Clinical Trials Register

Summary
EudraCT Number:	2016-003477-18
Sponsor's Protocol Code Number:	Empabrain01
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-01-12
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

2016-003477-18

A.3

Full title of the trial

A double-blind randomized study to determine the effect of empagliflozin versus placebo on brain insulin sensitivity in patients with prediabetes

A.4.1

Sponsor's protocol code number

Empabrain01

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	University Hospital Tuebingen
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	Boehringer Ingelheim
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	University Hospital Tuebingen
B.5.2	Functional name of contact point	PD Dr.med. Martin Heni
B.5.3	Address:
B.5.3.1	Street Address	Otfried-Mueller Str. 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	+4970712982711
B.5.5	Fax number	+497071294454
B.5.6	E-mail	martin.heni@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	Jardiance
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International 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	Empagliflozin
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	Empagliflozin
D.3.9.1	CAS number	864070-44-0
D.3.9.3	Other descriptive name	EMPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB35915
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	25
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	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	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
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

brain insulin sensitivity in patients with prediabetes

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	LLT
E.1.2	Classification code	10065542
E.1.2	Term	Prediabetes
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

Key objective: to assess the effect of treatment with 25 mg empagliflozin daily versus placebo on regional brain insulin sensitivity.

Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity assessed by functional magnetic resonance imaging as change in regional cerebral blood flow from before to 30 minutes after nasal insulin spray application.

E.2.2

Secondary objectives of the trial

Effect of 8 weeks treatment with 25 mg empagliflozin or placebo:
on glucose tolerance status (ADA criteria) in patients with prediabetes.
on body fat composition assessed by whole-body MRI and liver MR-spectroscopy.
on brain control over peripheral insulin sensitivity assessed as change in glucose infusion rate after
nasal insulin during an hyperinsulinemic euglycemic clamp.
on autonomic nervous system activity assessed as heart rate variability under fasting conditions as well as during hyperinsulinemic euglycemic clamp.
on brain response to food pictures and control pictures as assessed by functional magnetic resonance imaging.
on the correlation between regional brain insulin sensitivity and insulin secretion capacity during an oral glucose tolerance test, adjusted for whole body insulin sensitivity.
on energy expenditure assessed by indirect calorimetry.
on body composition assessed by bioimpedance analysis.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects meeting all of the following criteria will be considered for admission to the trial:
• Must be between 30 and 75 years at the time of signing the informed consent.
• Fasting blood glucose between 100 and 125 mg/dl and/or 2-hour post load glucose between 140 and 199 mg/dl during a 75 g oral glucose tolerance test (ADA criteria for prediabetes).
• Body mass index (BMI) between 25 and 40 kg/m².
• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
• Ability to adhere to the study visit schedule and other protocol requirements.
• Females of childbearing potential (FCBP1) must agree
 to utilize two reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation and must agree to pregnancy testing during this timeframe
 to abstain from breastfeeding during study participation and 28 days after study drug discontinuation.
• Males must agree
 to use a latex condom during any sexual contact with FCBP while participating in the study and for 28 days following discontinuation from this study, even if he has undergone a successful vasectomy
 to refrain from donating semen or sperm while participating in this study and for 28 days after discontinuation from this study treatment.
• All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
• All subjects must agree not to share medication.

E.4

Principal exclusion criteria

Subjects presenting with any of the following criteria will not be included in the trial:
• Women during pregnancy and lactation.
• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal products. This includes empagliflozin, placebo and human insulin.
• Participation in other clinical trials or observation period of competing trials up to 30 days prior to this study.
• Diabetes mellitus
• Known malformation of the central nervous system
• Persons working nightshift
• Treatment with glucose lowering drugs, drugs with central nervous actions or systemic steroid therapy
• Any relevant (according to investigator’s judgment) cardiovascular disease, e.g. myocardial infarction, acute coronary syndrome, unstable angina pectoris, PTCA, heart failure (NYHA II-IV), stroke or transient ischemic attack (TIA), within 12 months prior to screening.
• Indication of liver disease, as per medical history or defined by serum levels of either Alanine Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening.
• Alcohol abuse, defined as more than 20 gr/day
• Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min (MDRD formula) as determined during screening.
• Known structural and functional urogenital abnormalities, that predispose for urogenital infections.
• Patients with a haemoglobin (Hb) ≤ 11.5 g/dl (for males) and Hb ≤ 10.5 g/dl (for females) at screening.
• Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption within the last 5 years.
• Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.
• Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight.
• Known autoimmune disease (except autoimmune disease of the thyroid gland) or chronic inflammatory condition.
• Claustrophobia
• Any other clinically significant major organ system disease at screening such as relevant gastrointestinal, neurologic, psychiatric, endocrine (i.e. pancreatic), hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult.
• Presence of any contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
Any other clinical condition that would jeopardize patients’ safety while participating in this clinical trial.

E.5 End points

E.5.1

Primary end point(s)

• Effect of 8 weeks treatment with 25 mg empagliflozin or placebo on regional brain insulin sensitivity assessed by functional magnetic resonance imaging as change in regional cerebral blood flow from before to 30 minutes after nasal insulin spray application.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline Measurement at Week 0
Assessment of safety parameters and body weight at Week 2 and 4
Assessment of regional brain insulin sensivity, brain effects on peripheral metabolism, food preference, body fat distribution, glucose tolerance at Week 8

E.5.2

Secondary end point(s)

Effect of 8 weeks treatment with 25 mg empagliflozin or placebo:
on glucose tolerance status (ADA criteria) in patients with prediabetes.
on body fat composition assessed by whole-body MRI and liver MR-spectroscopy.
on brain control over peripheral insulin sensitivity assessed as change in glucose infusion rate after
nasal insulin during an hyperinsulinemic euglycemic clamp.
on autonomic nervous system activity assessed as heart rate variability under fasting conditions as well as during hyperinsulinemic euglycemic clamp.
on brain response to food pictures and control pictures as assessed by functional magnetic resonance imaging. Food intake and food preference will be monitored during an ad libitum buffet.
on the correlation between regional brain insulin sensitivity and insulin secretion capacity during an oral glucose tolerance test, adjusted for whole body insulin sensitivity.
on energy expenditure assessed by indirect calorimetry.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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

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

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

The end of the study is defined as the date of the last visit of the last patient in the trial. Last patient last visit (LPLV) is either the date of the last visit of the last patient to complete the study, or the date at which the last data point from the last patient, which was required for statistical analysis (i.e. key safety and efficacy results for decision making), was received, whichever the later date.

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

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.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)

Since no specific treatment or regular care is recommended in prediabetes in clinical practice, no specific treatment or care is planned after the end of the study.

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

2017-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-01-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-12-04

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