Prevention Trial: Immune-tolerance With Alum-GAD (Diamyd) and Vitamin D3 to Children With Multiple Islet Autoantibodies (DiAPREV-IT2)

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

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.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 1; Prediabetic State
• Intervention / Treatment: Drug: Alum-GAD; Drug: Vitamin D3

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• 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 (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

1. Ongoing treatment with immunosuppressant therapy.
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 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.
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. History of hypercalcemia.
10. Unwilling to abstain from other medication with Vitamin D during the study period.
11. Significant illness within 2 weeks prior to first dosing.
12. Known Human Immuno Deficiency Virus infection or hepatitis.
13. Presence of associated serious disease or condition.
14. Diabetes-protective Human Leucocyte Antigen (HLA) DQ6.
15. Females who are lactating or pregnant.
16. Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last Diamyd administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alum-GAD, Vitamin D3; 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; Two doses à 20 microgram 30 days apart subcutaneously administrated; Other Names: Diamyd; GAD-Alum; Alumformulated GAD; Drug: Vitamin D3; 2000 Units (IE) (50 microgram) vitamin D3 daily; Other Names: Cholecalciferol
Placebo Comparator: Placebo, Vitamin D3; 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; 2000 Units (IE) (50 microgram) vitamin D3 daily; Other Names: Cholecalciferol

What is the study measuring?

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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• Ludvigsson J, Krisky D, Casas R, Battelino T, Castano L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, Veeze HJ, Palmer J, Samuelsson U, Elding Larsson H, Aman J, Kardell G, Neiderud Helsingborg J, Lundstrom G, Albinsson E, Carlsson A, Nordvall M, Fors H, Arvidsson CG, Edvardson S, Hanas R, Larsson K, Rathsman B, Forsgren H, Desaix H, Forsander G, Nilsson NO, Akesson CG, Keskinen P, Veijola R, Talvitie T, Raile K, Kapellen T, Burger W, Neu A, Engelsberger I, Heidtmann B, Bechtold S, Leslie D, Chiarelli F, Cicognani A, Chiumello G, Cerutti F, Zuccotti GV, Gomez Gila A, Rica I, Barrio R, Clemente M, Lopez Garcia MJ, Rodriguez M, Gonzalez I, Lopez JP, Oyarzabal M, Reeser HM, Nuboer R, Stouthart P, Bratina N, Bratanic N, de Kerdanet M, Weill J, Ser N, Barat P, Bertrand AM, Carel JC, Reynaud R, Coutant R, Baron S. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012 Feb 2;366(5):433-42. doi: 10.1056/NEJMoa1107096.

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2015
• Primary Completion (Actual): October 7, 2019
• Study Completion (Actual): October 7, 2019

Study Registration Dates

• First Submitted: March 5, 2015
• First Submitted That Met QC Criteria: March 6, 2015
• First Posted (Estimate): March 12, 2015

Study Record Updates

• Last Update Posted (Actual): November 17, 2020
• Last Update Submitted That Met QC Criteria: October 27, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Prediabetes; Children; Prevention; Type 1 diabetes; Glucose tolerance; Immune tolerance; Islet autoantibodies; glutamate decarboxylase autoantibodies (GADA); glutamate decarboxylase
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Prediabetic State; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: DiAPREV/2014