GAD-Alum (Diamyd) Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes (DIAGNODE-1) (DIAGNODE)

• ClinicalTrials.gov Identifier: NCT02352974
• Recruitment Status: Completed
• First Posted: February 2, 2015
• Results First Posted: April 27, 2020
• Last Update Posted: April 27, 2020
• Sponsor: Johnny Ludvigsson
• Collaborators: Swedish Child Diabetes Foundation; Ostergotland County Council, Sweden; Diamyd Medical AB
• Information provided by (Responsible Party): Johnny Ludvigsson, Linkoeping University

Study Description

Brief Summary:

The objectives of the main study is to:

• Evaluate the safety of giving GAD-Alum (Glutamic acid decarboxylase) (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.

The objective of the sub-study is to:

• Evaluate safety after a fourth injection with 4 μg GAD-Alum direct into an inguinal lymph gland in 3 adult patients from the main study
• Evaluate how the above mentioned treatment influences the immune system and endogenous insulin secretion.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: GAD-Alum; Drug: Vitamin D	Phase 1

Detailed Description:

Eligible patients will be treated with 4 µg GAD-Alum into an inguinal lymph gland at three occasions, with one month intervals in combination with Vitamin D (14 000 IU/week) for 4 months, starting 1 month prior to first GAD-Alum injection.

A sub-study will include three adult patients from the main study and evaluate safety after a fourth injection with 4 μg GAD-Alum into an inguinal lymph gland in combination with oral vitamin D intake. The Prolonged Extension Study Period is 12 months and will start 30,5 months after baseline.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Pilot Trial in Adults 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
• Study Start Date: January 2015
• Actual Primary Completion Date: October 2019
• Actual Study Completion Date: October 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: GAD-Alum+Vitamin D; GAD-Alum (Diamyd) injected into Lymph Nodes Dosage and interval: One injection of 4 µg Diamyd will be administered into the lymph nodes at three occasions, with one month intervals Vitamin D (Calciferol) in oral solution. Dosage and interval: 2000 IU daily for 120 days	Drug: GAD-Alum; Other Name: Diamyd; Drug: Vitamin D; Other Name: Calciferol

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects With Injection Site Reactions Month 1 [ Time Frame: Month 1 ]
   Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
2. Number of Subjects With Injection Site Reactions Month 2 [ Time Frame: Month 2 ]
   Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
3. Number of Subjects With Injection Site Reactions Month 3 [ Time Frame: Month 3 ]
   Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
4. Number of Subjects With Injection Site Reactions Month 32 [ Time Frame: Month 32, extension period ]
   Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)

Secondary Outcome Measures :

1. Mean Change in C-peptide AUC (Area Under the Curve) (Mean 120min) Value, Month 15 [ Time Frame: Baseline to month 15 at 0, 30, 60, 90, 120 minutes post-dose ]

   Change from baseline to month 15 in C-peptide AUC (Area Under the Curve) (mean 120min) value

   AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration

2. Mean Change in C-peptide AUC(Mean 120min) Value, Month 30 [ Time Frame: Baseline to month 30 at 0, 30, 60, 90, 120 minutes post-dose ]

   Change from baseline to month 30 in C-peptide AUC(mean 120min) value

   AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration

3. Mean Change in C-peptide AUC(Mean 120min) Value, Month 43 [ Time Frame: Baseline to month 43, extension period at 0, 30, 60, 90, 120 minutes post-dose ]

   Change from baseline to month 43 in C-peptide AUC(mean 120min) value

   AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration

4. Mean Change in C-peptide 90-minute Value, Month 15 [ Time Frame: Baseline to month 15 ]
   Change from baseline to month 15 in C-peptide 90-minute value
5. Mean Change in C-peptide 90-minute Value, Month 30 [ Time Frame: Baseline to month 30 ]
   Change from baseline to month 30 in C-peptide 90-minute value
6. Mean Change in C-peptide 90-minute Value, Month 43 [ Time Frame: Baseline to month 43, extension period ]
   Change from baseline to month 43 in C-peptide 90-minute value
7. Mean Change in Fasting C-peptide Value, Month 15 [ Time Frame: Baseline to month 15 ]
   Change from baseline to month 15 in fasting C-peptide value
8. Mean Change in Fasting C-peptide Value, Month 30 [ Time Frame: Baseline to month 30 ]
   Change from baseline to month 30 in fasting C-peptide value
9. Mean Change in Fasting C-peptide Value, Month 43 [ Time Frame: Baseline to month 43, extension period ]
   Change from baseline to month 43 in fasting C-peptide value
10. Mean Change in HbA1c, Month 15 [ Time Frame: Baseline to month 15 ]
    Change from baseline to month 15 in HbA1c
11. Mean Change in HbA1c, Month 30 [ Time Frame: Baseline to month 30 ]
    Change from baseline to month 30 in HbA1c
12. Mean Change in HbA1c, Month 43 [ Time Frame: Baseline to month 43, extension period ]
    Change from baseline to month 43 in HbA1c
13. External Insulin Dose, Baseline [ Time Frame: Baseline ]
    External insulin dose at baseline
14. External Insulin Dose, Month 15 [ Time Frame: Month 15 ]
    External insulin dose at month 15
15. External Insulin Dose, Month 30 [ Time Frame: Month 30 ]
    External insulin dose at month 30
16. External Insulin Dose, Month 43 [ Time Frame: Month 43, extension period ]
    External insulin dose at month 43
17. Mean IDAA1c Values, Baseline [ Time Frame: Baseline ]
    Insulin dose-adjusted HbA1c (IDAA1c)
18. Mean IDAA1c Values, Month 15 [ Time Frame: Month 15 ]
    Insulin dose-adjusted HbA1c (IDAA1c)
19. Mean IDAA1c Values, Month 30 [ Time Frame: Month 30 ]
    Insulin dose-adjusted HbA1c (IDAA1c)
20. Mean IDAA1c Values, Month 43 [ Time Frame: Month 43, extension period ]
    Insulin dose-adjusted HbA1c (IDAA1c)

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Informed consent given by patients
2. Type 1 diabetes according to the ADA (American Diabetes Association) 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(Antibodies to GAD with molecular mass 65,000) 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.

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 (beta-human chorionic gonadotropin) 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

Contacts and Locations

Locations

Sweden

Linköping University

Linköping, Sweden

Sponsors and Collaborators

Johnny Ludvigsson

Swedish Child Diabetes Foundation

Ostergotland County Council, Sweden

Diamyd Medical AB

Investigators

• Principal Investigator: Johnny Ludvigsson, Professor; Linkoeping University

  Study Documents (Full-Text)

Documents provided by Johnny Ludvigsson, Linkoeping University:

Study Protocol and Statistical Analysis Plan  [PDF] June 11, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Casas R, Dietrich F, Barcenilla H, Tavira B, Wahlberg J, Achenbach P, Ludvigsson J. Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients. Front Immunol. 2020 Oct 9;11:564921. doi: 10.3389/fimmu.2020.564921. eCollection 2020.

Tavira B, Barcenilla H, Wahlberg J, Achenbach P, Ludvigsson J, Casas R. Intralymphatic Glutamic Acid Decarboxylase-Alum Administration Induced Th2-Like-Specific Immunomodulation in Responder Patients: A Pilot Clinical Trial in Type 1 Diabetes. J Diabetes Res. 2018 May 24;2018:9391845. doi: 10.1155/2018/9391845. eCollection 2018.

• Responsible Party: Johnny Ludvigsson, MD, PhD, Professor, Linkoeping University
• ClinicalTrials.gov Identifier: NCT02352974
• Other Study ID Numbers: DIAGNODE-1
• First Posted: February 2, 2015
• Results First Posted: April 27, 2020
• Last Update Posted: April 27, 2020
• Last Verified: April 2020

Keywords provided by Johnny Ludvigsson, Linkoeping University:

Juvenile Diabetes; Diabetes Type 1; Type 1 Diabetes; Insulin Dependent Diabetes; Type 1 Diabetes Mellitus; Diabetes mellitus Type 1; Diamyd; Diabetes; Autoimmune Diabetes; rhGAD65 (Recombinant Human GAD with molecular mass 65,000); GAD65; GAD-Alum; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Vitamin D

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Vitamin D; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents