A double-blind, randomized investigator-initiated study to determine the safety and the effect of Diamyd® on the progression to type 1 diabetes in children with multiple islet cell autoantibodies

Eligible children are 4 years or older, have positive GAD-antibodies and at least one additional autoantibody and not yet diabetes.

Objectives:

DiAPREV-IT is the first prevention study with Diamyd®, where the drug is given before onset of type 1 diabetes.

The primary objective is to demonstrate that Diamyd® is safe in children at risk for type 1 diabetes.

The secondary objective is to evaluate if Diamyd® may delay or stop the autoimmune process leading to clinical type 1 diabetes in children with ongoing persistent beta-cell autoimmunity as indicated by multiple positive islet cell autoantibodies.

A double-blind, randomized investigator-initiated study to determine the safety and the effect of Diamyd® on the progression to type 1 diabetes in children with multiple islet cell autoantibodies

Eligible children are 4 years or older, have positive GAD-antibodies and at least one additional autoantibody and not yet diabetes.

Objectives:

DiAPREV-IT is the first prevention study with Diamyd®, where the drug is given before onset of type 1 diabetes.

The primary objective is to demonstrate that Diamyd® is safe in children at risk for type 1 diabetes.

The secondary objective is to evaluate if Diamyd® may delay or stop the autoimmune process leading to clinical type 1 diabetes in children with ongoing persistent beta-cell autoimmunity as indicated by multiple positive islet cell autoantibodies.

Procedure:

50 children will be randomized to 2 injections of Diamyd® or placebo. In DIAPREV-IT we will use the previously tested dose of 20 µg Diamyd® administered as a prime-and-boost at days 1 and 30, as no serious adverse reactions have been observed with this regimen. The children will be followed every 3rd month for 5 years. Before the first injection of study drug both intravenous (IvGTT) and oral (OGTT) glucose tolerance test will be performed. These will be repeated during the study with OGTT every 6 month visit and IvGTT every full year visit.

Safety variables:

Collection of adverse events, serious adverser events, hematology, chemistry, titles of autoantibodies.

Effect variables:

The cumulative incidence of diabetes onset over time since randomization within each treatment group will be estimated using the Kaplan-Meier method (proportion surviving diabetes-free as a function of time).

Secondary efficacy variables:

Change in first-phase insulin response and K-value on IvGTT from baseline Change in fasting, 120 minutes and AUC C-peptide levels on OGTT Change in fasting, 120 minutes and AUC glucose on OGTT Change in HbA1c from baseline All measures during 5 years follow-up.

Children developing diabetes in the study will be offered to participate in a postdiagnosis protocol. Children who have had two doses of active Diamyd in the main study will be given one additional dose of 20 microgram Diamyd followed by one dose of placebo after 30 days. Children who have had two doses of placebo will be given two doses of 20 microgram Diamyd with 30 days in between. Post diagnosis follow up will proceed for at least 15 months from the first post diagnosis injection with collection of adverse events and metabolic evaluation with Mixed meal tolerance tests.

Inclusion Criteria:

1. Children from four (4) years of age and participating in DiPiS, TEDDY or Trial Net.
2. Positive GAD65Ab and at least one additional type 1 diabetes-associated autoantibody (IA-2Ab, ZnT8R/W/QAb or IAA).
3. Written informed consent from the child and the child's parents or legal acceptable representative(s) according to local regulations.

Exclusion Criteria:

1. Ongoing treatment with immunosuppressant therapy (topical or inhaled steroids are accepted).
2. Diabetes.
3. Treatment with any oral or injected anti-diabetic medications.
4. Significantly abnormal hematology results at screening.
5. Clinically significant history of acute reaction to vaccines or other drugs.
6. Treatment with any vaccine, other than influenza, within one month prior to the first dose of the study drug or planned treatment with vaccine up to two months after the last injection with the study drug.
7. A history of epilepsy, serious head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles.
8. Participation in other clinical trials with a new chemical entity within the previous 3 months.
9. Significant illness other than diabetes within 2 weeks prior to first dosing.
10. Known human deficiency virus (HIV) or hepatitis.
11. Presence of associated serious disease or condition, including active skin infections that preclude subcutaneous injection, which in the opinion of the investigators makes the patient non-eligible for the study.
12. Diabetes-protective HLA-DQ6-genotype.

Adverse events and serious adverse events were recorded during 5 year follow-up.

Limitations: This study was a first study of Alum-GAD in non-diabetic children with multiple islet autoantibodies. The study was small in sample size which may limit the power.