Clinical Trials Register

Summary
EudraCT Number:	2020-000165-16
Sponsor's Protocol Code Number:	DC2019REGROUP01
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-03-24
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

Netherlands - Competent Authority

A.2

EudraCT number

2020-000165-16

A.3

Full title of the trial

A single-center, prospective, placebo-controlled, double-blind, randomized, cross-over mechanistic intervention study to investigate the effect of empagliflozin on kidney function in people with either preserved or impaired kidney function with or without type 2 diabetes

Een single-center, prospectieve, placebo-gecontroleerde, dubbelblinde, gerandomiseerde, cross-over mechanistische interventiestudie om het effect van empagliflozine op de nierfunctie te onderzoeken bij mensen met een behouden of verminderde nierfunctie met of zonder type 2 diabetes

A.3.1

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

Renohemodynamic Effects empaGliflozin in vaRiOUs Populations

Renohemodynamische effecten van empaGliflozine in verschillende populaties

A.3.2

Name or abbreviated title of the trial where available

REGROUP

A.4.1

Sponsor's protocol code number

DC2019REGROUP01

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	Amsterdam University Medical Center - location VU Medical Center
B.1.3.4	Country	Netherlands
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	Boehringer Ingelheim
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam University Medical Center - location VU Medical Center
B.5.2	Functional name of contact point	Daniel van Raalte
B.5.3	Address:
B.5.3.1	Street Address	Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.6	E-mail	d.vanraalte@vumc.nl

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	jardiance
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.1	Product name	Empagliflozine
D.3.2	Product code	A10BK03
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diabetes Mellitus type 2

Diabetes type 2

E.1.1.1

Medical condition in easily understood language

Diabetes type 2

Suikerziekte

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Investigate the effects of 7 days of therapy with the SGLT2 inhibitor empagliflozin (10 mg QD) versus placebo on measured glomerular filtration rate (mGFR)) in metformin and/or sulfonyl (SU) treated T2DM patients with normal kidney function, metformin, SU and/or insulin-treated T2DM patients with impaired kidney function and hypertensive people without T2DM with impaired kidney function, all treated with RAS blockers.

Onderzoek de effecten van 7 dagen therapie met de SGLT2-remmer empagliflozine (10 mg QD) versus placebo op gemeten glomerulaire filtratiesnelheid (mGFR)) in metformine en / of sulfonyl (SU) behandelde T2DM-patiënten met normale nierfunctie, metformine, SU en / of met insuline behandelde T2DM-patiënten met nierfunctiestoornis en hypertensieve mensen zonder T2DM met nierfunctiestoornis, alle behandeld met RAS-blokkers.

E.2.2

Secondary objectives of the trial

To assess the effects of 7 days treatment with SGLT2 inhibitor empagliflozin (10 mg QD) versus placebo in metformin and/or SU-treated T2DM patients with normal kidney function, metformin, SU and/or insulin-treated T2DM patients with impaired kidney function and hypertensive people without T2DM with impaired kidney function on:
1) Renal hemodynamics including effective renal plasma flow (ERPF) and renal vascular resistance (RVR)
2) Systemic hemodynamics (mean arterial pressure (MAP) & heart rate)
3) Caffeine-induced changes in renal hemodynamics including GFR, ERPF and RVR
4) Empagliflozin-induced proximal sodium excretion by using fractional excretion of lithium as a surrogate of proximal sodium handling.

Om de effecten van 7 dagen behandeling met SGLT2-remmer empagliflozine (10 mg QD) versus placebo te beoordelen bij metformine en / of SU-behandelde T2DM-patiënten met normale nierfunctie, metformine, SU en / of insuline-behandelde T2DM-patiënten met verminderde nierfunctie en hypertensieve mensen zonder T2DM met verminderde nierfunctie op:
1) Renale hemodynamiek inclusief effectieve renale plasmastroom (ERPF) en niervasculaire weerstand (RVR)
2) Systemische hemodynamica (gemiddelde arteriële druk (MAP) & hartslag)
3) Door cafeïne veroorzaakte veranderingen in de hemodynamiek van de nier, waaronder GFR, ERPF en RVR
4) Empagliflozine-geïnduceerde proximale natriumuitscheiding door fractionele uitscheiding van lithium te gebruiken als surrogaat van proximale natriumbehandeling.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Caucasian*
• Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
• Age: 45 - 80 years
• BMI: >25 kg/m2
• For with people with diabetes - a diagnosis of T2DM with glycosylated haemoglobin (HbA1c) ≥6.5% (≥48 mmol/mol) and <10.5% (<91 mmol/mol); and eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 or >75 mL/min/1.73m2 at the Screening Visit (Visit 1).
• In the normoglycemic, hypertensive, individuals: HbA1c <6.5% (<48 mmol/mol) and an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit (Visit 1).
• In the diabetic arm: people with an eGFR >75 ml/min/1.73m2 should be treated with a stable dose of metformin and/or SU, people with an eGFR between ≥25 and ≤50 mL/min/1.73m2 should be treated with a stable dose of metformin, SU and/or insulin therapy for at least 3 months prior to inclusion
• Patient specific antihypertensive dose of an angiotensin receptor blocker (ARB) (as per Investigator’s judgement) for at least 4 weeks prior to Visit 2 (Day 3).
• Written informed consent

- Kaukasische *
• Beide geslachten (vrouwen moeten postmenopauzaal zijn; geen menstruatie> 1 jaar; in geval van twijfel zal het follikelstimulerend hormoon (FSH) worden bepaald met een cut-off gedefinieerd als> 31 U / L)
• Leeftijd: 45 - 80 jaar
• BMI:> 25 kg / m2
• Voor mensen met diabetes - een diagnose van T2DM met geglycosyleerd hemoglobine (HbA1c) ≥6,5% (≥48 mmol / mol) en <10,5% (<91 mmol / mol); en eGFR (CKD-EPI) tussen ≥25 en ≤50 ml / min / 1,73 m2 of> 75 ml / min / 1,73 m2 bij het screeningsbezoek (bezoek 1).
• Bij de normoglycemische, hypertensieve personen: HbA1c <6,5% (<48 mmol / mol) en een eGFR (CKD-EPI) tussen ≥25 en ≤50 ml / min / 1,73 m2 bij het screeningsbezoek (bezoek 1).
• In de diabetische arm: mensen met een eGFR> 75 ml / min / 1,73 m2 moeten worden behandeld met een stabiele dosis metformine en / of SU, mensen met een eGFR tussen ≥25 en ≤50 ml / min / 1,73 m2 moeten behandeld met een stabiele dosis metformine, SU en / of insulinetherapie gedurende ten minste 3 maanden voorafgaand aan opname
• Patiënt specifieke anti-hypertensieve dosis van een angiotensinereceptorblokker (volgens het oordeel van de onderzoeker) gedurende ten minste 4 weken voorafgaand aan bezoek 2 (dag 3).
• Schriftelijke geïnformeerde toestemming

E.4

Principal exclusion criteria

History of unstable or rapidly progressing renal disease
• Diagnosis of polycystic kidney disease.
• Post renal transplant
• History of or current lupus nephritis.
• Abnormal vital signs, after 10 minutes supine rest, definas as any of the following (Visit 1):
o Systolic blood pressure above 180 mmHg
o Diastolic blood pressure above 110 mmHg
• Current/chronic use of the following medication: SGLT2 inhibitors,TZD, GLP-1RA, DPP-4 inhibitors, , antimicrobial agents or chemotherapeutics.
• Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
• Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drug can be taken within a time-frame of 2 weeks prior to renal-testing
• History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
• Current urinary tract infection and active nephritis
• Recent (<3 months) history of cardiovascular disease, including:
o Acute coronary syndrome
o Chronic heart failure (New York Heart Association grade II-IV)
o Stroke or transient ischemic neurologic disorder
• Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
• Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
• History of or actual malignancy (except basal cell carcinoma)
• History of or actual severe mental disease
• Substance abuse (alcohol: defined as >4 units/day)
• Allergy to any of the agents used in the study

Geschiedenis van instabiele of snel voortschrijdende nierziekte
• Diagnose van polycystische nierziekte.
• Post-niertransplantatie
• Geschiedenis van of huidige lupus nefritis.
• Abnormale vitale functies, na 10 minuten rugligging, gedefinieerd als een van de volgende (bezoek 1):
o Systolische bloeddruk boven 180 mmHg
o Diastolische bloeddruk boven 110 mmHg
• Huidig / chronisch gebruik van de volgende medicatie: SGLT2-remmers, TZD, GLP-1RA, DPP-4-remmers, antimicrobiële middelen of chemotherapeutica.
• Patiënten zonder volume. Patiënten met een risico op volumedepletie als gevolg van gelijktijdig bestaande aandoeningen of gelijktijdig toegediende medicijnen, zoals lisdiuretica, moeten zorgvuldige monitoring van hun volumestatus hebben.
• Chronisch gebruik van niet-steroïde ontstekingsremmende geneesmiddelen (NSAID's) is niet toegestaan, tenzij gebruikt als incidentele medicatie (1-2 tabletten) voor niet-chronische indicaties (d.w.z. sportletsel, hoofdpijn of rugpijn). Een dergelijk medicijn kan echter niet binnen een tijdsbestek van 2 weken voorafgaand aan niertesten worden ingenomen
• Geschiedenis van diabetische ketoacidose (DKA) die medische interventie (bijv. Spoedbezoek en / of ziekenhuisopname) vereist binnen 1 maand voorafgaand aan het screeningsbezoek.
• Huidige urineweginfectie en actieve nefritis
• Recente (<3 maanden) geschiedenis van hart- en vaatziekten, waaronder:
o acuut coronair syndroom
o Chronisch hartfalen (New York Heart Association graad II-IV)
o Beroerte of voorbijgaande ischemische neurologische aandoening
• Klachten die compatibel zijn met neurogene blaas en / of onvolledige lediging van de blaas (zoals bepaald door ultrasone blaasscan)
• Ernstige leverinsufficiëntie en / of significante abnormale leverfunctie gedefinieerd als aspartaat aminotransferase (AST)> 3x bovenlimiet van normaal (ULN) en / of alanine aminotransferase (ALT)> 3x ULN
• Geschiedenis van of werkelijke maligniteit (behalve basaalcelcarcinoom)
• Geschiedenis van of werkelijke ernstige psychische aandoeningen
• Misbruik van middelen (alcohol: gedefinieerd als> 4 eenheden / dag)
• Allergie voor een van de in het onderzoek gebruikte middelen

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

after 7 days

na 7 dagen

E.5.2

Secondary end point(s)

To investigate the effects of 7 days of therapy with SGLT-2 inhibitor empagliflozin (10 mg QD) versus placebo on:
• Other renal hemodynamics:
o Effective Renal Plasma Flow (ERPF)
o Renal Vascular Resistance (RVR)
• Systemic hemodynamics, measured as:
o Mean Arterial Pressure (MAP)
• Caffeine-induced changes in renal and systemic hemodynamics: GFR, ERPF, RVR and MAP
• Empagliflozin-induced proximal sodium excretion.
o Fractional excretion of lithium will be used as a surrogate to measure proximal tubular sodium handling, wheres fractional excretion of sodium assesses total overall (proximal and distal (tubular sodium handling).

Om de effecten van 7 dagen therapie met SGLT-2-remmer empagliflozine (10 mg QD) versus placebo te onderzoeken op:
• Andere renale hemodynamiek:
o Effectieve nierplasmastroom (ERPF)
o Niervasculaire weerstand (RVR)
• Systemische hemodynamiek, gemeten als:
o gemiddelde arteriële druk (MAP)
• Door cafeïne veroorzaakte veranderingen in nier- en systemische hemodynamica: GFR, ERPF, RVR en MAP
• Empagliflozine-geïnduceerde proximale natriumuitscheiding.
o Fractionele excretie van lithium zal worden gebruikt als een surrogaat om de proximale tubulaire natriumbehandeling te meten, waarbij fractionele excretie van natrium de totale totale (proximale en distale (tubulaire natriumbehandeling) bepaalt

E.5.2.1

Timepoint(s) of evaluation of this end point

7 days

7 dagen

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

mechanistic

mechanistisch

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

LVLS

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

Information not present in EudraCT

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

geen

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

2020-03-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-16

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

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