

Full analysis

Subject analysis set description

Plasma apixaban and its effect on the coagulation profile in patients with nephrotic syndrome

Subject analysis sets values	Apixaban - Neprhtotic syndrome	Apixaban - Healthy individuals
Number of subjects	11	10
Age categorical
Age
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	11	10
From 65-84 years	0	0
85 years and over	0	0
Age continuous
Mean age ± SD at time of inclusion.
Units: years
arithmetic mean (standard deviation)	51 ( 19 )	36 ( 19 )
Gender categorical
Sex distribution at baseline.
Units: Subjects
Female	4	6
Male	7	4
Renal diagnosis
Underlying renal diagnosis classified according to kidney biopsy or clinical evaluation at baseline.
Units: Subjects
Membranous nephropathy	5	0
Minimal change disease	4	0
Focal secmental glomerulosclerosis	2	0
Proliferative glomerulonephritis	0	0
Amyloidosis/Myeloma	0	0
Other diagnosis	0	0
Normal kidney	0	10
Comorbidities
Relevant comorbidities at baseline that may influence fluid balance or mimic nephrotic syndrome, including hypertension, heart failure, and liver failure
Units: Subjects
Hypertension	5	0
Heart failure	1	0
Liver failure	0	0
No comorbidities	5	10
eGFR
Kidney function
Units: Subjects
eGFR > 90	4	8
eGFR 60-90	5	2
eGFR 30-59	2	0
Plasma albumin
Measured at baseline prior to any study treatment. Plasma albumin is a key clinical marker of nephrotic syndrome severity.
Units: g/L
arithmetic mean (standard deviation)	19 ( 3 )	39 ( 3 )
Urine albumin creatinine ratio
Measured at baseline prior to treatment. uACR is used to quantify proteinuria and assess disease severity in nephrotic syndrome.
Units: mg/g
median (inter-quartile range (Q1-Q3))	5029 (3919 to 8115)	6.5 (2 to 11)
D-dimer
D-dimer measured at baseline to assess fibrin turnover and potential prothrombotic state.
Units: mg/L
median (inter-quartile range (Q1-Q3))	0 (0 to 0)	0 (0 to 0)
Fibrinogen
Fibrinogen measured at baseline as a marker of coagulation activity and inflammation
Units: µmol/L
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Median glycated hemoglobin
Glycated hemoglobin (HbA1c) measured at baseline to assess long-term glucose regulation.
Units: mmol/mol
median (inter-quartile range (Q1-Q3))	0 (0 to 0)	0 (0 to 0)
Hemoblobin
Hemoglobin measured at baseline as part of routine hematological assessment.
Units: mmol/L
arithmetic mean (standard deviation)	8.8 ( 0.9 )	8.5 ( 1.1 )
White blood cells
Leukocyte count measured at baseline as part of routine hematological assessment.
Units: x 10^9/L
arithmetic mean (standard deviation)	8.0 ( 0.9 )	5.9 ( 1.0 )
Antithrombin
Antithrombin activity measured at baseline to assess natural anticoagulant capacity
Units: 10^3 IU/L
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Protein C
Protein C activity measured at baseline to evaluate natural anticoagulant function.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	1.53 ( 0.17 )	1.13 ( 0.14 )
Protein S
Protein S activity measured at baseline to assess natural anticoagulant status.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	1.12 ( 0.16 )	0.92 ( 0.16 )
Coagulation factor VIII
Factor VIII activity measured at baseline to assess procoagulant potential.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Coagulation factor X
Factor X activity measured at baseline as part of the coagulation profile.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Platelet count
Platelet count measured at baseline as part of routine hematological and coagulation assessment.
Units: x 10^9/L
arithmetic mean (standard deviation)	314 ( 101 )	276 ( 86 )
TRAP
Thrombin receptor-activating peptide (TRAP)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
ADP
Adenosine diphosphate (ADP)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
ASPI
Arachidonic acid (ASPI)-induced platelet aggregation measured at baseline to assess platelet function.
Units: AU x min
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Thrombomodulin
Soluble thrombomodulin measured at baseline as a marker of endothelial cell injury.
Units: ng/mL
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Syndecan-1
Syndecan-1 measured at baseline to assess shedding of the endothelial glycocalyx.
Units: ng/mL
median (inter-quartile range (Q1-Q3))	0 (0 to 0)	0 (0 to 0)
sE-selectin
Soluble E-selectin measured at baseline as a marker of endothelial activation.
Units: ng/mL
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )
Von Willebrand factor antigen
von Willebrand factor measured at baseline as a marker of endothelial activation and prothrombotic potential.
Units: 10^3 IU/L
arithmetic mean (standard deviation)	3.1 ( 1.2 )	1.4 ( 0.03 )
ETP
Endogenous thrombin potential (ETP) measured at baseline to assess thrombin-generating capacity ex vivo.
Units: nM x min
arithmetic mean (standard deviation)	1435 ( 453 )	1190 ( 340 )
F1+F2
Prothrombin fragments 1+2 (F1+F2) measured at baseline as markers of in vivo thrombin generation.
Units: pmol/L
arithmetic mean (standard deviation)	420 ( 179 )	193 ( 71 )
TAT complex
Thrombin-antithrombin (TAT) complexes measured at baseline to assess in vivo thrombin generation and coagulation activation.
Units: µmol/l
arithmetic mean (standard deviation)	3.3 ( 1.0 )	3.0 ( 1.9 )
50% clot lysis
Time to 50% clot lysis measured at baseline to evaluate fibrinolytic capacity.
Units: s.
arithmetic mean (standard deviation)	1180 ( 368 )	751 ( 232 )
Thromboxane B₂
Thromboxane B₂ (TXB₂) measured at baseline as a marker of platelet activation and thromboxane synthesis.
Units: ng/L
arithmetic mean (standard deviation)	0 ( 0 )	0 ( 0 )

End points

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Reporting group title

Apixaban - Nephrotic syndrome

Reporting group description

Reporting group title

Apixaban - Nephrotic syndrome

Reporting group description

Reporting group title

Apixaban - Healthy individuals

Reporting group description

Subject analysis set title

Apixaban - Neprhtotic syndrome

Subject analysis set type

Full analysis

Subject analysis set description

Plasma apixaban and its effect on the coagulation profile in patients with nephrotic syndrome

Subject analysis set title

Apixaban - Healthy individuals

Subject analysis set type

Full analysis

Subject analysis set description

Plasma apixaban and its effect on the coagulation profile in patients with nephrotic syndrome

Primary: Plasma apixaban concentration at steady state

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End point title

Plasma apixaban concentration at steady state

End point description

Plasma apixaban concentrations were measured at steady state (Day 4–7) to evaluate drug exposure in patients with nephrotic syndrome and healthy volunteers after 5 mg twice daily dosing.

End point type

Primary

End point timeframe

Day 4–7 after start of apixaban treatment (steady state).

End point values	Apixaban - Nephrotic syndrome	Apixaban - Healthy individuals
Number of subjects analysed	11	10
Units: µg/L
arithmetic mean (confidence interval 95%)	35 (28 to 43)	51 (39 to 64)

Unpaired t-test

Comparison groups

Apixaban - Healthy individuals v Apixaban - Nephrotic syndrome

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.02

Method

t-test, 2-sided

Confidence interval

Secondary: ETP at steady state

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End point title

ETP at steady state

End point description

Endogenous thrombin potential (ETP) measured at steady state (Day 4–7) to assess thrombin-generating capacity following apixaban treatment in nephrotic patients and healthy individuals.

End point type

Secondary

End point timeframe

Day 4–7 (steady state)

End point values	Apixaban - Nephrotic syndrome	Apixaban - Healthy individuals
Number of subjects analysed	11	10
Units: mmol x min
arithmetic mean (confidence interval 95%)	1096 (868 to 1324)	910 (713 to 1107)

Unpaired t-test

Comparison groups

Apixaban - Nephrotic syndrome v Apixaban - Healthy individuals

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.18

Method

t-test, 2-sided

Confidence interval

Secondary: F1+F2 at steady state

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End point title

F1+F2 at steady state

End point description

rothrombin fragments 1+2 (F1+F2) measured at steady state (Day 4–7) as markers of in vivo thrombin generation and coagulation activation in nephrotic patients and healthy individuals.

End point type

Secondary

End point timeframe

Day 4–7 (steady state)

End point values	Apixaban - Nephrotic syndrome	Apixaban - Healthy individuals
Number of subjects analysed	11	10
Units: pmol
arithmetic mean (confidence interval 95%)	223 (175 to 268)	145 (98 to 191)

Unpaired t-test

Comparison groups

Apixaban - Nephrotic syndrome v Apixaban - Healthy individuals

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.02

Method

t-test, 2-sided

Confidence interval

Secondary: TAT at steady state

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End point title

TAT at steady state

End point description

Thrombin-antithrombin (TAT) complexes measured at steady state (Day 4–7) as markers of in vivo thrombin generation and coagulation activation in nephrotic patients and healthy individuals.

End point type

Secondary

End point timeframe

Day 4–7 (steady state)

End point values	Apixaban - Nephrotic syndrome	Apixaban - Healthy individuals
Number of subjects analysed	11	10
Units: µmol/L
arithmetic mean (confidence interval 95%)	2.2 (1.5 to 29)	2.2 (1.1 to 3.0)

Unpaired t-test

Comparison groups

Apixaban - Nephrotic syndrome v Apixaban - Healthy individuals

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.95

Method

t-test, 2-sided

Confidence interval

Adverse events

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Timeframe for reporting adverse events

From treatment initiation (Day 1) to 7 days after the end of treatment (Day 7).

Adverse event reporting additional description

Adverse events were recorded from treatment initiation (Day 1) through 7 days after the end of treatment (Day 7) for both Dalteparin and Apixaban. Events were classified and graded according to standard clinical guidelines. Follow-up included assessment of any ongoing or new adverse events at Day 7 after treatment cessation.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Nephrotic patients

Reporting group description

Reporting group title

Healthy individuals

Reporting group description

Serious adverse events	Nephrotic patients	Healthy individuals
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 11 (0.00%)	0 / 10 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Nephrotic patients	Healthy individuals
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 11 (18.18%)	1 / 10 (10.00%)
Gastrointestinal disorders
Hemorrhoidal bleeding
Additional description: One patient with nephrotic syndrome reported well- known intermittent hemorrhoidal bleeding, which similarly occurred under apixaban treatment.
subjects affected / exposed	1 / 11 (9.09%)	0 / 10 (0.00%)
occurrences all number	1	0
Reproductive system and breast disorders
Heavyer menstrual bleeding
Additional description: One healthy individual reported slightly heavier menstrual bleeding while on apixaban.
subjects affected / exposed	0 / 11 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Epistaxis
Additional description: One patient with nephrotic syndrome experienced known intermittent epistaxis, which also occurred during apixaban treatment.
subjects affected / exposed	1 / 11 (9.09%)	0 / 10 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

10 Jan 2021

1) Increased participant number in sub-study 2 from 30 to 50. 2) Treatment duration for both sub-study 2 and 3 extended from 4 days to 4-7 days for Fragmin and Eliquis. 3) Participants will keep a medication diary. 4) Additional blood samples for endothelial function and hyperlipidemia analysis. 5) Optional kidney biopsy for up to 10 participants in sub-study 1 (Jan 10, 2021). 6) Optional transjugular liver biopsy for up to 10 participants in sub-study 1.

19 Mar 2021

1) Inclusion criterion for plasma albumin changed in all three sub-studies: Sub-study 1: Plasma albumin increased from <20 g/L to <30 g/L Sub-studies 2 and 3: Plasma albumin increased from <20 g/L to <25 g/L 2) Participant number in sub-study 1 increased to 60. Stubstudy 1: coagulation profile, substudy 2: dalteaprin, substudy 3: apixaban

08 Aug 2021

1) Inclusion criteria changed for all sub-studies and control groups: Age increased from 18-80 years to > 18 years eGFR increased from > 49 to > 30 ml/min/1.73m² Well-regulated diabetes with HbA1c < 65 mmol/mol Exclusion criteria updated: Diabetes excluded from all sub-studies and control groups New exclusion criterion for AFIB patients: If infection suspected, CRP must be < 30 g/L Study medication dosage updated: Apixaban can be administered as 5 mg x 2 or 2.5 mg x 2 depending on age, weight, and renal function Follow-up via journal audit within 5 years: Added follow-up via journal audit within 5 years to the protocol and participant information.

21 Dec 2021

1) Two new sites added: Department of Medicine, Regional Hospital Gødstrup, Hospitalsparken 15, DK-7400 Herning Department of Medicine, Regional Hospital Viborg, Heibergs Alle 5A, DK-8800 Viborg

29 Apr 2022

1) The control group in sub-study 3 is changed from 10 patients with atrial fibrillation (no patients enrolled yet) to 10 healthy volunteers. 2) Justification for change: This change is requested because atrial fibrillation patients were more comorbid than expected, which could have a significant impact on coagulation. Therefore, it was concluded that the comparison group would not provide sufficient data, and healthy volunteers are now sought to achieve more valid comparison results.

11 Jul 2022

1) Inclusion criteria for the disease group in the apixaban group are expanded to include not only patients with membranous nephropathy, but also patients with Minimal Change Disease and Focal Segmental Glomerulosclerosis. 2) Justification for change: The inclusion criteria are expanded to ensure inclusion of more patients, and by including multiple glomerular diseases, a broader understanding of how Eliquis works in patients with nephrotic syndrome can be achieved.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The study had a small sample size, which limits the statistical power and generalizability of the results. The study only followed patients for a short period (4-7 days), so long-term effects of treatment are unknown.

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Clinical trials

Clinical Trial Results:
Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Plasma apixaban concentration at steady state

Primary: Plasma apixaban concentration at steady state

Secondary: ETP at steady state

Secondary: ETP at steady state

Secondary: F1+F2 at steady state

Secondary: F1+F2 at steady state

Secondary: TAT at steady state

Secondary: TAT at steady state

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Plasma apixaban concentration at steady state

Primary: Plasma apixaban concentration at steady state

Secondary: ETP at steady state

Secondary: ETP at steady state

Secondary: F1+F2 at steady state

Secondary: F1+F2 at steady state

Secondary: TAT at steady state

Secondary: TAT at steady state

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome