Clinical Trials Register

Summary
EudraCT Number:	2019-001212-29
Sponsor's Protocol Code Number:	Prot-0824-2019
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-06-09
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2019-001212-29

A.3

Full title of the trial

Causes and Prevention of Thromboembolic Disease in Nephrotic Syndrome

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Causes and prevention of thrombosis developed due to the kidney disease nephrotic syndrome

A.4.1

Sponsor's protocol code number

Prot-0824-2019

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Aarhus University Hospital, Henrik Birn
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Nyreforeningen
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Dansk Nefrologisk Selskab
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Nyresygdomme, Aarhus University Hospital
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Helen og Ejnar Bjørnows Fond
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Augustinus Fonden
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Region Midtjyllands Sundhedsvidenskabelige Forskningsfond
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Aarhus Universitets Hospital
B.5.2	Functional name of contact point	Sarah Kelddal
B.5.3	Address:
B.5.3.1	Street Address	Palle Juul-Jensens BLVD. 99
B.5.3.2	Town/ city	8210
B.5.3.3	Post code	Aarhus N
B.5.3.4	Country	Denmark
B.5.6	E-mail	sarah.kelddal@midt.rm.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Fragmin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer ApS
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Dalteparin
D.3.9.3	Other descriptive name	Dalteparin
D.3.9.4	EV Substance Code	SUB33617
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	18000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Eliquis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Apixaban
D.3.9.3	Other descriptive name	Apixaban
D.3.9.4	EV Substance Code	SUB25425
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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.

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.

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

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

E.1.3

Condition being studied is a rare disease

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.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

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

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.

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.

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.

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetic trial

Farmakokinetisk studie

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Blood and urine samples are compared to healthy controls

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

The project is expected to extend over 36 months.
Inclusion of patients comences 01.09.2020 with expected completion 01.09.2023.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-26

P. End of Trial
P.	End of Trial Status	Ongoing

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