Diabetes Prevention - Immune Tolerance

Phase 2

Completed

Conditions: Prediabetes
Type 1 Diabetes

Interventions: Other: Placebo comparator
Drug: Diamyd

Registration Number: NCT01122446

Lead Sponsor: Lund University

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

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

Exclusion Criteria

Ongoing treatment with immunosuppressant therapy (topical or inhaled steroids are accepted).
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, 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.
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.
Significant illness other than diabetes within 2 weeks prior to first dosing.
Known human deficiency virus (HIV) or hepatitis.
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.
Diabetes-protective HLA-DQ6-genotype.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo comparator	Placebo comparator	Two doses of placebo day 1 and 30
Alum-GAD (Diamyd)	Diamyd	20 microgram Diamyd day 1 and 30

Primary Outcome Measures

Name	Time	Method
Adverse Events	During 5 years follow up from treatment	Adverse events, serious adverse events, hematology, chemistry, autoantibody titles by treatment group

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Type 1 Diabetes	During 5 years follow up from treatment	Onset of Type 1 diabetes, defined according to ADA criteria, by treatment
Fasting Glucose Over Time	During 5 year follow-up from treatment	Fasting glucose is measured at baseline and every 6 months within the study. Glucose is analysed by Hemocue.
120 Min C-peptide on OGTT Over Time	During 5 year follow-up from treatment	OGTT is performed at baseline, after 6 months and thereafter annually
First-phase Insulin Response From IvGTT Over Time	During 5 year follow-up from treatment	As secondary variables of effect we will measure the change in first-phase insulin response. In all children a baseline IvGTT is performed and after that annual IvGTT´s are performed within the study. First phase insulin response is calculated from insulin 1 and 3 minutes after the given glucose solution. Insulin is measured by Laboratory of Clinical Chemistry at Skåne University Hospital, Malmö. Change in first phase insulin response will be calculated for each individual and compared between the groups.
AUC Glucose From OGTT Over Time	During 5 year follow-up from treatment	OGTT is performed at baseline, after 6 months and thereafter annually.
Fasting C-peptide Over Time	During 5 year follow-up from treatment	Fasting C-peptide is performed at baseline and thereafter every 6 months
120 Minutes Glucose From OGTT Over Time	During 5 year follow-up from treatment	OGTT is performed at baseline, after 6 months and thereafter annually. Children meeting the primary endpoint type 1 diabetes are not included in the analysis - therefore the number of analysed children drops during follow-up.
AUC C-peptide From OGTT Over Time	During 5 year follow-up from treatment	OGTT is performed at baseline, after 6 months and thereafter annually
HbA1c	During 5 year follow-up	At all visits in the study HbA1c is measured. The change in HbA1c from baseline HbA1c is analysed at Laboratory of Clinical Chemistry, Skåne University Hospital, Malmö