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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Vitamin D; Drug: GAD-Alum

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Linköping, Sweden
    • Linköping University

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Vitamin D; Other Names: Calciferol; Drug: GAD-Alum; Other Names: Diamyd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Injection Site Reactions Month 1	Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)	Month 1
Number of Subjects With Injection Site Reactions Month 2	Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)	Month 2
Number of Subjects With Injection Site Reactions Month 3	Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)	Month 3
Number of Subjects With Injection Site Reactions Month 32	Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)	Month 32, extension period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in C-peptide AUC (Area Under the Curve) (Mean 120min) Value, Month 15	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	Baseline to month 15 at 0, 30, 60, 90, 120 minutes post-dose
Mean Change in C-peptide AUC(Mean 120min) Value, Month 30	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	Baseline to month 30 at 0, 30, 60, 90, 120 minutes post-dose
Mean Change in C-peptide AUC(Mean 120min) Value, Month 43	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	Baseline to month 43, extension period at 0, 30, 60, 90, 120 minutes post-dose
Mean Change in C-peptide 90-minute Value, Month 15	Change from baseline to month 15 in C-peptide 90-minute value	Baseline to month 15
Mean Change in C-peptide 90-minute Value, Month 30	Change from baseline to month 30 in C-peptide 90-minute value	Baseline to month 30
Mean Change in C-peptide 90-minute Value, Month 43	Change from baseline to month 43 in C-peptide 90-minute value	Baseline to month 43, extension period
Mean Change in Fasting C-peptide Value, Month 15	Change from baseline to month 15 in fasting C-peptide value	Baseline to month 15
Mean Change in Fasting C-peptide Value, Month 30	Change from baseline to month 30 in fasting C-peptide value	Baseline to month 30
Mean Change in Fasting C-peptide Value, Month 43	Change from baseline to month 43 in fasting C-peptide value	Baseline to month 43, extension period
Mean Change in HbA1c, Month 15	Change from baseline to month 15 in HbA1c	Baseline to month 15
Mean Change in HbA1c, Month 30	Change from baseline to month 30 in HbA1c	Baseline to month 30
Mean Change in HbA1c, Month 43	Change from baseline to month 43 in HbA1c	Baseline to month 43, extension period
External Insulin Dose, Baseline	External insulin dose at baseline	Baseline
External Insulin Dose, Month 15	External insulin dose at month 15	Month 15
External Insulin Dose, Month 30	External insulin dose at month 30	Month 30
External Insulin Dose, Month 43	External insulin dose at month 43	Month 43, extension period
Mean IDAA1c Values, Baseline	Insulin dose-adjusted HbA1c (IDAA1c)	Baseline
Mean IDAA1c Values, Month 15	Insulin dose-adjusted HbA1c (IDAA1c)	Month 15
Mean IDAA1c Values, Month 30	Insulin dose-adjusted HbA1c (IDAA1c)	Month 30
Mean IDAA1c Values, Month 43	Insulin dose-adjusted HbA1c (IDAA1c)	Month 43, extension period

Collaborators and Investigators

• Sponsor: Johnny Ludvigsson
• Collaborators: Ostergotland County Council, Sweden; Diamyd Medical AB; Swedish Child Diabetes Foundation
• Investigators: Principal Investigator: Johnny Ludvigsson, Professor, Linkoeping University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): October 1, 2019

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): April 27, 2020
• Last Update Submitted That Met QC Criteria: April 15, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Diabetes; Vitamin D; Diabetes Mellitus; Type 1 Diabetes Mellitus; Type 1 Diabetes; Diamyd; Diabetes Type 1; GAD65; GAD-Alum; rhGAD65 (Recombinant Human GAD with molecular mass 65,000); Diabetes mellitus Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Autoimmune Diabetes; Juvenile Diabetes; Insulin Dependent Diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Vitamin D
• Other Study ID Numbers: DIAGNODE-1