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

Primary Purpose

Diabetes Mellitus, Type 1, Prediabetic State

Status
Terminated
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Alum-GAD
Vitamin D3
Sponsored by
Lund University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Diabetes Mellitus, Type 1 focused on measuring Type 1 diabetes, Islet autoantibodies, glutamate decarboxylase autoantibodies (GADA), Immune tolerance, Prediabetes, Glucose tolerance, glutamate decarboxylase, Prevention, Children

Eligibility Criteria

4 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Alum-GAD, Vitamin D3

Placebo, Vitamin D3

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

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.
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.
Injection Site Reactions Day 1
Number of patients experiencing injection site reactions at day 1
Injection Site Reactions Month 1
Number of patients experiencing injection site reactions at month 1
Change From Baseline in GADA Month 1
Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers
Change From Baseline in GADA Month 12
Change from baseline to month 12 in GADA titers
Change From Baseline in GADA Month 24
Change from baseline to month 24 in GADA titers

Full Information

First Posted
March 5, 2015
Last Updated
October 27, 2020
Sponsor
Lund University
Collaborators
Region Skane
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1. Study Identification

Unique Protocol Identification Number
NCT02387164
Brief Title
Prevention Trial: Immune-tolerance With Alum-GAD (Diamyd) and Vitamin D3 to Children With Multiple Islet Autoantibodies
Acronym
DiAPREV-IT2
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Terminated
Why Stopped
The study was interrupted early and terminated when only 26 out of 80 patients were enrolled due to new clinical study results indicating that the current study would not be informative.
Study Start Date
March 9, 2015 (Actual)
Primary Completion Date
October 7, 2019 (Actual)
Study Completion Date
October 7, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Lund University
Collaborators
Region Skane

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1, Prediabetic State
Keywords
Type 1 diabetes, Islet autoantibodies, glutamate decarboxylase autoantibodies (GADA), Immune tolerance, Prediabetes, Glucose tolerance, glutamate decarboxylase, Prevention, Children

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alum-GAD, Vitamin D3
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo, Vitamin D3
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Alum-GAD
Other Intervention Name(s)
Diamyd, GAD-Alum, Alumformulated GAD
Intervention Description
Two doses à 20 microgram 30 days apart subcutaneously administrated
Intervention Type
Drug
Intervention Name(s)
Vitamin D3
Other Intervention Name(s)
Cholecalciferol
Intervention Description
2000 Units (IE) (50 microgram) vitamin D3 daily
Primary Outcome Measure Information:
Title
Type 1 Diabetes Month 24
Description
Number of patients diagnosed with type 1 diabetes according to ADA (American Diabetes Association) criteria in each study arm month 24
Time Frame
24 months
Title
Type 1 Diabetes Status Overall
Description
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.
Time Frame
Over the entire study period up to 2 years
Secondary Outcome Measure Information:
Title
Number of Patients Developing Impaired Glucose Metabolism Until Month 18
Description
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.
Time Frame
During 18 months follow-up
Title
Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18
Description
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.
Time Frame
During 18 months follow-up
Title
Injection Site Reactions Day 1
Description
Number of patients experiencing injection site reactions at day 1
Time Frame
Day 1
Title
Injection Site Reactions Month 1
Description
Number of patients experiencing injection site reactions at month 1
Time Frame
Month 1
Title
Change From Baseline in GADA Month 1
Description
Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers
Time Frame
Month 1
Title
Change From Baseline in GADA Month 12
Description
Change from baseline to month 12 in GADA titers
Time Frame
Month 12
Title
Change From Baseline in GADA Month 24
Description
Change from baseline to month 24 in GADA titers
Time Frame
Month 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Helena Elding Larsson, MD, PhD
Organizational Affiliation
Lund University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11
City
Malmö
ZIP/Postal Code
205 02
Country
Sweden

12. IPD Sharing Statement

Citations:
PubMed Identifier
25381193
Citation
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.
Results Reference
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PubMed Identifier
23469940
Citation
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.
Results Reference
background
PubMed Identifier
22296077
Citation
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.
Results Reference
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Links:
URL
http://www.ludc.med.lu.se/research-units/diabetes-and-celiac-disease/research-projects/diabetes-prevention-immune-tolerance/
Description
Link to the description of the first DiAPREV-IT study, that have included 50 children and is still ongoing

Learn more about this trial

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

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