Clinical Trials Register

Summary
EudraCT Number:	2014-003503-29
Sponsor's Protocol Code Number:	D5553C00003
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-01-26
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2014-003503-29

A.3

Full title of the trial

A 28-week, Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study with a 24-week Extension Phase Followed by a 52-week Extension Phase to Evaluate the Efficacy and Safety of Simultaneous Administration of Exenatide Once Weekly 2 mg and Dapagliflozin Once Daily 10 mg Compared to Exenatide Once Weekly 2 mg Alone and Dapagliflozin Once Daily 10 mg Alone in Patients with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin

28 hetes, multicentrikus, randomizált, kettős vak, aktív készítménnyel kontrollált, III. fázisú vizsgálat, egy 24 hetes, majd egy 52 hetes kiterjesztésű szakasszal, az egyidejűleg alkalmazott hetente egyszer 2 mg exenatid és naponta egyszer 10 mg dapagliflozin kezelés hatásosságának és biztonságosságának értékelésére az önmagában alkalmazott hetente egyszer 2 mg exenatid és az önmagában alkalmazott naponta egyszer 10 mg dapagliflozin kezeléssel összehasonlítva, olyan 2-es típusú cukorbetegségben szenvedő betegek esetében, akiknél a metformin nem biztosít megfelelő glikémiás kontrollt

A.3.1

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

28 Week Phase 3 study and 24 Week extension followed by a 52-week extension to evaluate efficacy and safety of Exenatide once weekly and Dapagliflozin versus Exenatide and Dapagliflozin matching placebo

A.3.2

Name or abbreviated title of the trial where available

DURATION 8

A.4.1

Sponsor's protocol code number

D5553C00003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02229396

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	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	Not applicable
B.5.3.2	Town/ city	Not applicable
B.5.3.3	Post code	Not applicable
B.5.3.4	Country	United States
B.5.6	E-mail	information.centre@astrazeneca.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 (2 mg powder and solvent for prolonged-release suspension for injection)
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	European Union
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	Exenatide
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection in pre-filled syringe
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	EXENATIDE
D.3.9.1	CAS number	141758-74-9
D.3.9.4	EV Substance Code	SUB21818
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
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	Forxiga (10 mg film-coated tablets)
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	European Union
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	dapagliflozin
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	DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
D.3.9.1	CAS number	960404-48-2
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB90205
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.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	Powder and solvent for suspension for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
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

Diabetes Mellitus

Diabétesz

E.1.1.1

Medical condition in easily understood language

Diabetes (High blood sugar)

Magas vércukor

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	HLT
E.1.2	Classification code	10012602
E.1.2	Term	Diabetes mellitus (incl subtypes)
E.1.2	System Organ Class	100000004860

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 change from baseline in HbA1c at 28 weeks between EQW 2 mg and dapagliflozin
10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.

E.2.2

Secondary objectives of the trial

To compare the effect of EQW + dapagliflozin to EQW + placebo and/or to dapagliflozin + placebo,
on changes in glycemic control and anthropometric measures.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Is at least 18 years old at Screening; the upper age limit should be based on local metformin label restrictions.
2) Has a diagnosis of T2DM.
3) Has HbA1c of 8.0% to 12.0%, inclusive, at Visit 1 and Visit 2.
4) Treated with a stable dose of metformin ≥1500 mg/day for at least 2 months prior to Screening.
5) Is male, or is female and meets all the following criteria:
-Not breastfeeding.
-Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at Visit 1 (Screening) (not applicable to hysterectomized females).
-If of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year), must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, ie, less than 1% per year, when used consistently and correctly, such as implants, injectables, hormonal contraceptives [pills, vaginal rings, or patches], some intrauterine contraceptive devices [levonorgestrel-releasing or copper-T], tubal ligation or occlusion, or a vasectomized partner) during the entire duration of the study. As applicable, all methods must be in effect prior to receiving the first dose of study medication.
-Must practice appropriate birth control as stated above for 10 weeks after the last dose of study medication.
6) Patients who are receiving the following medications must be on a stable treatment regimen for a minimum of 2 months prior to Visit 1 (Screening):
 -Antihypertensive agents
 -Thyroid replacement therapy
 -Antidepressant agents.

E.4

Principal exclusion criteria

1. FPG ≥280 mg/dL (15.6 mmol/L).
2. Serum calcitonin concentration ≥40 pg/mL (≥40 ng/L) at Visit 1 (Screening).
3. Clinically significant abnormal free T4 values or patients needing initiation or adjustment of thyroid treatment according to the investigator. Abnormal thyroid stimulating hormone (TSH) value at Screening will be further evaluated by free T4. Patients with clinically significant abnormal free T4 values will be excluded.
4. Known active proliferative retinopathy.
5. History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥500 mg/dL (≥5.65 mmol/L) at Visit 1 (Screening).
6. History or presence of inflammatory bowel disease or other severe GI diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis.
7. History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study. Current use of gastric balloons is also excluded.
8. Significant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or total bilirubin (TB) >2 mg/dL (>34.2 μmol/L) (patients with TB >2 mg/dL [>34.2 μmol/L] and documented Gilbert’s syndrome will be allowed to participate).
9. Known history of hepatotoxicity with any medication.
10. Known history of severe hepatobiliary disease.
11. Positive serological test for hepatitis B or hepatitis C.
12. Clinically significant cardiovascular disease or procedure within 3 months of Visit 1, including but not limited to myocardial infarction, clinically significant arrhythmia, unstable angina, coronary artery bypass surgery, or angioplasty; or are expected to require coronary artery bypass surgery or angioplasty during the course of the study.
13. Presence or history of severe congestive heart failure (New York Heart Association Class IV [CCNYHA 1994]).
14. Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg.
15. Creatinine clearance <60 mL/min (1 mL/s) (calculated by Cockcroft-Gault formula) or a measured serum creatinine value of ≥1.5 mg/dL (133 µmol/L) for male patients and ≥1.4 mg/dL (124 µmol/L) for female patients.
16. Congenital renal glucosuria.
17. History of unstable or rapidly progressing renal disease.
18. History of unexplained microscopic or gross hematuria, or microscopic hematuria at Visit 1, confirmed by a follow-up sample at next scheduled visit, where according to the investigator a satisfactory evaluation of hematuria has not been conducted based on guidance in Section 6.3.9.
19. Known or suspected human immunodeficiency virus (HIV) infection.
20. Presence or history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2) OR a family history of medullary thyroid carcinoma or MEN 2.
21. Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 1 (Screening).
22. Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) or any other condition known to interfere with the HbA1c methodology.
23. Has donated blood or had a significant blood loss within 2 months of first dose of study medication or is planning to donate blood during the study.
24. Any exposure to exenatide (including BYETTA®, BYDUREON™, or exenatide suspension) or any GLP-1 analog.
25. Any exposure to dapagliflozin (FORXIGA, FARXIGA) or any SGLT-2 inhibitor.
26. Administration of any antihyperglycemic therapy, other than metformin, for more than 14 days (consecutive or not) during the 12 weeks prior to Visit 1 (Screening). In addition, administration of any antihyperglycemic therapy, other than metformin, at any dose, at any time during the 4 weeks prior to Visit 1 (Screening).

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the change in HbA1c.

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to Week 28.

E.5.2

Secondary end point(s)

Secondary efficacy endpoints
• Change in total body weight from baseline to Week 28
• Change in FPG from baseline to Week 28
• Change from baseline in 2-hour PPG after standardized MTT at Week 28
• Proportion of patients achieving HbA1c <7.0% at Week 28
• Proportion of patients achieving weight loss ≥5.0% at Week 28
• Change from baseline in FPG to Week 2 (dapagliflozin+exenatide vs exenatide)
• Change from baseline in seated systolic BP from baseline to Week 28

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline to Week 28.

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

Yes

E.6.5

Efficacy

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Hungary

Poland

Romania

Slovakia

South Africa

United States

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:

594

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

314

F.4.2

For a multinational trial

F.4.2.1

In the EEA

252

F.4.2.2

In the whole clinical trial

660

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)

None

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

2015-03-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-28

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