Diabetes Prevention - Immune Tolerance (DIAPREV-IT)

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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes; Prediabetes
• Intervention / Treatment: Other: Placebo comparator; Drug: Diamyd

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Malmö, Sweden, 205 02
    • Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo comparator; Two doses of placebo day 1 and 30	Other: Placebo comparator; Placebo comparator day 1 and 30 in non-diabetic children with multiple islet autoantibodies. Post diagnosis: Two doses of 20 microgram Diamyd day 1 and 30 in children originally receiving placebo.
ACTIVE_COMPARATOR: Alum-GAD (Diamyd); 20 microgram Diamyd day 1 and 30	Drug: Diamyd; 20 microgram day 1 and 30 in non-diabetic children with multiple islet autoantibodies. Post diagnosis: Two doses of Diamyd followed to children originally receiving Diamyd; Other Names: Alum-GAD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Adverse events, serious adverse events, hematology, chemistry, autoantibody titles by treatment group	During 5 years follow up from treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Type 1 Diabetes	Onset of Type 1 diabetes, defined according to ADA criteria, by treatment	During 5 years follow up from treatment
Fasting Glucose Over Time	Fasting glucose is measured at baseline and every 6 months within the study. Glucose is analysed by Hemocue.	During 5 year follow-up from treatment
120 Minutes Glucose From OGTT Over Time	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.	During 5 year follow-up from treatment
AUC Glucose From OGTT Over Time	OGTT is performed at baseline, after 6 months and thereafter annually.	During 5 year follow-up from treatment
Fasting C-peptide Over Time	Fasting C-peptide is performed at baseline and thereafter every 6 months	During 5 year follow-up from treatment
120 Min C-peptide on OGTT Over Time	OGTT is performed at baseline, after 6 months and thereafter annually	During 5 year follow-up from treatment
AUC C-peptide From OGTT Over Time	OGTT is performed at baseline, after 6 months and thereafter annually	During 5 year follow-up from treatment
HbA1c	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	During 5 year follow-up
First-phase Insulin Response From IvGTT Over Time	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.	During 5 year follow-up from treatment

Collaborators and Investigators

• Sponsor: Lund University
• Collaborators: Region Skane
• Investigators: Principal Investigator: Helena Elding Larsson, MD, PhD, Region Skane and Lund University

Publications and helpful links

General Publications

• Andersson C, Carlsson A, Cilio C, Cedervall E, Ivarsson SA, Jonsdottir B, Jonsson B, Larsson K, Neiderud J, Lernmark A, Elding Larsson H; DiAPREV-IT Study Group. Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study. Pediatr Diabetes. 2013 Aug;14(5):341-9. doi: 10.1111/pedi.12023. Epub 2013 Mar 8.
• Elding Larsson H, Larsson C, Lernmark A; DiAPREV-IT study group. Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention. Acta Diabetol. 2015 Jun;52(3):473-81. doi: 10.1007/s00592-014-0680-1. Epub 2014 Nov 8.
• Elding Larsson H, Lundgren M, Jonsdottir B, Cuthbertson D, Krischer J; DiAPREV-IT Study Group. Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial. Pediatr Diabetes. 2018 May;19(3):410-419. doi: 10.1111/pedi.12611. Epub 2017 Nov 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2009
• Primary Completion (ACTUAL): December 1, 2016
• Study Completion (ACTUAL): December 1, 2016

Study Registration Dates

• First Submitted: May 12, 2010
• First Submitted That Met QC Criteria: May 12, 2010
• First Posted (ESTIMATE): May 13, 2010

Study Record Updates

• Last Update Posted (ACTUAL): May 6, 2019
• Last Update Submitted That Met QC Criteria: May 2, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: prevention; Type 1 diabetes; glucose tolerance; immune tolerance; Alum-GAD; glutamate decarboxylase autoantibodies
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: DIAPREV/2008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No