Clinical Trials Register

Summary
EudraCT Number:	2014-001417-79
Sponsor's Protocol Code Number:	DIAGNODE-1
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:	2014-07-02
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

Sweden - MPA

A.2

EudraCT number

2014-001417-79

A.3

Full title of the trial

Open Label Pilot Trial in patients with recent-onset T1D to evaluate the safety, diabetes status and immune response of GAD-antigen (Diamyd®) therapy administered into lymph nodes in combination with an oral vitamin D regimen

A.3.1

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

Trial to evaluate the safety and diabetes status in patients with recent-onset Type 1 diabetes by giving GAD-antigen (Diamyd®) therapy into lymph NODEs in combination with an oral Vitamin D regimen

A.3.2

Name or abbreviated title of the trial where available

DIAGNODE-1

A.4.1

Sponsor's protocol code number

DIAGNODE-1

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 Medical AB, Other applications TBD, e.g BDF, Vinnova etc
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	Intralymphatic 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	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	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
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	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

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

E.1.1.1

Medical condition in easily understood language

Type 1 diabetes

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	20.0
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 safety of giving Diamyd directly into lymph glands in combination with an oral vitamin D regimen
• Evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title: Prolonged Extension Study Period for study DIAGNODE-1 - Open Label Pilot Trial in patients with recent-onset T1D to evaluate the safety, diabetes status and immune response of GAD-antigen (Diamyd®) therapy administered into lymph nodes in combination with an oral vitamin D regimen
Date: 2018-04-05
Subjects: The sub-study will include 3 adult patients from the main study.
Objective:
• To evaluate safety after a fourth injection with 4 µg GAD-Alum direct into an inguinal lymph gland
• To evaluate how the above mentioned treatment influences the immune system and endogenous insulin secretion.

E.3

Principal inclusion criteria

1. Informed consent given by patients and/or patient’s parent (s) or legal acceptable representative(s) (guardian(s)) according to national regulations
2. Type 1 diabetes according to the ADA classification with < 6 months diabetes duration
3. Age 12.00-29.99 years at diagnosis of Type 1 diabetes
4. Fasting C-peptide ≥0.12 nmol/L
5. Pos GADA but < 50 000 random units
6. Females must agree to avoid pregnancy and have a negative urine pregnancy test
7. Patients of childbearing potential must agree to using adequate contraception, until 1 year after the last administration of GAD-Alum. Adequate contraception is as follows:

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

For males of childbearing potential:
e. 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 any 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 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 anaemia or significantly abnormal haematology results at screening
6. A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles
7. Clinically significant history of acute reaction to vaccines or other drugs in the past
8. Treatment with any vaccine, including influenza vaccine, within 4 months prior to planned first study drug dose or planned treatment with any vaccine up to 4 months after the last injection with study drug.
9. Participation in other clinical trials with a new chemical entity within the previous 3 months
10. Inability or unwillingness to comply with the provisions of this protocol
11. A history of alcohol or drug abuse
12. A significant illness other than diabetes within 2 weeks prior to first dosing
13. Known human immunodeficiency virus (HIV) or hepatitis
14. Females who are lactating or pregnant (the possibility of pregnancy must be excluded by urine βHCG on-site within 24 hours prior to the GAD-Alum treatment)
15. Males or females not willing to use adequate contraception until 1 year after the last GAD-Alum treatment
16. 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
17. Deemed by the investigator not being able to follow instructions and/or follow the study protocol

E.5 End points

E.5.1

Primary end point(s)

Primary endpoints:
To evaluate the safety of giving Diamyd directly into lymph glands in combination with an oral vitamin D regimen at Month 6 (main study period) and Month 15 and 30 (extension study period).

Variables to evaluate safety:
• Reactions of the injection site
• Occurrence of adverse events (AEs)
• Laboratory measurements (biochemistry and haematology), including Calcium and Vitamin D in serum
• Urinalysis (microalbuminuria, creatinine)
• Physical examinations, including neurological assessments
• 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 from baseline to Month 6 (main study period) and subsequent visits during the 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)
• 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)

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

First adminstration in lymph nodes

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

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

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

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

2014-08-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-10-08

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