Diabetes Mellitus, Type 1, Prediabetic State
Conditions
Keywords
Type 1 diabetes, Islet autoantibodies, glutamate decarboxylase autoantibodies (GADA), Immune tolerance, Prediabetes, Glucose tolerance, glutamate decarboxylase, Prevention, Children
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.
Interventions
DRUGAlum-GAD
Two doses à 20 microgram 30 days apart subcutaneously administrated
DRUGVitamin D3
2000 Units (IE) (50 microgram) vitamin D3 daily
Sponsors
Region Skane
Lund University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Type 1 Diabetes Month 24 | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Injection Site Reactions Day 1 | Day 1 | Number of patients experiencing injection site reactions at day 1 |
| Injection Site Reactions Month 1 | Month 1 | Number of patients experiencing injection site reactions at month 1 |
| Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | 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. |
| Change From Baseline in GADA Month 12 | Month 12 | Change from baseline to month 12 in GADA titers |
| Change From Baseline in GADA Month 24 | Month 24 | Change from baseline to month 24 in GADA titers |
| Change From Baseline in GADA Month 1 | Month 1 | Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers |
| Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | 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. |
Countries
Sweden
Participant flow
Pre-assignment details
29 patients were screened for the study and 26 entered the study. Three patients were screening failures.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Alum-GAD: Two doses à 20 microgram 30 days apart subcutaneously administrated
Vitamin D3: 2000 Units (IE) (50 microgram) vitamin D3 daily | 13 |
| 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
Vitamin D3: 2000 Units (IE) (50 microgram) vitamin D3 daily | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Diagnosed | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Alum-GAD, Vitamin D3 | Placebo, Vitamin D3 |
|---|---|---|---|
| Age, Categorical <=18 years | 26 Participants | 13 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.2 years STANDARD_DEVIATION 2.76 | 9.0 years STANDARD_DEVIATION 2.89 | 9.4 years STANDARD_DEVIATION 2.73 |
| Celiac disease No | 24 Participants | 11 Participants | 13 Participants |
| Celiac disease Yes | 2 Participants | 2 Participants | 0 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment Sweden | 26 participants | 13 participants | 13 participants |
| Relatedness First degree relative diagnosed with type 1 diabetes | 6 Participants | 4 Participants | 2 Participants |
| Relatedness General population (no relative diagnosed with type 1 diabetes) | 20 Participants | 9 Participants | 11 Participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 15 Participants | 6 Participants | 9 Participants |
| Thyroid disease No | 26 Participants | 13 Participants | 13 Participants |
| Thyroid disease Yes | 0 Participants | 0 Participants | 0 Participants |
| Weight | 35.1 kg STANDARD_DEVIATION 14.53 | 33.7 kg STANDARD_DEVIATION 14.51 | 36.6 kg STANDARD_DEVIATION 14.99 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 12 / 13 | 12 / 13 |
| serious Total, serious adverse events | 1 / 13 | 1 / 13 |
Outcome results
Primary
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
Time frame: 24 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Type 1 Diabetes Month 24 | Yes | 1 Participants |
| Alum-GAD, Vitamin D3 | Type 1 Diabetes Month 24 | No | 12 Participants |
| Placebo, Vitamin D3 | Type 1 Diabetes Month 24 | Yes | 2 Participants |
| Placebo, Vitamin D3 | Type 1 Diabetes Month 24 | No | 11 Participants |
Primary
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.
Time frame: Over the entire study period up to 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Type 1 Diabetes Status Overall | Yes | 2 Participants |
| Alum-GAD, Vitamin D3 | Type 1 Diabetes Status Overall | No | 11 Participants |
| Placebo, Vitamin D3 | Type 1 Diabetes Status Overall | Yes | 2 Participants |
| Placebo, Vitamin D3 | Type 1 Diabetes Status Overall | No | 11 Participants |
Secondary
Change From Baseline in GADA Month 1
Change from baseline to month 1 in GADA (Glutamic Acid Decarboxylase Antibodies) titers
Time frame: Month 1
Population: Only patients with GADA measured both at baseline and month 1 are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Change From Baseline in GADA Month 1 | 1619.1 U/mL | Standard Deviation 2608.9 |
| Placebo, Vitamin D3 | Change From Baseline in GADA Month 1 | -51.9 U/mL | Standard Deviation 197.8 |
Secondary
Change From Baseline in GADA Month 12
Change from baseline to month 12 in GADA titers
Time frame: Month 12
Population: Only patients with GADA measured at baseline and at month 12 are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Change From Baseline in GADA Month 12 | 7916.9 U/mL | Standard Deviation 10694.55 |
| Placebo, Vitamin D3 | Change From Baseline in GADA Month 12 | -120.0 U/mL | Standard Deviation 592.09 |
Secondary
Change From Baseline in GADA Month 24
Change from baseline to month 24 in GADA titers
Time frame: Month 24
Population: Only patients with GADA measured at baseline and month 24 are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Change From Baseline in GADA Month 24 | 3216.6 U/mL | Standard Deviation 4628.53 |
| Placebo, Vitamin D3 | Change From Baseline in GADA Month 24 | 1062.7 U/mL | Standard Deviation 3380.26 |
Secondary
Injection Site Reactions Day 1
Number of patients experiencing injection site reactions at day 1
Time frame: Day 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Erythema | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Haematoma | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Itching | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Oedema | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Pain | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Day 1 | Tenderness | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Pain | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Erythema | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Oedema | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Haematoma | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Tenderness | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Day 1 | Itching | 0 participants |
Secondary
Injection Site Reactions Month 1
Number of patients experiencing injection site reactions at month 1
Time frame: Month 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Erythema | 1 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Haematoma | 1 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Itching | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Oedema | 2 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Pain | 0 participants |
| Alum-GAD, Vitamin D3 | Injection Site Reactions Month 1 | Tenderness | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Pain | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Erythema | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Oedema | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Haematoma | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Tenderness | 0 participants |
| Placebo, Vitamin D3 | Injection Site Reactions Month 1 | Itching | 0 participants |
Secondary
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.
Time frame: During 18 months follow-up
Population: Only patients with normal glucose at baseline and glucose measured at month 18 are included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | Yes | 3 Participants |
| Alum-GAD, Vitamin D3 | Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | No | 5 Participants |
| Placebo, Vitamin D3 | Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | Yes | 1 Participants |
| Placebo, Vitamin D3 | Number of Patients Developing Impaired Glucose Metabolism Until Month 18 | No | 5 Participants |
Secondary
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.
Time frame: During 18 months follow-up
Population: Only patients with impaired glucose at baseline and glucose measured at month 18 are included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alum-GAD, Vitamin D3 | Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | Yes | 1 Participants |
| Alum-GAD, Vitamin D3 | Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | No | 1 Participants |
| Placebo, Vitamin D3 | Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | Yes | 0 Participants |
| Placebo, Vitamin D3 | Number of Patients With Progressive Impaired Glucose Metabolism Until Month 18 | No | 4 Participants |