Clinical Trials Register

Summary
EudraCT Number:	2015-005727-80
Sponsor's Protocol Code Number:	EMPA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-01-21
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

2015-005727-80

A.3

Full title of the trial

Effect of insulin on renal maximum glucose transport capacity: interaction with empagliflozin. A not randomized pilot study.

Effetto dell'insulina sulla massima capacità di riassorbimento del glucosio del tubulo renale: interazione con empagliflozin.
Studio pilota non randomizzato.

A.3.1

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

Effect of insulin on renal maximum glucose transport capacity: interaction with empagliflozin.

Effetto dell'insulina sulla massima capacità di riassorbimento del glucosio del tubulo renale: interazione con il farmaco empagliflozin.

A.3.2

Name or abbreviated title of the trial where available

EMPA

A.4.1

Sponsor's protocol code number

EMPA

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	FONDAZIONE TOSCANA GABRIELE MONASTERIO
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	Fondazione Toscana Gabriele Monasterio
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Boehringer Ingelheim Italia Spa
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	Fondazione Toscana Gabriele Monasterio
B.5.2	Functional name of contact point	UO Farmaceutica Ospedaliera
B.5.3	Address:
B.5.3.1	Street Address	via aurelia sud
B.5.3.2	Town/ city	massa
B.5.3.3	Post code	545100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0585493507
B.5.5	Fax number	0585493508
B.5.6	E-mail	farmacisti@ftgm.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.3.2	Product code	[JARDIANCE 25 mg 28 compresse]
D.3.4	Pharmaceutical form
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	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.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	HUMULIN - R 1 FLAC. 10 ML 100 U/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY ITALIA S.P.A.
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.3.2	Product code	[Humulin R]
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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.IMP: 3
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	SOMATOSTATINA HIKMA - 3 MG/2 ML POLVERE E SOLVENTE PER SOLUZIONE PER INFUSIONE ENDOVENOSA 3 FLACONCINI POLVERE + 3 FIALE SOLVENTE 2 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	HIKMA ITALIA S.P.A.
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.3.2	Product code	[Somatostatina 3mg/2ml]
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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.IMP: 4
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	GLUCAGEN - 1 FLAC. LIOF 1 MG + FIALA 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVO NORDISK A/S
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.3.2	Product code	[GLUCAGEN]
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Patients with diabetes mellitus type 2

Pazienti con diabete mellito di tipo 2

E.1.1.1

Medical condition in easily understood language

Patients with diabetes mellitus type 2

Pazienti con diabete mellito di tipo 2

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

1. to measure glycosuria in type 2 diabetic patients during hyperglycaemia
2. to investigate the effect of physiological hyperinsulinaemia on renal glucose excretion in patients with type 2 diabetes.
3. to test the effect of empagliflozin on renal glucose excretion in diabetic patients and to test whether any renal effect of insulin is synergic with SGLT-2 inhibition by empagliflozin.

1. Misurare la glicosuria nei pazienti nei soggetti con diabete di tipo 2 in condizioni di iperglicemia controllata
2. Determinare l¿effetto dell¿insulina sulla glicosuria in soggetti diabetici.
3. Misurare l¿effetto di empagliflozin sulla glicosuria nei soggetti diabetici e testare se l¿insulina ha effetto sinergico con l¿inibizione di SGLT-2 mediata da empagliflozin in soggetti diabetici.

E.2.2

Secondary objectives of the trial

1. to investigate whether any difference in creatinine clearance, as well as in measured glomerular filtration rate is present among the three studies conditions (hyperglycemia [CT period] vs hyperglycemia/hyperinsulinemia [INS1 period] vs
hyperglycemia/hyperinsulinemia/SGLT2 inhibition [EMPA period]) in diabetic patients.

1. Valutare se vi sia una differenza nella clearance della creatinina, misurata come velocit¿ di filtrazione glomerulare nelle tre condizioni di studio [iperglicemia (CT), iperinsulinemia/iperinsulinemia (INS1) e iperglicemia /iperinsulinemia/inibizione SGLT2 (EMPA)] in pazienti diabetici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria: - Type 2 diabetic patients, age = 18 and = 64 years, male and female, BMI 20-40 kg/m2, HbA1c 6.5-10.5%, on diet and exercise regimen, or on therapy with stable dose of metformin, sulphonylurea (ATC A10BB), DPP4-inhibitors (ATC A10BH) and GLP-1 agonists (i.e. liraglutide, albiglutide, exenantide) or their combinations, signed informed consent.

Criteri di inclusione (prinicipali):– pazienti con diabete mellito di tipo 2, età = 18 e = 64 anni; entrambi i sessi; indice di massa corporea tra 20 e 40 Kg.m2, con valori di HbA1c tra 6.5 e 10.5%, in terapia con regime dietetico, o con metformina e/o sulfanilurea (ATC A10BB), inibitori di DPP4 (ATC A10BH), agosti GLP-1(i.e.liraglutide, albiglutide, exenantide) o loro associazioni, firma del consenso informato.

E.4

Principal exclusion criteria

Exclusion criteria: - Patients on insulin or on thiazolidinediones (i.e. pioglitazone) and SGLT2 inhibitors (i.e. canagliflozin, dapagliflozin, empagliflozin), subjects with hepatic and renal disease, pregnancy and childbearing potential, alcohol or drug abuse, concomitant use of drugs that may increase or decrease the activity of the metabolizing enzymes of the cytochrome P450, hypersensitivity to the active substances of the study drugs or to any of their excipients or known pre-existing contraindication tothe administration of the experimental study drugs.

Criteri di esclusione (prinicipali):– pazienti in trattamento con insulina, tiazolidindioni (i.e. pioglitazone) o inibitori del SGLT2 (i.e. canagliflozin, dapagliflozin, empagliflozin), insufficienza epatica o renale, soggetti di sesso femminile in età fertile che non facciano uso di contraccettivi, gravidanza potenziale o in atto, abuso di droghe o alcool, uso concomitante di terapie che interferiscono con il sistema di metabolismo del CYP450 epatico, ipersensibilità ai principi attivi o agli eccipienti dei farmaci in studio o qualsiasi controindicazione nota pre-esistente alla somministrazione dei farmaci in studio

E.5 End points

E.5.1

Primary end point(s)

1. glucose excretion in 180 minutes during CT period from urinary glucose sample in diabetic patients during hyperglycemia;
2. glucose excretion in 180 minutes during INS1 period (from urinary sample) in diabetic patients;
3. glucose excretion in 180 minutes during EMPA period and glucose excretion in 180 minutes during INS1 period from urinary sample in diabetic patients.

1. Glicosuria in 180 minuti durante il periodo CT in soggetti diabetici in condizioni di iperglicemia controllata
2. Glicosuria in 180 minuti durante il periodo INS1 da campioni di urina di soggetti diabetici
3. Glicosuria in 180 minuti durante il periodo EMPA ed escrezione urinaria di glucosio durante il periodo INS1 da campioni di urina in soggetti diabetici.

E.5.1.1

Timepoint(s) of evaluation of this end point

180 minutes for each study period

180 minuti per ciascun periodo di studio

E.5.2

Secondary end point(s)

Difference in glomerular filtration rate measured as creatinine clearance in the three studies periods CT, EMPA and INS1 (a difference < 5-10% is expected).

Differenza nella velocit¿ di filtrazione glomerulare misurata come clearance della creatinina durante i tre periodi CT, EMPA ed INS 1 (differenza attesa <5-10%).

E.5.2.1

Timepoint(s) of evaluation of this end point

180 minutes for each study period; 180 minuti per ciascun periodo di studio

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

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

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

E.6.13

Others

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

E.8.1.1

Randomised

E.8.1.2

Open

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

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)

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 study does not have any plans for treament after its concluison.

Non sono previsti programmi di trattamento una volta conclusa la sperimentazione.

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

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-05-07

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