Clinical Trials Register

Summary
EudraCT Number:	2014-001323-76
Sponsor's Protocol Code Number:	EDCR_IIa
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-06-05
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

Sweden - MPA

A.2

EudraCT number

2014-001323-76

A.3

Full title of the trial

Open Label trial to evaluate the tolerability of a combination therapy consisting of GAD-alum (Diamyd®), etanercept and vitamin D in children and adolescents newly diagnosed with type 1 diabetes

A.3.1

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

Study to evaluate the tolerability of a combination therapy consisting of GAD-alum (Diamyd®), etanercept and vitamin D in children and adolescents newly diagnosed with type 1 diabetes

A.3.2

Name or abbreviated title of the trial where available

EDCR (Etanercept Diamyd Combination Regimen)

A.4.1

Sponsor's protocol code number

EDCR_IIa

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	Linköping University
B.1.3.4	Country	Sweden
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	Linköping University, County Council, Östergötland, Diamyd
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	Linköping University
B.5.2	Functional name of contact point	Johnny Ludvigsson
B.5.3	Address:
B.5.3.1	Street Address	Div of Pediatrics, Linköping University
B.5.3.2	Town/ city	Linköping
B.5.3.3	Post code	SE-581 85
B.5.3.4	Country	Sweden
B.5.6	E-mail	johnny.ludvigsson@liu.se

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	No
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	Diamyd
D.3.2	Product code	rhGAD65 formulated in alum (GAD-alum)
D.3.4	Pharmaceutical form	Suspension 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	No INN proposed, rhGAD65 formulated in alum (GAD-alum)
D.3.9.3	Other descriptive name	RHGAD65; Diamyd
D.3.9.4	EV Substance Code	SUB32062
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	30 to 50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	Yes
D.3.11.13.1	Other medicinal product type	immunomodulator
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	Enbrel 25 mg pulver och vätska till injektionsvätska, lösning
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	Enbrel 25 mg pulver och vätska till injektionsvätska, lösning
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	ETANERCEPT
D.3.9.1	CAS number	185243-69-0
D.3.9.4	EV Substance Code	SUB01984MIG
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	No
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.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	D-vitamin, Olja ACO orala droppar, lösning
D.2.1.1.2	Name of the Marketing Authorisation holder	ACO HUD NORDIC AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	D-vitamin, Olja ACO 80 IE per droppe, orala droppar, lösning
D.3.4	Pharmaceutical form	Oral drops
D.3.4.1	Specific paediatric formulation	Yes
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	KOLEKALCIFEROL (D3)
D.3.9.3	Other descriptive name	VITAMIN D
D.3.9.4	EV Substance Code	SUB129580
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	68.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Newly diagnosed Type 1 diabetes (within 100 days)

E.1.1.1

Medical condition in easily understood language

Newly Diagnosed Type 1 diabetes (within 100 days)

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
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

Evaluate the tolerability of a combination therapy with Diamyd, vitamin D and etanercept

E.2.2

Secondary objectives of the trial

Evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Informed consent given by patients and parent(s)/legal guardian(s)
2. Type 1 diabetes according to the ADA classification, diagnosed within the previous 100 days at the time of screening
3. Age 8.00 -17.99 years at time of screening
4. Fasting C-peptide at time of screening ≥0.12 nmol/l
5. Positive for GADA but < 50 000 Units
6. Menarchal females must agree to avoid pregnancy and have a negative urine pregnancy test
7. Immunity against Varicella, either through previous infection or vaccination
8. Patients must follow the Swedish vaccination programme
9. Patients of childbearing potential must agree to using adequate contraception, if sexually active, until 1 year after the last administration of GAD-alum and etanercept. Adequate contraception is as follows:

For females of childbearing potential:

a. oral (except low-dose gestagen (lynestrenol and norestisteron), injectable, or implanted hormonal contraceptives (females)
b. intrauterine device (females)
c. intrauterine system (for example, progestin-releasing coil) (females)
d. vasectomized male (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate)

For males of childbearing potential:

a. Condom (male)

E.4

Principal exclusion criteria

1. Previous or current treatment with immunosuppressant therapy (although topical or inhaled steroids are accepted)
2. Continuous treatment with anti-inflammatory drug (sporadic treatment e.g. because of headache or in connection with fever a few days will be accepted)
3. Treatment with any oral or injected anti-diabetic medications (especially hypoglycemic agents) other than insulin
4. Treatment with Vitamin D, marketed or not, or unwilling to abstain from such medication during the trial
5. A history of hypercalcemia
6. A history of anaemia or significantly abnormal haematology results at screening
7. A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles
8. Clinically significant history of acute reaction to vaccines or other drugs in the past
9. Treatment with any vaccine within 4 months prior to planned first administration of GAD-Alum or planned treatment with vaccine up to 4 months after the last injection with GAD-Alum, including influenza vaccine
10. Participation in other clinical trials with a new chemical entity within the previous 3 months
11. Inability or unwillingness to comply with the provisions of this protocol
12. A history of alcohol or drug abuse
13. A significant illness other than diabetes within 2 weeks prior to first dosing
14. Known human immunodeficiency virus (HIV)
15. Prior or active viral hepatitis B or C infection
16. Females who are lactating or pregnant (for females who have started menstruating the possibility of pregnancy must be excluded by urine βHCG on-site within 24 hours prior to the GAD-Alum and etanercept administration, respectively)
17. Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last GAD-Alum and etanercept administration, respectively
18. Presence of associated serious disease or condition, including active skin infections that preclude subcutaneous injection, which in the opinion of the investigator makes the patient non-eligible for the study.
19. Deemed by the investigator not being able to follow instructions and/or follow the study protocol
20. Active infection, including chronic and local infection or a history of previous tendency to serious infections, recent or ongoing uncontrolled bacterial, viral, fungal or other opportunistic infections, or known infection with active EBV or CMV
21. Hypersensivity to the active substance in Enbrel (etanercept) or other ingredients in Enbrel
22. Active or inactive (latent) tuberculosis (TBC) at screening
23. History of malignancy or significant cardiovascular disease
24. Current or history of leukopenia, anemia and/or thrombocytopeni
25. Liver disease (clinical or hepatic enzymes >3 times the upper limit of normal (ULN))
26. Renal insufficiency (clinical or creatinine >3 times the upper limit of normal (ULN))
27. MS, undefined neurologic condition or known SLE, or anti-nuclear or known double-stranded DNA antibody positivity
28. Arrhythmia
29. Pancreatitis
30. Vitamin D serum levels > 100 nmol/L at screening

E.5 End points

E.5.1

Primary end point(s)

Primary endpoints:
To Evaluate the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period), 9, 15 and 30 (extension study period)

Variables to evaluate tolerability:

• Reactions of the injection site
• Infections
• Occurrence of Adverse Events (AEs)
• Occurrence of Serious Adverse Events
• Physiological and Neurology assessments
• Laboratory measurments (biochemistry and haematology), including Calcium and Vitamin D in serum
• GAD65AB titer (GADA)

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 6, 15 and 30

E.5.2

Secondary end point(s)

Secondary endpoints:
To evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion at at Month 6 (main study Period), 9, 15 and 30 (extension study period)

Variables to evaluate the influence on the immune system:

• Inflammatory markers, especially TNF-alfa, IL-1 beta, IL-2, IL-17
• Th2-deviation of cell-mediated immune response seen e.g. as increased ratio of IL-5,10, 13 in comparison with IFN-gamma, TNF-alfa, IL-1 beta and IL-17
• Increase of T-regulatory cells

Variables to evaluate the effect of endogenous insulin secretion:

• C-peptide (90 minute value and AUCmean 0-120 min) during an MMTT
• Proportion of patients with a stimulated maximum C-peptide level above 0.2 nmol/L
• Fasting C-peptide
• Hemoglobin A1c (HbA1c)
• Exogenous insulin dose per kg body weight and 24 hours

E.5.2.1

Timepoint(s) of evaluation of this end point

Month 6, 15 and 30

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

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)

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

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

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

Last visit of last subject and all data have been collected

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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)

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

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.4.2.2

In the whole clinical trial

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

2014-11-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-08-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-25

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