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

Overview

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.

Full Title of Study: “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

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: October 7, 2019

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.

Interventions

  • Drug: Alum-GAD
    • Two doses à 20 microgram 30 days apart subcutaneously administrated
  • Drug: Vitamin D3
    • 2000 Units (IE) (50 microgram) vitamin D3 daily

Arms, Groups and Cohorts

  • 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.
  • 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

Clinical Trial Outcome Measures

Primary Measures

  • Type 1 Diabetes Month 24
    • Time Frame: 24 months
    • 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
    • Time Frame: Over the entire study period up to 2 years
    • 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 Measures

  • Number of Patients Developing Impaired Glucose Metabolism Until Month 18
    • Time Frame: During 18 months 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.
  • Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18
    • Time Frame: During 18 months follow-up
    • 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
    • Time Frame: Day 1
    • Number of patients experiencing injection site reactions at day 1
  • Injection Site Reactions Month 1
    • Time Frame: Month 1
    • Number of patients experiencing injection site reactions at month 1
  • Change From Baseline in GADA Month 1
    • Time Frame: Month 1
    • Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers
  • Change From Baseline in GADA Month 12
    • Time Frame: Month 12
    • Change from baseline to month 12 in GADA titers
  • Change From Baseline in GADA Month 24
    • Time Frame: Month 24
    • Change from baseline to month 24 in GADA titers

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 4 Years

Maximum Age: 18 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Lund University
  • Collaborator
    • Region Skane
  • Provider of Information About this Clinical Study
    • Principal Investigator: Helena Elding Larsson, Docent, MD, PhD – Lund University
  • Overall Official(s)
    • Helena Elding Larsson, MD, PhD, Principal Investigator, Lund University

References

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.

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