Prevention Trial: Immune-tolerance With Alum-GAD (Diamyd) and Vitamin D3 to Children With Multiple Islet Autoantibodies

Study Overview
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Brief Summary
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The purpose of this study is to evaluate if immune-tolerance with Alum-formulated GAD (Diamyd), in combination with high dose Vitamin D3, may delay or stop the autoimmune process leading to clinical type 1 diabetes in non-diabetic children with ongoing beta-cell autoimmunity as indicated by positive islet autoantibodies.

Detailed Description
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The primary objective of this study is to evaluate if immune-tolerance with Alum-formulated GAD (Diamyd), combined with high dose Vitamin D3, may delay or stop the autoimmune process leading to clinical type 1 diabetes (diagnosed according to American Diabetes Association criteria) in non-diabetic 4-17.99 year old children with ongoing beta-cell autoimmunity as indicated by positive islet autoantibodies. The secondary objective is to demonstrate that treatment with Diamyd is safe in children at risk for type 1 diabetes. The children will be followed for 5 years in the study. Primary endpoint is proportion of subjects diagnosed with type 1 diabetes in each treatment arm. Secondary endpoints are 1) safety, 2) change in metabolic status from normal to impaired glucose metabolism in the group of children with normal glucose metabolism at baseline screening.

Official Title
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Double-blind, Investigator-initiated Study to Determine the Effect of Alum-GAD (Diamyd) in Combination With Vitamin D3 on the Progression to Type 1 Diabetes in Children With Multiple Islet Autoantibodies

Conditions
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Diabetes Mellitus, Type 1, Prediabetic State

Intervention / Treatment
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* Drug: Alum-GAD
* Drug: Vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 4-17.99 years of age with positive autoantibodies to glutamate decarboxylase (GADA) and at least one additional type 1 diabetes associated autoantibody (to insulinoma associated protein 2 (IA-2A), Zinktransporter 8 (ZnT8R/Q/WA) or insulin (IAA)). Written informed consent from the child and the childs legal representative(s). Exclusion Criteria: Ongoing treatment with immunosuppressant therapy. Diabetes. Treatment with any oral or injected anti-diabetic medications Significantly abnormal hematology results at screening. Clinically significant history of acute reaction to vaccines or other drugs Treatment with any vaccine within one month prior to the first dose of the study drug or planned treatment with vaccine up to three months after the last injection with the study drug. A history of epilepsy, serious head trauma or cerebrovascular accident, or Clinical features of continuous motor unit activity in proximal muscles Participation in other Clinical trials with a new chemical entity within the previous 3 months. History of hypercalcemia. Unwilling to abstain from other medication with Vitamin D during the study period. Significant illness within 2 weeks prior to first dosing. Known Human Immuno Deficiency Virus infection or hepatitis. Presence of associated serious disease or condition. Diabetes-protective Human Leucocyte Antigen (HLA) DQ6. Females who are lactating or pregnant. Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last Diamyd administration.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alum-GAD, Vitamin D3<br>Two doses à 20 microgram of subcutaneous alum-GAD (Diamyd), 30 Days apart. Vitamin D 2000 U/Daily with start 30 days before the first injection of Diamyd. Vitamin D treatment will continue throughout the whole study period of 5 years. | Drug: Alum-GAD<br>* Two doses à 20 microgram 30 days apart subcutaneously administrated<br>* Other names: Alumformulated GAD;Drug: Vitamin D3<br>* 2000 Units (IE) (50 microgram) vitamin D3 daily<br>* Other names: Cholecalciferol;|
| Placebo Comparator: Placebo, Vitamin D3<br>Two doses of subcutaneous placebo, 30 Days apart. Vitamin D 2000 U/Daily with start 30 days before the first injection of Diamyd. Vitamin D treatment will continue throughout the whole study period of 5 years | Drug: Vitamin D3<br>* 2000 Units (IE) (50 microgram) vitamin D3 daily<br>* Other names: Cholecalciferol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type 1 Diabetes Month 24 | Number of patients diagnosed with type 1 diabetes according to ADA (American Diabetes Association) criteria in each study arm month 24 | 24 months | 
| Type 1 Diabetes Status Overall | Number of patients diagnosed with type 1 diabetes according to ADA (American Diabetes Association) criteria in each study arm overall. Including one patient diagnosed shortly after the month 24 visit. | Over the entire study period up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | Change in metabolic status from normal to impaired glucose metabolism during follow-up in the group of children with normal glucose metabolism at baseline screening. Impaired glucose metabolism is defined as a) fasting plasma glucose 6.1 mmol/L or more, b) maximum plasma glucose 30, 60, 90 min during oral glucose tolerance test (OGTT) 11.1 mmol/L or more, c) 120 min plasma glucose on OGTT 7.8 mmol/L or more, d) HbA1c 39 mmol/L or more. | During 18 months follow-up | 
| Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | Number of patients who have progression from already impaired glucose metabolism from one or several criteria to additional signs of reduced glucose metabolism (within children with impaired glucose metabolism at screening). Impaired glucose metabolism is defined as a) fasting plasma glucose 6.1 mmol/L or more, b) maximum plasma glucose 30, 60, 90 min during oral glucose tolerance test (OGTT) 11.1 mmol/L or more, c) 120 min plasma glucose on OGTT 7.8 mmol/L or more, d) HbA1c 39 mmol/L or more. | During 18 months follow-up | 
| Injection Site Reactions Day 1 | Number of patients experiencing injection site reactions at day 1 | Day 1 | 
| Injection Site Reactions Month 1 | Number of patients experiencing injection site reactions at month 1 | Month 1 | 
| Change From Baseline in GADA Month 1 | Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers | Month 1 | 
| Change From Baseline in GADA Month 12 | Change from baseline to month 12 in GADA titers | Month 12 | 
| Change From Baseline in GADA Month 24 | Change from baseline to month 24 in GADA titers | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Islet autoantibodies, glutamate decarboxylase autoantibodies (GADA), Immune tolerance, Prediabetes, Glucose tolerance, glutamate decarboxylase, Prevention, Children