Clinical Trials Register

Summary
EudraCT Number:	2015-001702-33
Sponsor's Protocol Code Number:	CV181-369
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-24
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

Denmark - DHMA

A.2

EudraCT number

2015-001702-33

A.3

Full title of the trial

A 24-week International, Multicenter, Randomized, Open-Label, Active-Controlled, Parallel Group, Phase 3b Trial with a 28-week Extension to Evaluate the Efficacy and Safety of Saxagliptin Co-administered with Dapagliflozin Compared to Insulin Glargine in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin with or without Sulfonylurea Therapy

A.3.1

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

A comparison of treatment with Saxagliptin and Dapagliflozin against Insulin Glargine in Type 2 Diabetes patients whose current treatment of Metformin with or without Sulfonylurea Therapy is not adequate.

A.4.1

Sponsor's protocol code number

CV181-369

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	1800 Concord Pike, PO Box 15437
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	19850-5437
B.5.3.4	Country	United States
B.5.4	Telephone number	001800236993
B.5.6	E-mail	information.center@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	Onglyza
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
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	Saxagliptin
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	SAXAGLIPTIN
D.3.9.1	CAS number	361442-04-8
D.3.9.2	Current sponsor code	BMS-477118-11
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	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.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
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
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
D.3.9.1	CAS number	461432-26-8
D.3.9.2	Current sponsor code	BMS-512148
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: 3
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	Glargine Insulin
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	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	Glargine Insulin
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	Glargine Insulin
D.3.9.3	Other descriptive name	INSULIN
D.3.9.4	EV Substance Code	SUB02689MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml 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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Type 2 diabetes mellitus and inadequate glycemic control on a stable dose of metformin

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes not being controlled by current medication

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	10049746
E.1.2	Term	Insulin-requiring type II diabetes mellitus
E.1.2	System Organ Class	100000004861

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

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	10045242
E.1.2	Term	Type II diabetes mellitus
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 examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is non-inferior to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment.

E.2.2

Secondary objectives of the trial

•To compare co-administered saxagliptin 5mg and dapagliflozin 10mg plus metformin with/without SU versus titrated insulin glargine plus metformin with/without SU after 24 weeks:
- the mean change from baseline in total body weight
- the proportion of confirmed hypoglycemia
[defined as: a) plasma glucose ≤70 mg/dL (3.9 mmol/L);
or b) signs / symptoms of hypoglycemia with self-monitored blood glucose ≤70 mg/dL (3.9 mmol/L)]
- the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, without any hypoglycemia.

•To examine whether with co-administered saxagliptin 5mg and dapagliflozin 10mg plus metformin with/without SU is non-inferior to titrated insulin glargine plus metformin with/without SU after 24 weeks:
- the change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring
- the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Continuous Glucose Monitoring (CGM) Sub-Study
In the this study, a sub-population of approximately 250 subjects with valid CGM data at the baseline assessment performed at Week -2 (approximately 125 subjects per treatment arm stratified by background SU use) who agree to participate (separate informed consent) will have a CGM sensor inserted subcutaneously to measure glucose levels in tissue fluid. The glucose sensor will be inserted and removed by trained personnel at the site. Subjects will wear the glucose sensor for 7 consecutive days at 4 different time periods during the study:
• At baseline, prior to receiving study medication, between Week -2 and Week-1
• Between Week 2 and Week 3 of treatment
• Between Week 11 and Week 12 of treatment
• Between Week 23 and Week 24 of treatment.
Subjects in the sub-study will have 4 site visits added to the regularly scheduled visits ( Week -1, Week 3, Week 11 and Week 23). If CGM recording is insufficient at any of these timepoints, subjects may be required to wear the glucose sensor for an additional 7 day period to obtain sufficient data.
Subjects in the CGM sub-study will be required to perform a 4-point SMBG profile on days of CGM monitoring when they are not performing the 6-point SMBG profile (see Section 5.3.1.2).
This 4-point SMBG should be performed at the approximate times: before breakfast, before lunch, before dinner and before bedtime and the values recorded in the subject’s diary.

Detailed procedures (including calibration, insertion/removal and upload of data) will be described in an operations manual and site staff will be trained on the use of the CGM. Subjects will be instructed on use of the device according to the manufacturer’s instructions.

E.3

Principal inclusion criteria

• Males and females aged ≥ 18 years old at the time of screening visit.
• Subjects with T2DM with inadequate glycemic control, defined as a central laboratory HbA1c ≥ 8 % and ≤ 12 % obtained at the screening visit.
• Subjects must be taking a stable dose of metformin ≥ 1500 mg/day for at least 8 weeks prior to screening visit with or without a stable dose of SU of at least 50% maximal dose per local label for at least 8 weeks prior to screening visit. Subjects must not take any other antidiabetic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening.
• BMI ≤ 45.0 kg/m2 at the screening visit.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) at screening and within 24 hours prior to the start of study drug.

E.4

Principal exclusion criteria

• Clinical diagnosis of Type 1 Diabetes.
• History of diabetic ketoacidosis
• History of unstable or rapidly progressing renal disease, hepatic insufficiency or current, acute or chronic pancreatitis.
• Any of the following cardiovascular/vascular diseases within 3 months of enrollment visit: myocardial infarction (MI), coronary arterial bypass graft (CABG), percutaneous coronary intervention (PCI), valvular disease or repair, unstable angina or unstable congestive heart failure (CHF), transient ischemic attack (TIA), Class III or IV heart failure, known left ventricular ejection fraction of < 40%, or significant cerebrovascular disease.
• Impairment of renal function (defined as creatinine clearance [CrCl] < 60 mL/min [estimated by Cockcroft-Gault] or serum creatinine [SCr] ≥ 1.5 mg/dL in male subjects or ≥ 1.4 mg/dL in female subjects).
• Bladder cancer
• Hematuria (confirmed by microscopy at screening) with no explanation as judged by the investigator up to randomization.
• Other hematological or oncological diseases or conditions.
• Participation in a commercial weight loss program or history of bariatric surgery.
• Replacement or chronic systemic corticosteroid therapy.
• Administration of any other investigational drug or participation in any interventional clinical study within (30) days prior to screening for this study.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HbA1c at Week 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24

E.5.2

Secondary end point(s)

The secondary efficacy endpoints for the short-term treatment period include:
1) Change from baseline in total body weight at Week 24
2) Proportion of subjects with confirmed hypoglycemia [defined as: a) plasma glucose ≤ 70 mg/dL (3.9 mmol/L); or b) signs / symptoms of hypoglycemia with self-monitored blood glucose ≤ 70 mg/dL (3.9 mmol/L)] at Week 24
3) Proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, without any reported hypoglycemia (for the duration of the Short-term Period) at Week 24
4) In a sub-study, change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring (CGM) at Week 2
5) Proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0% at Week 24

E.5.2.1

Timepoint(s) of evaluation of this end point

1) At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24
2) Week 24
3) Week 24
4) At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24
5) Week 24

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

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

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

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

Czech Republic

Denmark

Germany

Hungary

Mexico

Poland

Romania

Russian Federation

South Africa

Spain

Sweden

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LSLV

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:

478

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

253

F.4.2.2

In the whole clinical trial

598

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

2016-01-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-10

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