Clinical Trials Register

Summary
EudraCT Number:	2015-004723-31
Sponsor's Protocol Code Number:	ESR-14-10145
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

2015-004723-31

A.3

Full title of the trial

Proof of concept study, a randomized, controlled, open and prospective period of one year to evaluate the effectiveness of treatment with saxagliptin / dapagliflozin + metformin vs insulin glargine + metformin in patients with Autoimmune Diabetes of the Adult (LADA)

Proof of concept study, randomizzato, controllato, aperto e prospettico della durata di un anno per valutare l¿efficacia di un trattamento con Saxagliptin / Dapagliflozin + Metformina vs insulina glargine + metformina in soggetti affetti da Diabete Autoimmune dell¿Adulto (LADA)

A.3.1

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

Study to assess the efficacy of treatment of autoimmune diabetes of adults (LADA) with metformin / dapagliflozin / saxagliptin against metformin / insulin glargine (LADA)

Studio per valutare l'efficacia della terapia del diabete autoimmune dell'adulto (LADA) con metformina/dapagliflozin/saxagliptin contro metformina/insulina glargine

A.3.2

Name or abbreviated title of the trial where available

Proof of concept study on LADA

proof of concept study su LADA

A.4.1

Sponsor's protocol code number

ESR-14-10145

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 CAMPUS BIO-MEDICO DI ROMA
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	Astra Zeneca S.p.A.
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	Universit¿ Campus Bio-Medico di Roma
B.5.2	Functional name of contact point	Endocrinologia e diabetologia
B.5.3	Address:
B.5.3.1	Street Address	via Alvaro del Portillo, 200
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00128
B.5.3.4	Country	Italy
B.5.4	Telephone number	0622541984
B.5.5	Fax number	06225411
B.5.6	E-mail	c.guglielmi@unicampus.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	ONGLYZA - 5 MG-COMPRESSE RIVESTITE CON FILM -USO ORALE-BLISTER NON PERFORATO(ALU/ALU) 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL- MYERS SQUIBB/ASTRAZENECA EEIG
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	ONGLYZA
D.3.2	Product code	039453016
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.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	FORXIGA - 10 MG - COMPRESSE RIVESTITE CON FILM- USO ORALE - BLISTER CALENDARIZZATO (ALU/ALU) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL- MYERS SQUIBB/ASTRAZENECA EEIG
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	FORXIGA
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.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	No
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	metformina
D.3.4	Pharmaceutical form	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.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	LANTUS - 100 IU/ML OPTISET SOLUZIONE INIETTABILE CARTUCCE IN 5 PENNE MONOUSO 3 ML USO SOTTOCUTANEO
D.2.1.1.2	Name of the Marketing Authorisation holder	SANOFI-AVENTIS DEUTSCHLAND 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	LANTUS
D.3.4	Pharmaceutical form	Solution for 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	INSULINA GLARGINE
D.3.9.1	CAS number	160337-95-1
D.3.9.2	Current sponsor code	X
D.3.9.3	Other descriptive name	Recombinant human insulin
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	Yes
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	Yes
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

LADA

Diabete autoimmune dell'adulto LADA

E.1.1.1

Medical condition in easily understood language

autoimmune diabetes of adults

diabete autoimmune dell'adulto

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10066389
E.1.2	Term	Latent autoimmune diabetes in adults
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

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 evaluate if the combination saxagliptin/dapagliflozin + metformin is non-inferior to treatment with metformin + insulin glargine in terms to improveof ¿ -cell function in patients with LADA

valutare se la combinazione saxagliptin/dapaglifozin+metformina ¿ non inferiore al trattamento con metformina+insulina glargine in termini di miglioramento di funzione beta cellulare nei pazienti con LADA

E.2.2

Secondary objectives of the trial

To evaluate if the combination saxagliptin/dapagliflozin + metformin is associated with a better metabolic control (measured by HbA1c), improved insulin sensitivity (measured by HOMA-IR index), lower number of self-reported hypoglycaemic events and a reduction of body weight, as compared with the association metformin + insulin

Assess whether the combination of saxagliptin / dapagliflozin plus metformin than with the insulin + metformin is associated with a better metabolic control (HbA1c evaluation), improved insulin sensitivity (as measured by the HOMA-IR), the lowest number hypoglycemic events and weight reduction.

Valutare se la combinazione di saxagliptin / dapagliflozin + metformina rispetto all'associazione metformina + insulina si associa ad un migliore controllo metabolico (valutazione di HbA1c), migliore sensibilit¿ all'insulina (misurata in base all'indice HOMA-IR), pi¿ basso numero di eventi ipoglicemici e riduzione del peso corporeo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures
2. Female and Male subjects aged >18 years and < 75 years
3. Previous diagnosis of diabetes
4. Duration of diabetes at entry >6 months
5. Positivity for GAD antibodies
6. Treatment with any anti-diabetic drug but insulin at the time of entry into the trial.

1. Fornitura di consenso informato prima di qualsiasi procedura di studio specifici
2. femminile e soggetti maschi di età> 18 anni e <75 anni
3. precedente diagnosi di diabete
4. Durata del diabete in ingresso> 6 mesi
5. positività per gli anticorpi GAD
6. Il trattamento con qualsiasi farmaco anti-diabetici insulino ma al momento dell'ingresso nello studio.

E.4

Principal exclusion criteria

1. Insulin therapy at diagnosis of diabetes. Subjects on saxagliptin and on dapagliflozin will be included in the study. As for study protocol (see section 5.3.2) saxagliptin and daplagliflozin will be suspended before randomization.
2. Weight loss >20% of body weight within the previous six months
3. Baseline C-peptide <0.6ng/ml
4. Estimated glomerular filtration rate (eGFR) < 60mL/min/1,73m2 and Serum Creatinine (Scr) = 1.5 mg/dL in males or = 1.4 mg/dL in females
5. Alanine aminotransferase and/or aspartate aminotransferase levels >2 x ULN
6. History of malignancy (including bladder neoplasia), psychiatric disorders and substance abuse
7. History diabetic ketoacidosis
8. Concomitant use of corticosteroids and/or concomitant use of loop diuretics
9. Evidence of sever diabetes-related complications interfering, in the opinion of the investigator, with the participation of subjects in the trial.
10. Pregnancy
11. Lactation

1. La terapia insulinica al momento della diagnosi di diabete. I soggetti in terapia con saxagliptin e/o dapaglifozin saranno inclusi nello studio. Come da protocollo saxagliptin e dapaglifozin saranno sospese prima della randomizzazione.
2. La perdita di peso> 20% del peso corporeo entro i sei mesi precedenti
3. Baseline C-peptide <0.6ng / ml
4. tasso stimato di filtrazione glomerulare (eGFR) <60 ml / min / 1,73m2 e creatinina sierica (Scr) = 1,5 mg / dl nei maschi o = 1,4 mg / dl nelle femmine
5. aminotransferasi e / o aspartato aminotransferasi livelli> 2 x ULN
6. Storia di malignità (compresi vescica neoplasia), disturbi psichiatrici e abuso di sostanze
7. Storia chetoacidosi diabetica
8. L'uso concomitante di corticosteroidi e / o l'uso concomitante di diuretici dell'ansa
9. La prova di complicanze legate al diabete sever interferire, a giudizio dello sperimentatore, con la partecipazione dei soggetti in studio.
10. Gravidanza
11. Allattamento

E.5 End points

E.5.1

Primary end point(s)

Change in the area under the curve (AUC) of C-peptide after running a MMTT in patients treated for one year with saxagliptin / dapagliflozin plus metformin vs patients treated with insulin glargine + metformin

Cambio dell’area sotto la curva (AUC) del C-peptide dopo esecuzione di un MMTT in pazienti trattati per un anno con saxagliptin / dapagliflozin + metformina vs pazienti trattati con insulina glargine + metformina

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after beginning treatment

6 mesi dopo inizio trattamento

E.5.2

Secondary end point(s)

HbA1c, number hypoglycemic events (blood glucose <70 mg / dl), HOMA-IR index and weight loss in patients treated for one year with saxagliptin / dapagliflozin plus metformin vs patients treated with insulin glargine + metformin

HbA1c, numero eventi ipoglicemici (glicemia < 70 mg/dl), HOMA-IR index e Perdita di peso in in pazienti trattati per un anno con saxagliptin / dapagliflozin + metformina vs pazienti trattati con insulina glargine + metformina

E.5.2.1

Timepoint(s) of evaluation of this end point

end of trial

fine 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

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)

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

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

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.8.5.1

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

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

F.4 Planned number of subjects to be included

F.4.1

In the member state

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

100

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)

standard of care

standard di cura

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

2016-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-10

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

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