Latent Autoimmune Diabetes in Adults
Conditions
Keywords
Glutamic Acid Decarboxylase, Alum Compounds, Injections, Inguinal Canal, Diamyd, rhGAD65, Vitamin D
Brief summary
This study will evaluate the effects of 3 intra-nodal injections of GAD-alum (Diamyd), together with oral vitamin D supplementation. Safety and feasibility of the treatment will be evaluated and also effects on the immune system and on the preservation of endogenous insulin production.
Detailed description
The purpose of the trial is to evaluate the effects of 3 intra-nodal injections of GAD-alum, together with oral vitamin D supplementation, in a population of LADA patients with high GADA titers. Effects will be summarized at 5 and 12 months after the first injection. * The primary objective is to evaluate safety and feasibility of this treatment regimen. * Secondary objectives are to test if the treatment induces a strong GAD-specific immune response similar to what has previously been observed in type 1 diabetes patients and to test for indications of preservation of endogenous insulin production. The study is an open label Phase IIa feasibility trial. It is a pilot study that does not include a placebo arm. Antidiabetic medication in the form of metformin is acceptable before and during the trial. Study participants must be insulin independent at baseline, but if the need for insulin treatment develops during the trial, such treatment will be given. GAD-alum will be injected directly into an inguinal lymph node by a qualified radiologist. Patients will be followed for a total of 12 months during which their endogenous insulin production and immune response will be evaluated at regular intervals throughout the study period. Urine and blood samples will be taken for safety, diabetes status assessments, vitamin D levels and immunological assessments. Concomitant medication and demographics will be collected.
Interventions
DRUGrecombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel
3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart. Supplier Diamyd Medical AB in Stockholm, Sweden
DRUGVitamin D
1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90. Supplier Meda, Solna, Sweden
Sponsors
St. Olavs Hospital
Diamyd Medical AB
Karolinska Institutet
Linkoeping University
Norwegian University of Science and Technology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent by the patient. 2. Diagnosis of LADA and diabetes debut within the last 18 months before inclusion. LADA should be defined by the criteria of age ≥30 years at the onset of diabetes, anti-GAD positivity and no clinical need for permanent insulin treatment during the first 3 months after the diagnosis of diabetes. 3. Fasting C-peptid levels ≥ 0.3 nmol/l 4. High GADA titers (\>190 U/ml) 5. Patients must be insulin independent at baseline by clinical judgement and C-peptide criteria 6. Antidiabetic medication in the form of metformin is acceptable for inclusion as well as medications not mentioned under
Exclusion criteria
7. Females must agree to avoid pregnancy, and must have a negative urine pregnancy test. Patients of childbearing potential must agree to use adequate contraception, until one (1) year after the last administration of GAD-alum. Adequate contraception is as follows: For females of childbearing potential: 1. oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives 2. combined (estrogen and progestogen containing) 3. oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation 4. intrauterine device 5. intrauterine hormone-releasing system (for example, progestin-releasing coil) 6. bilateral tubal occlusion 7. vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate) 8. male partner using condom 9. abstinence from heterosexual intercourse For males of childbearing potential: 1. condom (male) 2. abstinence from heterosexual intercourse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Injection Site Skin Reactions | 1 hour | Injection site skin reactions 1 hour post injection, i.e., erythema, oedema, haematoa, tenderness, pain, itching or other finding. |
| Occurrence of Adverse Events (AEs) During 5 Months From Baseline. | From baseline (first injection of GAD-alum) to 5 months after baseline. | AEs were continuously monitored and registered from the baseline visit (first injection of GAD-alum) to the end of study (12 months after the baseline visit). The total number of AEs registered for all 14 participants during the first 5 months from baseline was summarized when all 14 participants had completed their 5 months study visit (i.e., 5 months after the baseline visit). At the end of study, when all 14 participants had completed their 12 months study visit, the total number of AEs registered for all 14 participants during the 12 months from baseline was summarized. |
| Occurrence of Adverse Events (AEs) During the Study. | From baseline (first injection of GAD-alum) to 12 months after baseline. | AEs were continuously monitored and registered from the baseline visit (first injection of GAD-alum) to the end of study (12 months after the baseline visit/first injection of GAD-alum). The total number of AEs registered for all 14 participants during the first 5 months from baseline was summarized when all 14 participants had completed their 5 months study visit (i.e., 5 months after the baseline visit). At the end of study, when all 14 participants had completed their 12 months study visit, the total number of AEs registered for all 14 participants during the 12 months from baseline was summarized. |
| Serum GAD65A Titers, Change From Baseline at 5 Months After Baseline. | Baseline (first injection of GAD-alum) and 5 months after baseline. | Values present changes in serum GAD65A titers from baseline (first injection of GAD-alum) to 5 months after baseline. Calculation: Value at 5 months minus value at baseline. |
| Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline. | Baseline and 12 months after baseline. | Values present changes in serum GAD65A titers from baseline (first injection of GAD-alum) to 12 months after baseline. Calculation: Value at 12 months minus value at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion, Change From Baseline to 5 Months After Baseline. | Baseline (first injection of GAD-alum) and 5 months after baseline. | Values present changes in serum values of glucagon-stimulated C-peptide from baseline (first injection of GAD-alum) to 5 months after baseline. Calculation: Value at 5 months minus value at baseline. |
| Change in Maximum C-peptide During Mixed Meal Tolerance Test (MMTT) | between baseline 12 months after the first injection | Change in maximum C-peptide value at 12 months vs baseline (first injection) |
| Insulin Secretion, Change From Baseline to 12 Months After Baseline. | Baseline (first injection of GAD-alum) and 12 months after baseline. | Values present changes in serum values of glucagon-stimulated C-peptide from baseline (first injection of GAD-alum) to 12 months after baseline. Calculation: Value at 12 months minus value at baseline. |
| Change in HbA1c | from baseline to 12 months after the first injection | HbA1c at 12 months vs. baseline (first injection) |
| Change in Fasting Glucose | From baseline to 12 months after the first injection | Change in fasting glucose at 12 months vs baseline (first injection) |
| Change in Fasting C-peptide | Between baseline and 12 months after the first injection | Change in fasting glucose at 12 months vs baseline (first injection) |
Countries
Norway, Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GAD-vaccination With Vitamin D Suppletion Each study participant will receive 3 injections of 4 µg GAD-alum (Diamyd). The first, second and third injection will be one month apart.
Vitamin D (Divisun 2000 IE) will be given from one month before the first injection of GAD-alum until one month after the third injection (120 days in total).
recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel: 3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart.
Supplier Diamyd Medical AB in Stockholm, Sweden
Vitamin D: 1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90. Supplier Meda, Solna, Sweden | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | GAD-vaccination With Vitamin D Suppletion | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 14 Participants | — |
| Age, Continuous | 46 years | — |
| BMI, kg/m^2 | 25.1 kg/m^2 | — |
| Fasting C-peptide, nmol/L | 0.55 nmol/L | — |
| Fasting glucose, mmol/L | 6.7 mmol/L | — |
| HbA1c, mmol/mol | 42 mmol/mol | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Norway | 6 participants | — |
| Region of Enrollment Sweden | 8 participants | — |
| Sex: Female, Male Female | 7 Participants | — |
| Sex: Female, Male Male | 7 Participants | — |
| Time from diagnosis to inclusion, months | 4 months | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 12 / 14 |
| serious Total, serious adverse events | 2 / 14 |
Outcome results
Primary
Injection Site Skin Reactions
Injection site skin reactions 1 hour post injection, i.e., erythema, oedema, haematoa, tenderness, pain, itching or other finding.
Time frame: 1 hour
Population: All study participants received 3 injections of 4 µg GAD-alum.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Injection Site Skin Reactions | 4 events |
Primary
Occurrence of Adverse Events (AEs) During 5 Months From Baseline.
AEs were continuously monitored and registered from the baseline visit (first injection of GAD-alum) to the end of study (12 months after the baseline visit). The total number of AEs registered for all 14 participants during the first 5 months from baseline was summarized when all 14 participants had completed their 5 months study visit (i.e., 5 months after the baseline visit). At the end of study, when all 14 participants had completed their 12 months study visit, the total number of AEs registered for all 14 participants during the 12 months from baseline was summarized.
Time frame: From baseline (first injection of GAD-alum) to 5 months after baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Occurrence of Adverse Events (AEs) During 5 Months From Baseline. | 28 AEs |
Primary
Occurrence of Adverse Events (AEs) During the Study.
AEs were continuously monitored and registered from the baseline visit (first injection of GAD-alum) to the end of study (12 months after the baseline visit/first injection of GAD-alum). The total number of AEs registered for all 14 participants during the first 5 months from baseline was summarized when all 14 participants had completed their 5 months study visit (i.e., 5 months after the baseline visit). At the end of study, when all 14 participants had completed their 12 months study visit, the total number of AEs registered for all 14 participants during the 12 months from baseline was summarized.
Time frame: From baseline (first injection of GAD-alum) to 12 months after baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Occurrence of Adverse Events (AEs) During the Study. | 34 AEs |
Primary
Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline.
Values present changes in serum GAD65A titers from baseline (first injection of GAD-alum) to 12 months after baseline. Calculation: Value at 12 months minus value at baseline.
Time frame: Baseline (first injection of GAD-alum) and 12 months after baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline. | 26082 U/mL |
Primary
Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline.
Values present changes in serum GAD65A titers from baseline (first injection of GAD-alum) to 12 months after baseline. Calculation: Value at 12 months minus value at baseline.
Time frame: Baseline and 12 months after baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Serum GAD65A Titers, Change From Baseline at 12 Months After Baseline. | 26082 U/mL |
p-value: <0.05Wilcoxon signed rank test
Primary
Serum GAD65A Titers, Change From Baseline at 5 Months After Baseline.
Values present changes in serum GAD65A titers from baseline (first injection of GAD-alum) to 5 months after baseline. Calculation: Value at 5 months minus value at baseline.
Time frame: Baseline (first injection of GAD-alum) and 5 months after baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Serum GAD65A Titers, Change From Baseline at 5 Months After Baseline. | 59218 U/mL |
p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Fasting C-peptide
Change in fasting glucose at 12 months vs baseline (first injection)
Time frame: Between baseline and 12 months after the first injection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Change in Fasting C-peptide | -0.03 nmol/L |
p-value: <0.03Wilcoxon signed rank test
Secondary
Change in Fasting Glucose
Change in fasting glucose at 12 months vs baseline (first injection)
Time frame: From baseline to 12 months after the first injection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Change in Fasting Glucose | -0.05 mmol/L |
p-value: <0.72Wilcoxon signed rank test
Secondary
Change in HbA1c
HbA1c at 12 months vs. baseline (first injection)
Time frame: from baseline to 12 months after the first injection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Change in HbA1c | 3.0 mmol/mol |
p-value: <0.002Wilcoxon signed rank test
Secondary
Change in Maximum C-peptide During Mixed Meal Tolerance Test (MMTT)
Change in maximum C-peptide value at 12 months vs baseline (first injection)
Time frame: between baseline 12 months after the first injection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Change in Maximum C-peptide During Mixed Meal Tolerance Test (MMTT) | -0.30 nmol/L |
p-value: <0.044Wilcoxon signed rank test
Secondary
Insulin Secretion, Change From Baseline to 12 Months After Baseline.
Values present changes in serum values of glucagon-stimulated C-peptide from baseline (first injection of GAD-alum) to 12 months after baseline. Calculation: Value at 12 months minus value at baseline.
Time frame: Baseline (first injection of GAD-alum) and 12 months after baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Insulin Secretion, Change From Baseline to 12 Months After Baseline. | -0.10 nmol/L |
p-value: <0.3Wilcoxon signed rank test
Secondary
Insulin Secretion, Change From Baseline to 5 Months After Baseline.
Values present changes in serum values of glucagon-stimulated C-peptide from baseline (first injection of GAD-alum) to 5 months after baseline. Calculation: Value at 5 months minus value at baseline.
Time frame: Baseline (first injection of GAD-alum) and 5 months after baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GAD-vaccination With Vitamin D Suppletion | Insulin Secretion, Change From Baseline to 5 Months After Baseline. | 0.00 nmol/L |
p-value: <0.61Wilcoxon signed rank test