Injections of Glutamic Acid Decarboxylase (GAD) for LADA Type of Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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A Pilot Study on Safety, Feasibility and Insulin-promotion by Intra-inguinal Lymph Node Injections of Glutamic Acid Decarboxylase (GAD) in Patients With LADA Type of Diabetes

Conditions
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Latent Autoimmune Diabetes in Adults

Intervention / Treatment
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* Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel
* Drug: Vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent by the patient. 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. Fasting C-peptid levels ≥ 0.3 nmol/l High GADA titers (>190 U/ml) Patients must be insulin independent at baseline by clinical judgement and C-peptide criteria Antidiabetic medication in the form of metformin is acceptable for inclusion as well as medications not mentioned under exclusion criteria 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: oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives combined (estrogen and progestogen containing) oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation intrauterine device intrauterine hormone-releasing system (for example, progestin-releasing coil) bilateral tubal occlusion vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate) male partner using condom abstinence from heterosexual intercourse For males of childbearing potential: condom (male) abstinence from heterosexual intercourse Exclusion Criteria: Current or previous treatment with immunosuppressant therapy (topical or inhaled steroids are accepted) Continuous treatment with anti-inflammatory drug (sporadic treatment e.g. because of headache or in connection with fever a few days will be accepted) Systemic treatment with glucocorticoids Treatment with any vaccine, including influenza vaccine, within 1 month prior to planned first study drug dose or planned treatment with any vaccine up to 1 month after the last injection with study drug Antidiabetic medication (metformin excepted) Significantly abnormal hematology results at screening (i.e. anemia with hemoglobin < 12 g/L). A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles Clinically significant history of acute reaction to vaccines in the past. Renal disease (as defined by serum creatinine >150 µmol/l) Serious cardiovascular events (myocardial infarction, stroke) within the last year preceding recruitment. Participation in other clinical trials with a new chemical entity within the previous 3 months A history of alcohol or drug abuse Known HIV or hepatitis Presence of associated serious disease or condition, including active skin infections that preclude intralymphatic injection, which in the opinion of the investigator makes the patient non-eligible for the study Other serious chronic disease as judged by investigator. Females who are lactating, are pregnant or intend to become pregnant. Inability or unwillingness to comply with the provisions of this protocol Deemed by the investigator not being able to follow instructions and/or follow the study protocol Treatment any other supplementation of with vitamin D, marketed or not, or unwilling to abstain from such medication during the trial 120 days daily intake of Divisun (non-investigational medicinal product)

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GAD-vaccination with vitamin D suppletion<br>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). | Drug: recombinant human glutamic acid dehydrogenase (rhGAD65), formulated in aluminium hydrogel<br>* 3 intra-inguinal injections (into the lymph nodes) of GAD-alum one month apart. Supplier Diamyd Medical AB in Stockholm, Sweden<br>* Other names: GAD-alum (Diamyd(R));Drug: Vitamin D<br>* 1 tablet/day, total daily dose of 2000 IE given per os from day -30 through day 90. Supplier Meda, Solna, Sweden<br>* Other names: Divisun 2000 IE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| injection site skin reactions | skin reactions 1 hour post injection vs. before injection | 1 hour | 
| Occurrence of adverse events (AEs) | continuously monitored and registered | summarized at 5 months | 
| Occurrence of adverse events (AEs) | continuously monitored and registered | summarized at 12 months | 
| GAD65A titer in serum | concentration in serum after the first injection vs baseline | at 5 months | 
| GAD65A titer in serum | concentration in serum after the first injection vs baseline | at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretion | measured by glucagon- and MMTT stimulated C-peptide | 5 months after first injection | 
| insulin secretion | measured by glucagon- and MMTT stimulated C-peptide | 12 months after first injection | 
| Change in HbA1c |  | from baseline to 5 and 12 months after the first injection | 
| Change in fasting glucose |  | from baseline to 5 and 12 months after the first injection | 
| Change in Fasting C-peptide |  | between baseline and 5 and 12 months after the first injection | 
| Change in maximum C-peptide during Mixed Meal Tolerance Test (MMTT) |  | between baseline and 5 and 12 months after the first injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glutamic Acid Decarboxylase, Alum Compounds, Injections, Inguinal Canal, Diamyd, rhGAD65, Vitamin D