Clinical Trials Register

Summary
EudraCT Number:	2017-004326-15
Sponsor's Protocol Code Number:	PE-05
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:	2021-06-08
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

2017-004326-15

A.3

Full title of the trial

EXenatide onCe weekly or sitAgliptin as add on to basaL Insulin: effects on novel markers of endothelial fnction/dysfunction and on metaBolic control in T2DM sUbjects tRial: the EXCALIBUR Trial

Exenatide una volta a settimana o sitagliptin in aggiunta ad insulina basale: effetti su nuovi marker di funzione/disfunzione endoteliale e sul controllo metabolico in pazienti con Diabete Mellito di tipo 2: EXCALIBUR Trial

A.3.1

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

Evaluation of modified-release Exenatide or Sitagliptin in addition to baseline insulin in the modification of new cardiovascular risk markers in subjects with type 2 diabetes mellitus

Valutazione di Exenatide a rilascio modificato o Sitagliptin in aggiunta all'insulina basale nella modificazione di nuovi marcatori di rischio cardiovascolare in soggetti con Diabete mellito di tipo 2

A.3.2

Name or abbreviated title of the trial where available

EXCALIBUR trial

Studio EXCALIBUR

A.4.1

Sponsor's protocol code number

PE-05

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	UNIVERSITÀ DEGLI STUDI "G. D'ANNUNZIO" CHIETI-PESCARA
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	Astrazeneca
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	UOC territoriale di Endocrinologia e Malattie del Metabolismo
B.5.2	Functional name of contact point	Dott. Fabrizio Febo
B.5.3	Address:
B.5.3.1	Street Address	via Renato Paolinini, 51
B.5.3.2	Town/ city	Pescara
B.5.3.3	Post code	65125
B.5.3.4	Country	Italy
B.5.4	Telephone number	3930073586
B.5.5	Fax number	0871541374
B.5.6	E-mail	fabrizio.febo@gmail.com

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	Bydureon
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Bydureon
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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	Comparator
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	Januvia
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp Dohme ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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	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

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

Diabete mellito di tipo 2

E.1.1.1

Medical condition in easily understood language

Diabetes

Diabete

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	LLT
E.1.2	Classification code	10063624
E.1.2	Term	Type II diabetes mellitus inadequate control
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Change in EMVs levels as markers of endothelial dysfunction at week 38 compared to baseline

modifiche di livelli di EMV come marker disfunzione endoteliale alla settimana 38 rispetto ai valori basali.

E.2.2

Secondary objectives of the trial

-Change in HbA1c at week 38 compared to baseline
-Change in FPG, PPG at week 38 compared to baseline
-Change in BMI at week 38 compared to baseline
-Change in EPCs levels as markers of endothelial function at week 38 compared to baseline.
-Change in frequency of hypoglycemic episodes and AE during the study, between the two group of treatment
-Change in glucose variability indexes (SD, MAGE, CONGA) from baseline to Week 38 assessed by CGM in a subgroup of patients both in the exenatide and sitagliptin arm.
-Change in and body composition, Visceral/subcutaneous fat from baseline to Week 38 assessed by MRI in a subgroup of patients both in the exenatide and sitagliptin arm

- modifiche di EPC, HbA1c, BMI, medie delle glicemie a digiuno e post-prandiali, alla settimana 38 rispetto ai valori basali.
- differenze di incidenza di ipoglicemia severe e di altri eventi avversi tra i gruppi di trattamento durante l¿intero periodo di osservazione
- modifiche degli indici di variabilit¿ glicemica misurati mediante CGM (deviazione standard, indici MAGE, CONGA, ecc), della composizione corporea stimata mediante esame bioimpedenziometrico e modifiche di distribuzione del VAT/SAT mediante RMN dell¿addome alla settimana 38 rispetto ai valori basali, nei differenti gruppi di trattamento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study subjects should fulfill the following criteria:
1. Provision of informed consent prior to any study specific procedures
2. White/Caucasian Female or male aged between 40 and 70 years
3. T2DM diagnosed since at least 2 years;
4. Baseline HbA1c between 7.5 and 9% (as incretin based therapy reimbursement drug starting range in Italy);
5. Diabetes and Cardiovascular risk factors treatment unchanged during the last 3 months;
6. Not treated with DPP-IV inhibitors or GLP-Rxs during the last 6 months;
7. Not treated with SGLT-2 inhibitors during the last 6 months;
8. On a stable dose of metformin (at least 1000mg/qd) since at least 3 months
9. On stable Basal insulin therapy (glargine) + 10% since at least 3 months;

Soggetti:
1. Cha abbiano firmato il consenso informato
2. di origine caucasica con età compresa tra 40 e 70 anni
3. con diagnosi di Diabete Mellito di Tipo 2 effettuata secondo i criteri degli Standard Italiani per la cura del Diabete Mellito 2009-2010 effettuata da almeno 2 anni
4. con Emoglobina Glicata =7.5 % e = 9.0%
5. in trattamento con farmaci per il diabete e per il sistema cardiovascolare stabili negli ultimi tre mesi
6. Non in trattamento con agonisti del GLP-1 o DPP-IV inibitori negli ultimi sei mesi
7. Non in trattamento con SGLT-2 inibitori negli ultimi sei mesi
8. Trattamento con Metformina al dosaggio di almeno 1000mg stabile da almeno dodici settimane
9. Insulina basale (glargine) a dosaggio stabile (±10%) da almeno 12 settimane

E.4

Principal exclusion criteria

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1. Baseline HbA1c between <7.5 or > 9.0%;
2. T1DM or T2DM diagnosed less than 2 years;
3. Not White/Caucasian aged below 40 and over 70 years
4. Diabetes and Cardiovascular risk factors treatment changed during the last 3 months;
5. Treated with DPP-IV inhibitors or GLP-Rxs during the last 6 months;
6. Treated with SGLT-2 inhibitors during the last 6 months;
7. On different therapy than Basal insulin therapy (glargine) + OAD since at least 3 months;
8. Previous Cardiovascular Events;
9. Known disease of the immune system.
10. Known or suspected hypersensitivity to the trial product or related products.
11. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice.
12. Participation in another clinical trial of an investigational medicinal product. Participation in a clinical trial which evaluate stent(s) is allowed.
13. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or compliance with the protocol.
14. History of pancreatitis (acute or chronic).
15. Planned coronary, carotid or peripheral artery revascularization known on the day of screening.
16. Chronic or intermittent hemodialysis or peritoneal dialysis or moderate renal impairment (corresponding to eGFR <50 mL/min/1.73 m2).
17. History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ).
18. History of diabetic ketoacidosis.

Soggetti con:
1. Emoglobina glicata <7,5 o> 9,0%;
2. Diabete tipo 1 o diabete tipo 2 diagnosticato da meno di 2 anni;
3. Non bianco / caucasico di età inferiore a 40 e oltre 70 anni
4. Trattamento farmacologico cardiovascolare e del diabete modificato negli ultimi 3 mesi;
5. Trattato con inibitori DPP-IV o agonista GLP-1 negli ultimi 6 mesi;
6. Trattati con inibitori SGLT-2 negli ultimi 6 mesi;
7. In terapia diversa dalla terapia insulinica basale (glargine) da almeno 3 mesi;
8. Eventi cardiovascolari precedenti;
9. Malattia nota del sistema immunitario.
10. Ipersensibilità nota o sospetta al prodotto di studio o ai prodotti correlati. Donne incinta, che allatta al seno o che intendono intraprendere una gravidanza o potenzialmente fertili e
che non utilizzino metodi contraccettivi adeguati (misure contraccettive adeguate come richiesto dalla normativa o dalla pratica locale).
11. Partecipazione a un'altra sperimentazione clinica di un medicinale sperimentale..
12. Qualsiasi disturbo, che secondo l'opinione dello sperimentatore potrebbe compromettere la sicurezza del soggetto o la conformità al protocollo.
13. Storia di pancreatite (acuta o cronica).
14. Rivascolarizzazione coronarica pianificata, carotidea o periferica.
15. Emodialisi cronica o intermittente o dialisi peritoneale o insufficienza renale moderata (corrispondente a eGFR <60 ml / min / 1,73 m2).
16. Storia o presenza di neoplasie maligne negli ultimi 5 anni (eccetto carcinoma cutaneo basale e squamoso e carcinoma in situ).
17. Storia di chetoacidosi diabetica.

E.5 End points

E.5.1

Primary end point(s)

Change in EMVs levels as markers of endothelial dysfunction at week 38 compared to baseline

modifiche di livelli di EMV come marker disfunzione endoteliale alla settimana 38 rispetto ai valori basali.

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline and 38 weeks

tempo 0 e a 38 settimane

E.5.2

Secondary end point(s)

Change in HbA1c from baseline to Week 38, in FPG, PPG from baseline to Week 38, in BMI and body composition from baseline to Week 38. ; Safety objective: Change in frequency of hypoglycemic episodes and AE from baseline to Week 38 ; Exploratory objectives: Change in glucose variability indexes (SD, MAGE, CONGA) from baseline to Week 38 assessed by CGM in a subgroup of patients both in the exenatide and sitagliptin arm and change in Visceral/subcutaneous fat from baseline to Week 38 assessed by MRI in a subgroup of patients both in the exenatide and sitagliptin arm; Change in EPCs levels as markers of endothelial function at week 38 compared to baseline

Modifiche di HbA1c, medie delle glicemie a digiuno e pos-prandiali, indici di variabilit¿ glicemica misurati mediante CGM (deviazione standard, indici MAGE, CONGA, ecc) dal baseline alla settimana 38, modifiche del BMI e della composizione corporea dal baseline alla settimana 38. ; End-point di Safety: differenze di incidenza di ipoglicemia severe e di altri eventi avversi tra i gruppi di trattamento. ; Variabili esplorative: modifiche della composizione corporea stimata mediante esame bioimpedenziometrico e modifiche di distribuzione del VAT/SAT mediante RMN dell¿addome dal baseline alla settimana 38 nei differenti gruppi di trattamento; modifiche di EPC come markers di funzione endoteliale alla settimana 38 rispetto ai valori basali.

E.5.2.1

Timepoint(s) of evaluation of this end point

38 weeks; 38 weeks; 38 weeks; baseline and 38 weeks

38 settimane; 38 settimane; 38 settimane; tempo 0 e a 38 settimane

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

Yes

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

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.8.5.1

Number of sites anticipated in the EEA

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)

Patients will be treated according to local best clinical practice

I pazienti verranno seguiti secondo le linee guida locali

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

2018-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-19

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

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