Clinical Trials Register

Summary
EudraCT Number:	2015-004637-27
Sponsor's Protocol Code Number:	AZ-01_SGLT-2
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-12-14
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2015-004637-27

A.3

Full title of the trial

A randomized, double-blind, three arm, three treatment period, cross-over trial to investi-gate the effect of a SGLT-2 inhibitor, a DPP-4 inhibitor and a SGLT-2 inhibitor + DPP-4 inhibitor on glucagon levels, endogenous glucose production and lipolysis during hyper-, normo- and hypoglycaemia in subjects with type 2 diabetes using stable tracer technique.

Eine randomisierte , doppel-blinde , dreiarmige , drei-Behandlungsperioden- , Crossover -Studie zur Untersuchung des Effekts eines SGLT-2-Hemmers , eines DPP-4-Hemmers und eines SGLT-2-Hemmers + eines DPP-4 Hemmers auf Glukagonwerte , endogene Glukoseproduktion und Lipolyse während Hyper-, Normo- und Hypoglykämie bei Typ 2 DiabetikerInnen mittels der stabilen Marker-Technik zu untersuchen.

A.3.1

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

A trial to investigate the efffect of a SGLT-2 inhibitor a DPP-4 inhibitor and a SGLT-2 inhibitor + DPP-4 inhibitor on glucagon levels, endogenous glucose production and lipolysis.

A.4.1

Sponsor's protocol code number

AZ-01_SGLT-2

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	Medizinische Universität Graz
B.1.3.4	Country	Austria
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	Medizinische Universität Graz
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medizinische Universität Graz
B.5.2	Functional name of contact point	Study Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Stiftingtalstrasse 24
B.5.3.2	Town/ city	Graz
B.5.3.3	Post code	8010
B.5.3.4	Country	Austria
B.5.4	Telephone number	43 31638572835
B.5.5	Fax number	4331638572839
B.5.6	E-mail	stefanie.sach-friedl@medunigraz.at

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	Forxiga 10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	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	dapagliflozin
D.3.9.1	CAS number	461432-26-8
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB31650
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	10
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.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	Onglyza
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
D.2.1.2	Country which granted the Marketing Authorisation	Austria
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	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	saxagliptin
D.3.9.1	CAS number	361442-04-8
D.3.9.3	Other descriptive name	SAXAGLIPTIN
D.3.9.4	EV Substance Code	SUB25220
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	2.5
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	Coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	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 Typ 2

E.1.1.1

Medical condition in easily understood language

Type 2 Diabetes

Typ 2 Diabetes

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10012594
E.1.2	Term	Diabetes
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

To compare the glucagon response of a treatment with metformin monotherapy (baseline), a SGLT-2 inhibitor, a DPP-4 inhibitor and a combination of a SGLT-2 inhibitor and a DPP-4 inhibitor during normo-, hyper- and hypoglycaemia in a controlled clamp setting under stable metformin therapy.

E.2.2

Secondary objectives of the trial

To compare the effect of treatment with metformin monotherapy (baseline), an add-on SGLT-2 inhibitor, an add-on DPP-4 inhibitor and an add-on combination of a SGLT-2 inhibitor and a DPP-4 inhibitor on endogenous glucose production, peripheral glucose uptake, lipolysis, insulin sensitivity, metabolites, and glucose regulating hormones during normo-, hyper- and hypoglycaemia in a controlled clamp setting under stable metformin therapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female aged 18-64 years (both inclusive) at the time of signing informed consent.
• Subjects diagnosed with type 2 diabetes and on stable treatment for a period of 90 days prior to screening with metformin as monotherapy. Stable is defined as un-changed dose.
• Body mass index (BMI) between 20.0 and 35.0 kg/m2 (both inclusive).
• HbA1c between 47.5 and 85.8 mmol/mol (6.5 – 10.0%) (both inclusive).

E.4

Principal exclusion criteria

• Treatment with any glucose lowering agent(s) other than metformin in a period of 90 days before screening. An exception is short-term treatment (≤ 7 days in total) with insulin due to intercurrent illness.
• Clinically significant abnormal haematology, biochemistry, lipids, hormones, coagu-lation and urinalysis.
• Acute symptomatic (according to investigator’s judgement) urinary tract infection or genital infection, chronic or recurrent (≥ 3 annual episodes) cystitis.
• Uncontrolled hypertension defined as sitting blood pressure at screening (after resting for 5 min) outside the range of 90−160 mmHg for systolic or 50−100 mmHg for diastolic.
• Chronic liver failure with severe liver dysfunction as assessed by the investigator.

E.5 End points

E.5.1

Primary end point(s)

ΔGlucagon: Change in glucagon concentration from 5.5 mmol/L low insulin to 11.1 mmol/L: Glucagon11.1-Glucagon.

E.5.1.1

Timepoint(s) of evaluation of this end point

At each plateau of the hyper-, normo- and hypoglycaemic clamp

E.5.2

Secondary end point(s)

AUCGlucagon: area under the complete glucagon concentration curve during the clamp procedure.
GlucagonPG, glucagon concentration at different assessment plateaus (e.g. 11.1 mmol/L)
ΔGlucagona,b, change in glucagon concentration between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L)
EGPplateau, mean endogenous glucose production (EGP) at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L)
ΔEGPa,b, change in EGP between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L)
AUCGIR, area under the glucose infusion rate (GIR) curve at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L)
ΔGIRa,b, change in AUCGIR between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L)
PGUplateau, mean peripheral glucose uptake (PGU) at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L)
ΔPGUa,b, change in PGU between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L)
Lipoplateau, mean lipolysis at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L)
Δlipoa,b, change in lipolysis between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L)
MetabolPG, concentration of lactate, free fatty acids, glycerol and ketone bodies at different assessment plateaus(e.g. 11.1 mmol/L)
ΔMetabola,b, change in concentration of lactate, free fatty acids, glycerol and ketone bodies between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L)
CounterPG, concentration of adrenaline, noradrenaline, growth hormone and cortisol at different assessment plateaus (e.g. 11.1 mmol/L)
ΔCountera,b, change in concentration of adrenaline, noradrenaline, growth hormone and cortisol between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L)

E.5.2.1

Timepoint(s) of evaluation of this end point

At each plateau of the hyper-, normo- and hypoglycaemic clamp

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

Yes

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

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

LPLV

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)

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.4.2.2

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)

After the trial there will be no need for extra care or treatment. But standard care for type 2 diabetic patients at the diabetes outpatient clinic of the Department of Internal Medicine at the Medical University of Graz will be available.

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

2016-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-10-06

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