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

• ClinicalTrials.gov Identifier: NCT02387164
• Recruitment Status: Active, not recruiting
• First Posted: March 12, 2015
• Last Update Posted: January 15, 2019
• Sponsor: Lund University
• Collaborator: Region Skane
• Information provided by (Responsible Party): Lund University

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1; Prediabetic State	Drug: Alum-GAD; Drug: Vitamin D3	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: March 2015
• Estimated Primary Completion Date: January 2020
• Estimated Study Completion Date: January 2020

Arms and Interventions

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 Name: 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 Name: Cholecalciferol

Outcome Measures

Primary Outcome Measures :

1. Type 1 diabetes [ Time Frame: 5 years ]
   Proportion of subjects diagnosed with type 1 diabetes according to ADA criteria in each study arm

Secondary Outcome Measures :

1. Impaired glucose metabolism [ Time Frame: During 5 year follow-up ]

   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.

2. Safety as measured by occurrence of adverse events [ Time Frame: 5 years follow-up ]
   Evaluation of safety of Diamyd and high dose Vitamin D3 in non-diabetic children as measured by occurrence of adverse events, injection site reactions, abnormal laboratory parameters or physical exam.

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

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.

Contacts and Locations

Locations

Sweden

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

Malmö, Sweden, 205 02

Sponsors and Collaborators

Lund University

Region Skane

Investigators

• Principal Investigator: Helena Elding Larsson, MD, PhD; Lund University

More Information

Additional Information:

Link to the description of the first DiAPREV-IT study, that have included 50 children and is still ongoing 

Publications:

Elding Larsson H, Larsson C, Lernmark Å; 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, Jönsson 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, Castaño L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, Veeze HJ, Palmer J, Samuelsson U, Elding Larsson H, Åman J, Kärdell G, Neiderud Helsingborg J, Lundström G, Albinsson E, Carlsson A, Nordvall M, Fors H, Arvidsson CG, Edvardson S, Hanås R, Larsson K, Rathsman B, Forsgren H, Desaix H, Forsander G, Nilsson NÖ, Åkesson 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, López 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.

• Responsible Party: Lund University
• ClinicalTrials.gov Identifier: NCT02387164 History of Changes
• Other Study ID Numbers: DiAPREV/2014
• First Posted: March 12, 2015
• Last Update Posted: January 15, 2019
• Last Verified: January 2019

Keywords provided by Lund University:

Type 1 diabetes; Islet autoantibodies; glutamate decarboxylase autoantibodies (GADA); Immune tolerance; Prediabetes; Glucose tolerance; glutamate decarboxylase; Prevention; Children

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Prediabetic State; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins; Aluminum sulfate; Autoantibodies; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Adjuvants, Immunologic; Immunologic Factors