Clinical Trials Register

Summary
EudraCT Number:	2015-005740-34
Sponsor's Protocol Code Number:	ESR-14-10698
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-09-29
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2015-005740-34

A.3

Full title of the trial

Effectiveness of Dapagliflozin + Saxagliptin to revert from a standard basalbolus
insulin treatment (BBIT) regimen to a basal supported oral therapy
(BOT) in patients with Type 2 Diabetes – a randomised double-blinded
study – a randomised double-blinded study

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Dapa-Saxa-BBIT

A.4.1

Sponsor's protocol code number

ESR-14-10698

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	Universitätsklinikum Tübingen
B.1.3.4	Country	Germany
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	Universitätsklinikum Tübingen
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Tübingen
B.5.2	Functional name of contact point	Prof. Dr. Norbert Stefan
B.5.3	Address:
B.5.3.1	Street Address	Otfried-Müller-Straße 10
B.5.3.2	Town/ city	Tuebingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49707129 80390
B.5.5	Fax number	+49707129 5974
B.5.6	E-mail	norbert.stefan@med.uni-tuebingen.de

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
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca/BMS
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	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)	Yes
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	AstraZeneca/BMS
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 Filmtabletten
D.3.2	Product code	EU/1/09/545/001 – 010
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	INN-saxagliptin
D.3.9.1	CAS number	709031-78-7
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)	Yes
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	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	Actrapid
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Actrapid®
D.3.4	Pharmaceutical form	Nasal spray
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intranasal use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN HUMAN
D.3.9.1	CAS number	11061-68-0
D.3.9.3	Other descriptive name	ACTRAPID
D.3.9.4	EV Substance Code	SUB08197MIG
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	Yes
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	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	Film-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	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 Melitus Type 2

E.1.1.1

Medical condition in easily understood language

Investigation of effectiveness of adding the SGLT2 inhibitor dapagliflozin + the DPP-4 inhibitor saxagliptin vs placebo to revert from a BBIT regimen to a BOT regimen in patients with type 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	20.0
E.1.2	Level	HLGT
E.1.2	Classification code	10018424
E.1.2	Term	Glucose metabolism disorders (incl diabetes mellitus)
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10012601
E.1.2	Term	Diabetes mellitus
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 determine the efficacy of adding the
SGLT2 inhibitor dapagliflozin + the DPP-4
inhibitor saxagliptin vs placebo to revert from
a standard basal-bolus insulin treatment
(BBIT) regimen to a basal supported oral
therapy (BOT) regimen in patients with type 2
diabetes.
Percentage of subjects achieving a HbA1c ≤ 7.5%
and having a reversal from a BBIT to a BOT regimen

E.2.2

Secondary objectives of the trial

To determine the efficacy of adding the
SGLT2 inhibitor dapagliflozin + the DPP-4
inhibitor saxagliptin vs placebo to a standard
BBIT regimen to improve glycemic
parameters, insulin dose, bodyweight, body fat
mass and body fat distribution, blood pressure,
lipid profile, microalbuminuria, quality of life,
brain insulin resistance and blood parameters
of cardiometabolic risk.
To evaluate the safety and tolerability of
adding the SGLT2 inhibitor dapagliflozin + the
DPP-4 inhibitor saxagliptin vs placebo to a
standard BBIT regimen.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Type 2 diabetes
•Age 18 - 75 years
•Anti-GAD antibodies negative
•C-peptide levels ≥ 1.5 ng/mL
•Fasting blood glucose ≥ 126 mg/dl
•HbA1c 8.0 – 10.5 %
•BMI 25.0 – 45.0 kg/m2
•Previous therapy with standard BBIT (basal insulin and at least
once daily bolus insulin) when the bolus insulin dose is not adjusted
to exercise or nutrient intake.

E.4

Principal exclusion criteria

•Use of any oral antidiabetic treatment except for metformin (i.e.,
sulphonylureas, DPP-IV inhibitors, thiazolidinediones, SGLT-2
inhibitors) or GLP-1 analogues within the last three months prior to
Screening
•Repeated episodes of severe hypoglycaemia within the last six
months prior to Screening
•History of diabetic ketoacidosis, praecoma diabeticum, or diabetic
coma
•Treatment with any other investigational drug within the last three
months before Screening
•Acute infections within the last four weeks prior to Screening
•Recurrent urogenital infections
•History of pancreatitis
•Anamnestic history of hypersensitivity to the study drugs or to
drugs with similar chemical structures
•History of severe or multiple allergies
•Concomitant participation in other clinical trials
•Type 1 diabetes
•Cardiovascular disease
Clinically relevant ventricular tachycardia or ventricular
fibrillation, 3rd degree AV block or Torsades de Pointes or
treatment with antiarrhythmic drugs.
Percutaneous coronary intervention within the past 6 months.
Any of the following within the past 6 months: myocardial
infarction (MI), coronary artery bypass surgery; unstable angina;
or stroke.
Uncontrolled unstable angina pectoris or history of pericarditis,
myocarditis, endocarditis.
Congestive heart failure NYHA class III or IV.
Increased risk of thromboembolism, e.g. subjects with a history
of deep leg vein thrombosis or family history of deep leg vein
thrombosis, as judged by the Investigator.
•Malignancy including leukemia and lymphoma within the last 5y.
•Liver disease such as cirrhosis or chronic active hepatitis.
•Moderate or severe impaired liver function (serum AST or serum
ALT > 2.5 x ULN, serum total bilirubin ≥ 2.0 mg/dl or serum
albumin ≤ 3.5 g/dl)
•Significant renal dysfunction (see also exclusion criteria laboratory
abnormalities).
•State after kidney transplantation
•Endocrine disease:
Acromegaly or treatment with growth hormone or similar drugs.
Chronic oral or parenteral corticosteroid treatment (≥7
consecutive days of treatment) within 8 weeks; thyroid hormone
replacement is allowed if the dosage has been stable for at least 3
months and the TSH is within normal limits
•Any of the following significant laboratory abnormalities:
eGFR (as calculated by the MDRD equation) < 60 ml/min at
Screening
Fasting triglycerides ≥700 mg/dl (≥7.9 mmol/l)
•Systolic blood pressure outside the range of 100–160 mmHg or
diastolic blood pressure above 95 mmHg at Screening
•History of active substance abuse (including alcohol > 12g/day for
women and >24g/day for men) within the past 2 years.
•Pregnancy or childbearing potential without adequate
contraception
•Present therapy with systemic steroids
•Known hypersensitivity to Dapagliflozin or Saxagliptin or any of
the components of their formulation or human nasal insulin or any
of the components of its formulation
•Immune suppressive medication and/or immune deficiency
syndromes
•Presence of psychiatric disorder or intake of anti-depressive or
anti-psychotic agents with the exception of benzodiazepines and
SSRIs/SNRI´s
•Potentially unreliable subjects, and those judged by the
investigator to be unsuitable for the study (e.g. subjects needing
assistance for the application of insulin, subjects deemed not to be
compliant with the recommendations given during the study)
•Contraindications for Magnetic resonance (MR) scanning such as
persons with cardiac pacemaker and implants out of metal or
claustrophobia

E.5 End points

E.5.1

Primary end point(s)

Percentage of subjects achieving a HbA1c ≤ 7.5% and having a reversal from a BBIT to a BOT regimen

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 4: Week 0: On-site visit, dose adjustment
Visit 6: Week 2: On-site visit, dose adjustment
Visit 10: Week 8: On-site visit, dose adjustment
Visit 14: Week 16: On-site visit, dose adjustment
Visit 18.1: Week 24-day 1: Final visit, outcome parameters
Visit 18.2: Week 24-day 2: Final visit, outcome parameters

E.5.2

Secondary end point(s)

changes in HbA1c between groups
• changes in hypoglycaemic events between groups
• changes in fasting blood glucose between groups
• changes in daily insulin dose between groups
• changes in bodyweight between groups
• changes in body fat content and body fat distribution, both precisely measured with MR tomography, and liver fat content, precisely measured with 1H-MR spectroscopy, and intra-nasal insulin-induced brain fMR imaging results between groups (to be discussed – decreased insulinemia and lower energy availability are expected to decrease visceral fat mass and liver fat content and to improve brain insulin resistance)
• changes in blood pressure between groups
• changes in the blood lipid profile between groups
• changes in well being and disease perception between groups.
• changes in fear of hypoglycaemia
AEs/SAEs
Vital signs
Collection of clinical chemistry/haematology parameters
ECGs. The following parameters will be recorded for each ECG: date and time of ECG, heart rate (beats/min), QT (ms), QTcB (ms), sinus rhythm (yes/no), and overall evaluation (normal/abnormal)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

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

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

The total duration of the study for each subject will be up to 30 weeks.
Subjects have the right to withdraw of the informed consent at any time.
Withdrawal from investigations – Participants will not undergo study investigations if one or more of the respective inclusion criteria for the metabolic test/study investigation are not fulfilled.
Withdrawal from documentation – Subjects who gave consent to be included in the study can withdraw their specimen at any time for any reason.

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)

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

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)

Each study participant will be provided with treatment recommendations for their general practiotioners after the end of the treatment period. If participants are not referred by a doctor, treatment advice in the respective trial site clinic should be provided.

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

2017-08-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-02-03

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials