Clinical Trials Register

Summary
EudraCT Number:	2014-001922-14
Sponsor's Protocol Code Number:	1245.69
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-04-02
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

UK - MHRA

A.2

EudraCT number

2014-001922-14

A.3

Full title of the trial

A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive to inSulin thErapy over 52 weeks in patients with Type 1 diabetes mellitus (EASE-2)

A.3.1

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

Empagliflozin as Adjunctive to inSulin thErapy in Type 1 diabetes over 52 weeks (EASE-2)

A.3.2

Name or abbreviated title of the trial where available

EASE-2

A.4.1

Sponsor's protocol code number

1245.69

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	Boehringer Ingelheim Ltd
B.1.3.4	Country	United Kingdom
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	Boehringer Ingelheim Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	49800243 0127
B.5.5	Fax number	49800821 7119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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	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.3.4	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.3.9.2	Current sponsor code	BI 10773
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	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	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.3.4	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.3.9.2	Current sponsor code	BI 10773
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.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

Type 1 diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Type 1 diabetes

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10067584
E.1.2	Term	Type 1 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 assess the efficacy of empagliflozin in patients with T1DM as adjunctive to insulin therapy

E.2.2

Secondary objectives of the trial

To assess the safety and tolerability of empagliflozin in patients with T1DM as adjunctive to insulin therapy

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated written informed consent by the date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation

2. Male or female patient receiving insulin for the treatment of documented diagnosis of T1DM for at least 1 year at the time of Visit 1

3. Fasting C-peptide value of < 0.7 ng/mL (0.23 nmol/L) at Visit 2 measured by the central laboratory

4. Use of, and be willing, based on the Investigator's judgement, to continue throughout the duration of the trial, either:
- MDI of insulin consisting of at least one basal insulin injection and at least three daily
bolus injections OR
- CSII of any insulin type, with at least 5 months experience of using CSII prior to Visit 1

For both MDI and CSII, the total daily insulin dose must be ≥ 0.3 U/kg and ≤ 1.5 U/kg at Visit 1

5. HbA1c ≥ 7.5% and ≤ 10.0% at Visit 5 measured by the central laboratory, and provided that the patient's HbA1c does not increase by > 0.5% between Visit 1 and Visit 5

6. Based on the Investigator's judgement patient must have a good understanding of his/her disease and how to manage it, and be willing and capable of performing the following study assessments (assessed at Visits 1-5 and just before randomisation):
- patient-led management and adjustment of insulin therapy
- reliable approach to insulin dose adjustment for meals, such as carbohydrate counting
- reliable and regular home-based blood glucose monitoring
- recognise the symptoms of DKA, and reliably monitor for ketones
- implementation of an established "sick day" management regimen

7. Age ≥ 18 years at Visit 1

8. Body Mass Index (BMI) of ≥ 18.5 kg/m2 at Visit 1

9. eGFR ≥ 30 mL/min/1.73 m² as calculated by the CKD-EPI formula, based on creatinine measured by the central laboratory at Visit 1

10. Women of child-bearing potential* must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Such methods should be used throughout the study and the patient must agree to periodic pregnancy testing during participation in the trial. A list of contraceptive methods meeting these criteria will be provided in the patient information

*Women of child-bearing potential are defined as follows:
Any female who has experienced menarche and is not post-menopausal (defined as at least 12 months with no menses without an alternative medical cause) or who is not permanently sterilised (e.g. hysterectomy, bilateral oophorectomy or bilateral salpingectomy)

11. Compliance with trial medication administration must be between 80% and 120% during the open-label placebo run-in period (see Section 4.1.8.1 for calculation of compliance), to be judged before randomisation

Additional inclusion criteria may apply

E.4

Principal exclusion criteria

1. History of T2DM, maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis

2. Pancreas, pancreatic islet cells or renal transplant recipient

3. T1DM treatment with any other antihyperglycaemic drug (e.g. metformin, alphaglucosidase inhibitors, glucagon-like-peptide 1 (GLP-1) analogues, SGLT-2 inhibitors, pramlintide, inhaled insulin, pre-mixed insulins etc.) except subcutaneous basal and bolus insulin within 3 months prior to Visit 1 or any history of clinically relevant hypersensitivity according to Investigator's judgement

4. Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months prior to Visit 1 and until randomisation

5. Occurrence of DKA within 3 months prior to Visit 1 and until randomisation

6. Irregular sleep/wake cycle (e.g. patients who habitually sleep during the day and work during the night) based on Investigator's judgement

7. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischaemic attack (TIA) within 3 months prior to Visit 1

8. Diagnosis of severe gastroparesis (based on Investigator's judgement)

9. Diagnosis of brittle diabetes based on Investigator judgement

10. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 or Visit 5 as measured by the central laboratory

11. Eating disorders such as bulimia or anorexia nervosa

12. Treatment with anti-obesity drugs, weight-loss surgery or aggressive diet regimen leading to unstable body weight (based on Investigator's judgement) 3 months prior to Visit 1 and until randomisation

13. Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1
and until randomisation. Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary disease) is acceptable

14. Change in dose of thyroid hormones within 6 weeks prior to Visit 1 or planned change or
initiation of such a therapy at Visit 1 and until randomisation

15. Patient is unwilling, based on the Investigator's judgement, to avoid use of paracetamol (acetaminophen) containing drugs throughout the CGM monitoring periods, since this may falsely raise CGM glucose readings

16. Medical history of cancer or treatment for cancer in the last five years prior to Visit 1. Resected basal cell carcinoma considered cured is exempted

17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia) at Visit 1

18. Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial

19. Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation based on Investigator's judgement

20. Intake of an investigational drug in another trial within 30 days prior to Visit 1

21. Patient not able to understand and comply with study requirements, including the use of
an e-diary, based on Investigator's judgement

22. Any other clinical condition that, based on Investigator's judgement, would jeopardise patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections etc.)

Additional exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

1: Change from baseline in HbA1c

E.5.1.1

Timepoint(s) of evaluation of this end point

1: 26 weeks

E.5.2

Secondary end point(s)

1: Incidence rate of symptomatic hypoglycaemic AEs with confirmed plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe hypoglycaemic AEs per patient-year.

2: Incidence rate of symptomatic hypoglycaemic AEs with confirmed
plasma glucose < 54 mg/dL (< 3.0 mmol/L) and/or severe
hypoglycaemic AEs per patient-year

3: Change from baseline in body weight (kg)

4: Change from baseline in the percentage of time spent in target glucose range of > 70 to ≤ 180 mg/dL (> 3.9 to ≤ 10.0 mmol/L) as determined by continuous glucose monitoring (CGM)

5: Change from baseline in the inter quartile range (IQR) as determined by CGM

6: Change from baseline in total daily insulin dose (TDID), U/kg

7: Change from baseline in systolic blood pressure (SBP)

8: Change from baseline in diastolic blood pressure (DBP)

E.5.2.1

Timepoint(s) of evaluation of this end point

1: weeks 5 to 26

2: weeks 1 to 26

3: 26 weeks

4: weeks 23 to 26

5: weeks 23 to 26

6: 26 weeks

7: 26 weeks

8: 26 weeks

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

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

Yes

E.8.2.3.1

Comparator description

Dose Comparison

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

Australia

Austria

Belgium

Canada

Czech Republic

Denmark

Finland

France

Germany

Netherlands

Norway

Poland

Spain

Sweden

Taiwan

United Kingdom

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

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

Number of subjects for this age range:

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:

576

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

144

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

486

F.4.2.2

In the whole clinical trial

720

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Diabetes Research Network
G.4.3.4	Network Country	United Kingdom

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-23

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