Clinical Trials Register

Summary
EudraCT Number:	2016-002268-15
Sponsor's Protocol Code Number:	EMPA-1
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002268-15

A.3

Full title of the trial

A PHASE II, RANDOMIZED, CROSS-OVER, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE CENTER STUDY OF THE EFFECT OF EMPAGLIFLOZIN, A SGLT-2 INHIBITOR, ON ENDOGENOUS GLUCOSE PRODUCTION AND PLASMA GLUCAGON LEVELS IN PATIENTS WITH END-STAGE RENAL DISEASE (ESRD)

Studio clinico di fase 2 randomizzato, cross-over, in doppio cieco, controllato con placebo su singolo centro per valutare l¿effetto di Empagliflozin, un inibitore del SGLT-2, sulla produzione endogena di glucosio (EGP) ed i livelli plasmatici di glucagone in soggetti affetti da malattia renale cronica allo stadio terminale (ESRD)

A.3.1

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

Measurement of the effect of Empagliflozin versus Placebo in patients with end-stage renal disease(ESRD).

Valutazione dell¿effetto di Empagliflozin in confronto a placebo in soggetti affetti da malattia renale cronica allo stadio terminale (ESRD)

A.3.2

Name or abbreviated title of the trial where available

EMPA-1

A.4.1

Sponsor's protocol code number

EMPA-1

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	AZIENDA OSPEDALIERO-UNIVERSITARIA PISANA
B.1.3.4	Country	Italy
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	Italy
B.4.1	Name of organisation providing support	Dip. Univ. Medicina clinica e sperimentale Pisa
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UO MALATTIE METABOLICHE E DIABETOLOGIA
B.5.2	Functional name of contact point	UO MALATTIE METABOLICHE E DIABETOLO
B.5.3	Address:
B.5.3.1	Street Address	VIA PARADISA 2
B.5.3.2	Town/ city	PISA
B.5.3.3	Post code	56124
B.5.3.4	Country	Italy
B.5.4	Telephone number	050995103
B.5.5	Fax number	050541521
B.5.6	E-mail	stefano.delprato@med.unipi.it

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 - 25 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER (PVC/ALU) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BOEHRINGER INGELHEIM INTERNATIONAL GMBH
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	JARDIANCE
D.3.2	Product code	JARDIANCE
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMPAGLIFLOZIN
D.3.9.1	CAS number	864070-44-0
D.3.9.2	Current sponsor code	EMPAGLIFLOZIN
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	25
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Patients with end-stage renal disease (ESRD) with or without Type 2 diabetes

Pazienti affetti da malattia renale cronica allo stadio terminale con o senza diabete di tipo 2

E.1.1.1

Medical condition in easily understood language

Patients with end-stage renal disease (ESRD)

Pazienti affetti da malattia renale cronica allo stadio terminale

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

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	10014647
E.1.2	Term	End stage renal failure
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

To test the hypothesis that a single empagliflozin (25 mg) oral administration in subjects with ESRD (end-stage renal disease) will stimulate EGP (Endogenous Glucose Production) and increase plasma glucagon concentration as compared to placebo

Valutare l¿ipotesi che una singola somministrazione per os di Empagliflozin (25 mg) in pazienti con malttia renale terminale (ESRD) stimoli l¿EGP (endogenous glucose production) e aumenti la concentrazione di glucagone rispetto a placebo

E.2.2

Secondary objectives of the trial

To test the hypothesis that a single empagliflozin (25 mg) oral administration in subjects with ESRD (end-stage renal disease) will modulate plasma glucose, insulin, c-peptide, FFA, GH, epinephrine, norepinephrine, cortisol and blood pressure as compared to placebo

Valutare l¿ipotesi che una singola somministrazione per os di Empagliflozin (25 mg) in pazienti con malattia renale terminale moduli le concentrazioni plasmatiche di glucosio, insulina, c-peptide, FFA, GH, adrenalina, noradrenalina, cortisolo e la pressione arteriosa rispetto a palcebo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females
2. Age = 30-70 years
3. BMI< 40 Kg/m2 and stable weight (± 3 lbs) over the preceding three months
4. Normal Glucose Tolerance (HbA1c > 4.5 % and < 5.7%) or Type 2 diabetes (HbA1c > 5.7 % and <10.0%)
5. End Stage Renal Disease (GFR <15 ml/min/1.73 m2 or hemodialysis)
6. Subjects are capable of giving informed consent

1. Uomo o Donna
2. Eta’= 30-70 anni
3. BMI< 40 Kg/m2 e peso stabile (± 1.5 Kg) nei precedenti 3 mesi
4. Normale tolleranza glucidica (HbA1c > 4.5% e < 5.7%) o Diabete Tipo 2 (HbA1c > 5.7% e < 10%)
5. Malattia renale terminale (GFR <15 ml/min/1.73 m2 o emodialisi)
6. Soggetti in grado di dare il consenso informato

E.4

Principal exclusion criteria

1. Prednisone treatment
2. Insulin, Beta blocker or any medication that affects sympathetic/parasympathetic activity or known to affect glucose metabolism (other than metformin and sulfonylurea)
3. Known Empagliflozin Excipient Hypersensitivity
4. Liver function enzymes higher more than two times the upper limit
5. Ongoing urinary tract infection
6. history of cancer of any type;
7. cerebrovascular or symptomatic peripheral vascular disease;
8. heart disease class III or IV NYHA;
9. Type 1 Diabetes
10. drug or alcohol abuse;
11. life expectancy <3 yrs
12. blood pressure >150/100 mmHg
13. Donation of blood to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the enrollment visit and at least 8 weeks thereafter
14. Women of child bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study (estrogen and/or progesterone treatment)
15. Patient with a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose an unacceptable risk to the patient or interfere with trial procedures

1. Trattamento con Prednisone
2. Trattamento con insulina, beta-bloccanti o altri farmaci che interferiscono con l’attività simpatica/parasimpatica o sul metabolismo del glucosio (ad eccezione di metformina e sulfanilurea)
3. Ipersensibilità nota agli eccipienti di empagliflozin
4. Transaminasi maggiori di due volte il limite superiore di normalità
5. Infezioni delle vie urinarie in corso
6. Anamnesi di Neoplasia (qualsiasi tipo)
7. Anamnesi di evento Cardiovascolare oppure di malattia vascolare periferica
8. Scompenso Cardiaco ( stadio III oppure IV secondo NYHA)
9. Diabete tipo 1
10. Abuso di sostanze tossiche oppure di alcool
11. Aspettativa di vita < 3 anni
12. Pressione arteriosa > 150/100 mmHg
13. Recente (8 settimane) donazione di sangue o partecipazione a uno studio clinico con prelievo di sangue maggiore di 400 ml, oppure intenzione di essere donatore entro 8 settimane dalla conclusione dello studio
14. Donne potenzialmente fertili o che negano l’utilizzo di contraccezione durante il periodo dello studio per evitare una gravidanza (terapia con estrogeno e/o progesterone).
15. Paziente con storia, evidenza clinica, terapia, anomalia di laboratorio o ogni altra circostanza che a giudizio dell’investigatore pone il paziente a un rischio inaccettabile a causa delle procedure previste dallo studio

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the mean difference in EGP and plasma glucagon concentration during the last hour of EGP measurement between empagliflozin versus placebo administration in patients with end-stage renal disease

L’endpoint primario e’ la differenza media di EGP (endogenous glucose production) e la concentrazione plasmatica di glucagone durante l’ultima ora di misurazione dell’EGP tra empagliflozin e placebo in pazienti con malattia renale terminale

E.5.1.1

Timepoint(s) of evaluation of this end point

This timepoint will be achieved in a three-year study

3 anni

E.5.2

Secondary end point(s)

The secondary endpoints are the mean difference in plasma glucose, insulin, c-peptide, FFA, GH, epinephrine, norepinephrine, cortisol and blood pressure during the last hour of the experiment between empagliflozin versus placebo administration in patients with end-stage renal disease

L¿endopoint secondario e¿ la differenza media dell¿ultima ora della concentrazione di glucosio, insulina, c-peptide, FFA, adrenalina, noradrenalina, cortisolo, GH e la pressione arteriosa tra empagliflozin e placebo in pazienti con malattia renale terminale.

E.5.2.1

Timepoint(s) of evaluation of this end point

This timepoint will be achieved in a three-year study

3 anni

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

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Mechanism of kidney - liver relation to the control of the hepatic production of glucose

Meccanismo della relazione rene-fegato per il controllo della produzione epatica di glucosio

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)

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

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.8.4.1

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

Information not present in EudraCT

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

The plans for treatment or care after the subject has ended his/her participation will be not affected by this study and they will continue the standard care.

I programmi per il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio non saranno influenzati dallo studio ed essi continueranno lo standard previsto dal centro

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

2016-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-07

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

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