Diabetes Mellitus, Type 1
Conditions
Keywords
Diamyd, Diabetes, Juvenile Diabetes, Diabetes Type 1, Type 1 Diabetes, Autoimmune Diabetes, Insulin Dependent Diabetes, Type 1 Diabetes Mellitus, rhGAD65 (Recombinant Human GAD with molecular mass 65,000), GAD65, GAD-Alum, Diabetes Mellitus, Diabetes mellitus Type 1, Glucose Metabolism Disorders, Metabolic Diseases, Vitamin D
Brief summary
The objectives of the main study is to: * Evaluate the safety of giving GAD-Alum (Glutamic acid decarboxylase) (Diamyd) directly into lymph glands in combination with an oral vitamin D regimen * Evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion. The objective of the sub-study is to: * Evaluate safety after a fourth injection with 4 μg GAD-Alum direct into an inguinal lymph gland in 3 adult patients from the main study * Evaluate how the above mentioned treatment influences the immune system and endogenous insulin secretion.
Detailed description
Eligible patients will be treated with 4 µg GAD-Alum into an inguinal lymph gland at three occasions, with one month intervals in combination with Vitamin D (14 000 IU/week) for 4 months, starting 1 month prior to first GAD-Alum injection. A sub-study will include three adult patients from the main study and evaluate safety after a fourth injection with 4 μg GAD-Alum into an inguinal lymph gland in combination with oral vitamin D intake. The Prolonged Extension Study Period is 12 months and will start 30,5 months after baseline.
Interventions
DRUGGAD-Alum
DRUGVitamin D
Sponsors
Johnny Ludvigsson
Swedish Child Diabetes Foundation
Ostergotland County Council, Sweden
Diamyd Medical AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
1. Informed consent given by patients 2. Type 1 diabetes according to the ADA (American Diabetes Association) classification with \< 6 months diabetes duration 3. Age 12.00-29.99 years at diagnosis of Type 1 diabetes 4. Fasting C-peptide ≥0.12 nmol/L 5. Pos GADA(Antibodies to GAD with molecular mass 65,000) but \< 50 000 random units 6. Females must agree to avoid pregnancy and have a negative urine pregnancy test 7. Patients of childbearing potential must agree to using adequate contraception, until 1 year after the last administration of GAD-Alum.
Exclusion criteria
1. Previous or current treatment with immunosuppressant therapy (although topical or inhaled steroids are accepted) 2. Continuous treatment with any inflammatory drug (sporadic treatment e.g. because of headache or in connection with fever a few days will be accepted) 3. Treatment with any oral or injected anti-diabetic medications other than insulin 4. Treatment with Vitamin D, marketed or not, or unwilling to abstain from such medication during the trial 5. A history of anaemia or significantly abnormal haematology results at screening 6. A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles 7. Clinically significant history of acute reaction to vaccines or other drugs in the past 8. Treatment with any vaccine, including influenza vaccine, within 4 months prior to planned first study drug dose or planned treatment with any vaccine up to 4 months after the last injection with study drug. 9. Participation in other clinical trials with a new chemical entity within the previous 3 months 10. Inability or unwillingness to comply with the provisions of this protocol 11. A history of alcohol or drug abuse 12. A significant illness other than diabetes within 2 weeks prior to first dosing 13. Known human immunodeficiency virus (HIV) or hepatitis 14. Females who are lactating or pregnant (the possibility of pregnancy must be excluded by urine βHCG (beta-human chorionic gonadotropin) on-site within 24 hours prior to the GAD-Alum treatment) 15. Males or females not willing to use adequate contraception until 1 year after the last GAD-Alum treatment 16. Presence of associated serious disease or condition, including active skin infections that preclude subcutaneous injection, which in the opinion of the investigator makes the patient non-eligible for the study 17. Deemed by the investigator not being able to follow instructions and/or follow the study protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Injection Site Reactions Month 1 | Month 1 | Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching) |
| Number of Subjects With Injection Site Reactions Month 2 | Month 2 | Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching) |
| Number of Subjects With Injection Site Reactions Month 3 | Month 3 | Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching) |
| Number of Subjects With Injection Site Reactions Month 32 | Month 32, extension period | Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in C-peptide 90-minute Value, Month 30 | Baseline to month 30 | Change from baseline to month 30 in C-peptide 90-minute value |
| Mean Change in C-peptide 90-minute Value, Month 43 | Baseline to month 43, extension period | Change from baseline to month 43 in C-peptide 90-minute value |
| Mean Change in Fasting C-peptide Value, Month 15 | Baseline to month 15 | Change from baseline to month 15 in fasting C-peptide value |
| Mean Change in Fasting C-peptide Value, Month 30 | Baseline to month 30 | Change from baseline to month 30 in fasting C-peptide value |
| Mean Change in Fasting C-peptide Value, Month 43 | Baseline to month 43, extension period | Change from baseline to month 43 in fasting C-peptide value |
| Mean Change in HbA1c, Month 15 | Baseline to month 15 | Change from baseline to month 15 in HbA1c |
| Mean Change in HbA1c, Month 30 | Baseline to month 30 | Change from baseline to month 30 in HbA1c |
| Mean Change in HbA1c, Month 43 | Baseline to month 43, extension period | Change from baseline to month 43 in HbA1c |
| Mean Change in C-peptide AUC (Area Under the Curve) (Mean 120min) Value, Month 15 | Baseline to month 15 at 0, 30, 60, 90, 120 minutes post-dose | Change from baseline to month 15 in C-peptide AUC (Area Under the Curve) (mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration |
| External Insulin Dose, Month 15 | Month 15 | External insulin dose at month 15 |
| External Insulin Dose, Month 30 | Month 30 | External insulin dose at month 30 |
| External Insulin Dose, Month 43 | Month 43, extension period | External insulin dose at month 43 |
| Mean IDAA1c Values, Baseline | Baseline | Insulin dose-adjusted HbA1c (IDAA1c) |
| Mean IDAA1c Values, Month 15 | Month 15 | Insulin dose-adjusted HbA1c (IDAA1c) |
| Mean IDAA1c Values, Month 30 | Month 30 | Insulin dose-adjusted HbA1c (IDAA1c) |
| Mean IDAA1c Values, Month 43 | Month 43, extension period | Insulin dose-adjusted HbA1c (IDAA1c) |
| External Insulin Dose, Baseline | Baseline | External insulin dose at baseline |
| Mean Change in C-peptide AUC(Mean 120min) Value, Month 30 | Baseline to month 30 at 0, 30, 60, 90, 120 minutes post-dose | Change from baseline to month 30 in C-peptide AUC(mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration |
| Mean Change in C-peptide AUC(Mean 120min) Value, Month 43 | Baseline to month 43, extension period at 0, 30, 60, 90, 120 minutes post-dose | Change from baseline to month 43 in C-peptide AUC(mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration |
| Mean Change in C-peptide 90-minute Value, Month 15 | Baseline to month 15 | Change from baseline to month 15 in C-peptide 90-minute value |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GAD-Alum+Vitamin D GAD-Alum (Diamyd) injected into Lymph Nodes Dosage and interval: One injection of 4 µg Diamyd will be administered into the lymph nodes at three occasions, with one month intervals
Vitamin D (Calciferol) in oral solution. Dosage and interval: 2000 IU daily for 120 days
GAD-Alum
Vitamin D | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | GAD-Alum+Vitamin D | — |
|---|---|---|
| 90-minute C-peptide | 0.67 nmol/L STANDARD_DEVIATION 0.19 | — |
| Age, Categorical <=18 years | 4 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 8 Participants | — |
| Age, Continuous | 18.8 years STANDARD_DEVIATION 4.2 | — |
| Average insulin dose/kg/24 h | 0.40 IU STANDARD_DEVIATION 0.2 | — |
| BMI | 21.1 kg/m^2 STANDARD_DEVIATION 3.8 | — |
| Fasting C-peptide | 0.27 nmol/L STANDARD_DEVIATION 0.08 | — |
| GADA (Antibodies to GAD with molecular mass 65,000) | 4067.1 U/mL^2 STANDARD_DEVIATION 8491.6 | — |
| HbA1c | 67.17 mmol/mol STANDARD_DEVIATION 28.17 | — |
| IDAA1c | 9.91 IU/kg/day STANDARD_DEVIATION 3.1 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Sweden | 12 participants | — |
| Sex: Female, Male Female | 4 Participants | — |
| Sex: Female, Male Male | 8 Participants | — |
| Type 1 diabetes duration | 65.1 days STANDARD_DEVIATION 55.1 | — |
| Weight | 64.0 kg STANDARD_DEVIATION 13.6 | — |
| Weighted C-peptide | 0.55 nmol/L STANDARD_DEVIATION 0.19 | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 11 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Number of Subjects With Injection Site Reactions Month 1
Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
Time frame: Month 1
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Erythema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Oedema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Haematoma | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Tenderness | 1 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Pain | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Itching | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 1 | Other | 0 Participants |
Primary
Number of Subjects With Injection Site Reactions Month 2
Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
Time frame: Month 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Erythema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Oedema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Haematoma | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Tenderness | 1 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Pain | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Itching | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 2 | Other | 0 Participants |
Primary
Number of Subjects With Injection Site Reactions Month 3
Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
Time frame: Month 3
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Erythema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Oedema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Haematoma | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Tenderness | 2 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Pain | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Itching | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 3 | Other | 0 Participants |
Primary
Number of Subjects With Injection Site Reactions Month 32
Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
Time frame: Month 32, extension period
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Erythema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Oedema | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Haematoma | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Tenderness | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Pain | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Itching | 0 Participants |
| GAD-Alum+Vitamin D | Number of Subjects With Injection Site Reactions Month 32 | Other | 0 Participants |
Secondary
External Insulin Dose, Baseline
External insulin dose at baseline
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | External Insulin Dose, Baseline | 0.36 IU/kg/day | Standard Deviation 0.13 |
Secondary
External Insulin Dose, Month 15
External insulin dose at month 15
Time frame: Month 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | External Insulin Dose, Month 15 | 0.34 IU/kg/day | Standard Deviation 0.2 |
Secondary
External Insulin Dose, Month 30
External insulin dose at month 30
Time frame: Month 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | External Insulin Dose, Month 30 | 0.44 IU/kg/day | Standard Deviation 0.22 |
Secondary
External Insulin Dose, Month 43
External insulin dose at month 43
Time frame: Month 43, extension period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | External Insulin Dose, Month 43 | 0.25 IU/kg/day | Standard Deviation 0.02 |
Secondary
Mean Change in C-peptide 90-minute Value, Month 15
Change from baseline to month 15 in C-peptide 90-minute value
Time frame: Baseline to month 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide 90-minute Value, Month 15 | -0.16 nmol/L | Standard Deviation 0.15 |
Secondary
Mean Change in C-peptide 90-minute Value, Month 30
Change from baseline to month 30 in C-peptide 90-minute value
Time frame: Baseline to month 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide 90-minute Value, Month 30 | -0.29 nmol/L | Standard Deviation 0.17 |
Secondary
Mean Change in C-peptide 90-minute Value, Month 43
Change from baseline to month 43 in C-peptide 90-minute value
Time frame: Baseline to month 43, extension period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide 90-minute Value, Month 43 | -0.16 nmol/L | Standard Deviation 0.03 |
Secondary
Mean Change in C-peptide AUC (Area Under the Curve) (Mean 120min) Value, Month 15
Change from baseline to month 15 in C-peptide AUC (Area Under the Curve) (mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration
Time frame: Baseline to month 15 at 0, 30, 60, 90, 120 minutes post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide AUC (Area Under the Curve) (Mean 120min) Value, Month 15 | -0.11 nmol/L | Standard Deviation 0.12 |
Secondary
Mean Change in C-peptide AUC(Mean 120min) Value, Month 30
Change from baseline to month 30 in C-peptide AUC(mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration
Time frame: Baseline to month 30 at 0, 30, 60, 90, 120 minutes post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide AUC(Mean 120min) Value, Month 30 | -0.22 nmol/L | Standard Deviation 0.16 |
Secondary
Mean Change in C-peptide AUC(Mean 120min) Value, Month 43
Change from baseline to month 43 in C-peptide AUC(mean 120min) value AUC (mean 120min) (nmol/L) is the C-peptide AUC during an MMTT (nmol/L\*minutes) divided by the duration of the MMTT (minutes) i.e. C-peptide weighted average concentration
Time frame: Baseline to month 43, extension period at 0, 30, 60, 90, 120 minutes post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in C-peptide AUC(Mean 120min) Value, Month 43 | -0.13 nmol/L | Standard Deviation 0.05 |
Secondary
Mean Change in Fasting C-peptide Value, Month 15
Change from baseline to month 15 in fasting C-peptide value
Time frame: Baseline to month 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in Fasting C-peptide Value, Month 15 | -0.03 nmol/L | Standard Deviation 0.12 |
Secondary
Mean Change in Fasting C-peptide Value, Month 30
Change from baseline to month 30 in fasting C-peptide value
Time frame: Baseline to month 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in Fasting C-peptide Value, Month 30 | -0.10 nmol/L | Standard Deviation 0.12 |
Secondary
Mean Change in Fasting C-peptide Value, Month 43
Change from baseline to month 43 in fasting C-peptide value
Time frame: Baseline to month 43, extension period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in Fasting C-peptide Value, Month 43 | -0.07 nmol/L | Standard Deviation 0.04 |
Secondary
Mean Change in HbA1c, Month 15
Change from baseline to month 15 in HbA1c
Time frame: Baseline to month 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in HbA1c, Month 15 | -14.25 mmol/mol | Standard Deviation 18.91 |
Secondary
Mean Change in HbA1c, Month 30
Change from baseline to month 30 in HbA1c
Time frame: Baseline to month 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in HbA1c, Month 30 | -10.67 mmol/mol | Standard Deviation 18.67 |
Secondary
Mean Change in HbA1c, Month 43
Change from baseline to month 43 in HbA1c
Time frame: Baseline to month 43, extension period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean Change in HbA1c, Month 43 | -30.67 mmol/mol | Standard Deviation 21.22 |
Secondary
Mean IDAA1c Values, Baseline
Insulin dose-adjusted HbA1c (IDAA1c)
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean IDAA1c Values, Baseline | 9.00 IU/kg/day | Standard Deviation 1.89 |
Secondary
Mean IDAA1c Values, Month 15
Insulin dose-adjusted HbA1c (IDAA1c)
Time frame: Month 15
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean IDAA1c Values, Month 15 | 7.64 IU/kg/day | Standard Deviation 0.99 |
Secondary
Mean IDAA1c Values, Month 30
Insulin dose-adjusted HbA1c (IDAA1c)
Time frame: Month 30
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean IDAA1c Values, Month 30 | 8.36 IU/kg/day | Standard Deviation 1.28 |
Secondary
Mean IDAA1c Values, Month 43
Insulin dose-adjusted HbA1c (IDAA1c)
Time frame: Month 43, extension period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GAD-Alum+Vitamin D | Mean IDAA1c Values, Month 43 | 7.11 IU/kg/day | Standard Deviation 0.93 |