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

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ClinicalTrials.gov Identifier: NCT02387164
Recruitment Status : Terminated (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.)
First Posted : March 12, 2015
Results First Posted : October 27, 2020
Last Update Posted : November 17, 2020
Sponsor:
Collaborator:
Region Skane
Information provided by (Responsible Party):
Helena Elding Larsson, Lund University

Study Description
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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
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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 9, 2015
Actual Primary Completion Date : October 7, 2019
Actual Study Completion Date : October 7, 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
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Primary Outcome Measures :
  1. 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

  2. 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 Outcome Measures :
  1. 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.


  2. 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.


  3. Injection Site Reactions Day 1 [ Time Frame: Day 1 ]
    Number of patients experiencing injection site reactions at day 1

  4. Injection Site Reactions Month 1 [ Time Frame: Month 1 ]
    Number of patients experiencing injection site reactions at month 1

  5. Change From Baseline in GADA Month 1 [ Time Frame: Month 1 ]
    Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers

  6. Change From Baseline in GADA Month 12 [ Time Frame: Month 12 ]
    Change from baseline to month 12 in GADA titers

  7. Change From Baseline in GADA Month 24 [ Time Frame: Month 24 ]
    Change from baseline to month 24 in GADA titers


Eligibility Criteria
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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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02387164


Locations
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Sweden
Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11
Malmö, Sweden, 205 02
Sponsors and Collaborators
Lund University
Region Skane
Investigators
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Principal Investigator: Helena Elding Larsson, MD, PhD Lund University
  Study Documents (Full-Text)

Documents provided by Helena Elding Larsson, Lund University:
Study Protocol  [PDF] August 28, 2017
Statistical Analysis Plan  [PDF] May 5, 2020

More Information
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Publications:
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.

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Responsible Party: Helena Elding Larsson, Docent, MD, PhD, Lund University
ClinicalTrials.gov Identifier: NCT02387164    
Other Study ID Numbers: DiAPREV/2014
First Posted: March 12, 2015    Key Record Dates
Results First Posted: October 27, 2020
Last Update Posted: November 17, 2020
Last Verified: October 2020
Keywords provided by Helena Elding Larsson, Lund University:
Type 1 diabetes
Islet autoantibodies
glutamate decarboxylase autoantibodies (GADA)
Immune tolerance
Prediabetes
 Glucose tolerance
glutamate decarboxylase
Prevention
Children
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Prediabetic State
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Vitamin D
 Cholecalciferol
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents