Clinical Trials Register

Summary
EudraCT Number:	2016-002212-41
Sponsor's Protocol Code Number:	ESR-15-11453
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:	2016-08-04
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

Germany - BfArM

A.2

EudraCT number

2016-002212-41

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-controlled, Single-center Phase 1 Inpatient Pilot Study to Explore the Safety and Efficacy of DAPAglifozin as Add-on to day and night closed-loop control using the DreaMed Substance Administration Device Software in Adolescent and Adult Subjects with Type 1 Diabetes mellitus

Randomisierte, doppel-blinde, Plazebo-kontrollierte, monozentrische, Phase 1-Studie zur Untersuchung der Sicherheit und Wirksamkeit von Dapagliflozin als Zusatztherapie zu einem closed loop System (tagsüber und nachts) unter der Kontrolle des automatisierten DreamMed Systems bei jugendlichen und erwachsenen Patienten mit Typ 1 Diabetes mellitus.

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

DapaDream

A.4.1

Sponsor's protocol code number

ESR-15-11453

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	Stiftung Hannoversche Kinderheilanstalt, Kinder - und Jugendkrankenhaus AUF DER BULT, Diabeteszentrum für Kinder - und J
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	Astra Zeneca
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	Stiftung Hannoversche Kinderheilanstalt, Kinder - und Jugendkrankenhaus AUF DER BULT, Diabeteszentrum für Kinder - und J
B.5.2	Functional name of contact point	Deputy Principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Janusz-Korczak-Allee 12
B.5.3.2	Town/ city	Hannover
B.5.3.3	Post code	30173
B.5.3.4	Country	Germany
B.5.4	Telephone number	004951181153344
B.5.5	Fax number	00495118115993344
B.5.6	E-mail	biester@hka.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 AB
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Forxiga
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.3.9.3	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.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

Type 1 Diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Type 1 Diabetes mellitus in adults and adolescents

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The purpose of the pilot study is to collect clinical data of a single-dose of 10mg dapagliflozin as add-on to night and day closed-loop control using the DreaMed Algorithm on the time within glucose range 70-180 mg/dl (3.9-10mmol/l) [%] for the ensuing 24 hours with two oral mixed-meals.

E.2.2

Secondary objectives of the trial

• To investigate the degree of insulin dose reduction during the DreaMed automated insulin delivery 24 hours after a single dose of 10mg dapagliflozin in patients with type 1 diabetes
• To investigate the effect on urinary glucose excretion
• To investigate if dapagliflozin influences postprandial insulin need
• To investigate if dapagliflozin is associated with elevated ß-hydroxybutyrate levels
• One extra sample will be taken potentially for additional analysis of the incretin axis (for example GIP) in case that elevated β-Hydroxyburate levels need to be elucidated further

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female aged 12-21 years (both inclusive)
2. Type 1 diabetes mellitus (as diagnosed clinically) ≥ 12 months
3. No DKA 12 weeks prior to the study
4. On CSII (insulin pump therapy) since at least 3 months
5. Average daily dose of Insulin between 0.6 – 2.0 U/kg
6. Body mass index 18 to 35 kg/m2 or the 10th to 99th centile for BMI according to age and gender with a minimum weight of 50kg
7. A1c range 6,5% – 11% (inclusive)

E.4

Principal exclusion criteria

1. Anamnestic history of hypersensitivity to the study drugs (or any component of the study drug) or to drugs with similar chemical structures
3. History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.1 mg/dl in women and > 1.5 mg/dl in men), neurological, psychiatric and/or hematological disease as judged by the investigator
9. Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study
10. History of T2DM, maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis
11. Any use of oral hypoglycemic agents within 12 months prior to the screening visit
12. History of diabetes ketoacidosis (DKA) within 12 weeks prior to prior to the screening visit
13. History of diabetes insipidus
14. History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 3 months prior to prior to the screening visit
15. Frequent episodes of hypoglycemia as defined by more than one episode requiring assistance, emergency care (paramedics or emergency room care) or glucagon therapy, or more than 2 unexplained episodes of symptomatic hypoglycemia within 3 months prior to the screening visit. 16. Hypoglycemic unawareness
History of Addison’s disease or chronic adrenal insufficiency
18. Aspartate aminotransferase (AST) > 2X Upper limit of normal (ULN)
19. Alanine aminotransferase (ALT) > 2X ULN
20. Serum total bilirubin > 2X ULN
21. Estimated GFR (eGFR) by the Modification of Diet in Renal Disease (MDRD)
24. Hemoglobin ≤ 11.0 g/dl (110 g/l) for boys / men; hemoglobin ≤10.0 g/dl (100 g/L) for girls / women.
25. Creatine kinase (CK) > 3X ULN
27. Abnormal Free T4 Note: abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded. A one-time retest may be allowed, as determined by the Investigator, after a minimum of 6 weeks following the adjustment of thyroid hormone replacement therapy in subject who have had a prior diagnosis of a thyroid disorder and who are currently receiving thyroid replacement therapy. Such cases should be discussed with the Investigator prior to retesting. The subject must have all screening procedures and laboratory assessments performed as part of this re-test, and all of these must meet enrolment eligibility criteria. The subject’s number will, however, remain the same as initially assigned.
28. Allergies or contraindication to the contents of dapagliflozin tablets or insulin
29. Renal, Hepatic, Hemotological/Oncological Diseases/Conditions
30. History of unstable or rapidly progressing renal disease
31. Conditions of congenital renal glucosuria
32. Renal allograft
33. Significant hepatic disease, including but not limited to, chronic active hepatitis and/or severe hepatic insufficiency
34. Documented history of hepatotoxicity with any medication
35. Documented history of severe hepatobiliary disease
36. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis
52. No clinical conditions or clinically significant abnormalities, in any laboratory value(s) collected after screening and prior to randomization which, in the Investigator’s judgment, should preclude entry into the treatment period.
53. Subjects who meet one or more of the dosing day exclusion criteria will be excluded from the dosing visit or withdrawn from the trial as specified below:
54. Non-fasting, ie, consumption of food or beverages other than water, later than at 23:00 hours the evening before dosing.
55. Clinically significant illness with onset within 4 weeks prior to dosing
56. Presence of clinically significant acute gastrointestinal symptoms (eg nausea, vomiting, heartburn or diarrhoea), as judged by the investigator
57. Consumption of alcohol within 24 hours prior to dosing
58. Episode of severe hypoglycemia occurring within the last 24 hours prior to dosing
59. Any medical condition that, in the opinion of the Investigator, could interfere with insulin pharmacokinetics and/or glucose metabolism.
60. Use of the following: systemic (oral or i.v.) corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-selective beta-blockers, growth hormone, non-routine vitamins or herbal products. Furthermore, thyroid hormones are not allowed unless the subject has used stable medication during the past 3 months.
61. Non-adherence to pre-dosing insulin regimen consisting of CSII
62. Subjects who meet one or more of dosing day exclusion criteria will be excluded from the dosing visit. In case a subject is excluded from the dosing visit, the dosing visit can be rescheduled 1–7 days later. Each of the dosing visits can only be rescheduled once.

E.5 End points

E.5.1

Primary end point(s)

Time within glucose range 70-180 mg/dl (3.9-10mmol/l) [%] during night and day closed-loop control using the DreaMed automated insulin delivery with two oral mixed-meals after oral administration of 10mg dapagliflozin

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 2 and visit 4

E.5.2

Secondary end point(s)

• Percentage of glucose sensor readings below 70 mg/dl (3.9 mmol/l)
• Percentage of glucose sensor readings above 180mg/dl (10 mmol/l)
• Average and SD of glucose sensor readings
• Percentage of elevated ß-hydroxybutyrate-levels in blood
• Insulin need during the DreaMed automated insulin delivery

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 2 and Visit 4

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

PK in adolescents (off label)

E.7.2

Therapeutic exploratory (Phase II)

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

Yes

E.8.1.6

Cross over

Yes

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

After 30 subjects have completed visit 6.
Certain circumstances may lead to early termination of an entire study, in particular for ethical or safety reasons such as:
- The high frequency and/or unexpected severity of adverse events.
- Unsatisfactory recruitment of patients as far as their quantity or quality is concerned or recurrent incomplete/inappropriate collection of data.
The decision to prematurely terminate the study will be made by the Sponsor.

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

Yes

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

under age 18 - adolescents

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)

Visit 6, the follow-up visit will take place 7–21 days after the end of Visit 4. Last Treatment occured in visit 4. Visit 5 is a phone call (3-5 days after treatment has stopped) to follow up in regards to safety and finally vist 6 takes place.

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

2016-09-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-19

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