EDCR Study - Etanercept Diamyd Combination Regimen -Open Trial to Evaluate Safety in Children With Type 1 Diabetes

Study Overview
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Brief Summary
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The objectives of this study is to: Evaluate the tolerability of a combination therapy with Diamyd, vitamin D and etanercept Evaluate how the above mentioned treatments influence the immune system and endogenous insulin secretion

Official Title
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Open Label Trial to Evaluate the Tolerability of a Combination Therapy Consisting of GAD-alum (Diamyd®), Etanercept and Vitamin D in Children and Adolescents Newly Diagnosed With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: GAD-Alum
* Drug: Vitamin D
* Drug: Etanercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent given by patients and parent(s)/legal guardian(s) Type 1 diabetes according to the ADA classification, diagnosed within the previous 100 days at the time of screening Age 8.00 -17.99 years at time of screening Fasting C-peptide at time of screening ≥0.12 nmol/L Positive for GADA but < 50 000 Units Menarchal females must agree to avoid pregnancy and have a negative urine pregnancy test Immunity against Varicella, either through previous infection or vaccination Patients must follow the Swedish vaccination programme Patients of childbearing potential must agree to using adequate contraception, if sexually active, until 1 year after the last administration of GAD-alum and etanercept. Adequate contraception is as follows: For females of childbearing potential: oral (except low-dose gestagen (lynestrenol and norethisterone), injectable, or implanted hormonal contraceptives (females) intrauterine device (females) intrauterine system (for example, progestin-releasing coil) (females) vasectomized male (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate) For males of childbearing potential: a. Condom (male) Exclusion Criteria: Previous or current treatment with immunosuppressant therapy (although 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) Treatment with any oral or injected anti-diabetic medications (especially hypoglycemic agents) other than insulin Treatment with Vitamin D, marketed or not, or unwilling to abstain from such medication during the trial A history of hypercalcemia A history of anaemia or significantly abnormal haematology results at screening A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles Clinically significant history of acute reaction to vaccines or other drugs in the past Treatment with any vaccine within 4 months prior to planned first administration of GAD-Alum or planned treatment with vaccine up to 4 months after the last injection with GAD-Alum, including influenza vaccine Participation in other clinical trials with a new chemical entity within the previous 3 months Inability or unwillingness to comply with the provisions of this protocol A history of alcohol or drug abuse A significant illness other than diabetes within 2 weeks prior to first dosing Known human immunodeficiency virus (HIV) Prior or active viral hepatitis B or C infection Females who are lactating or pregnant (for females who have started menstruating the possibility of pregnancy must be excluded by urine βHCG on-site within 24 hours prior to the GAD-Alum and etanercept administration, respectively) Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last GAD-Alum and etanercept administration, respectively 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. Deemed by the investigator not being able to follow instructions and/or follow the study protocol Active infection, including chronic and local infection or a history of previous tendency to serious infections, recent or ongoing uncontrolled bacterial, viral, fungal or other opportunistic infections, or known infection with active EBV or CMV Hypersensitivity to the active substance in Enbrel (etanercept) or other ingredients in Enbrel Active or inactive (latent) tuberculosis (TBC) at screening History of malignancy or significant cardiovascular disease Current or history of leukopenia, anemia and/or thrombocytopenia Liver disease (clinical or hepatic enzymes >3 times the upper limit of normal (ULN)) Renal insufficiency (clinical or creatinine >3 times the upper limit of normal (ULN)) MS, undefined neurologic condition or known SLE, or anti-nuclear or known doublestranded DNA antibody positivity Arrhythmia Pancreatitis Vitamin D serum levels >100 nmol/L at screening

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 18 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: A<br>All patients will from Day 1 receive 2 000 IU vitamin D per os per day during 15 months, and from Days 1-90 receive etanercept (Enbrel) injected subcutaneously 0.8 mg/kg body weight (max 50 mg) once a week, and receive 2 subcutaneous injections of 20 μg Diamyd in a prime-and-boost regimen on Days 30 and 60. | Drug: GAD-Alum<br>* Recombinant Human Glutamic Acid Decarboxylase (rhGAD65)<br>* Other names: Diamyd;Drug: Vitamin D<br> <br> * Other names: Cholecalciferol;Drug: Etanercept<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability | Number of patients with reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching, Other). Inspection of injection site 60 minutes after GAD-Alum injection by investigator or nurse | 1 months | 
| Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability | Number of patients with reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching, Other). Inspection of injection site 60 minutes after GAD-Alum injection by investigator or nurse | 2 months | 
| Number of Patients With Any Abnormal Findings From Physical Examinations After Baseline | Number of patients with any abnormal findings from physical examinations after baseline, including neurological assessments as an assessment of tolerability. | Month 1, 2, 3, 6, 9, 15 and 30 | 
| Number of Patients With Clinically Significant Laboratory Findings | Number of patients with clinically significant laboratory findings, laboratory measurements as an assessment of the tolerability | Month 1, 2, 3, 6, 9, 15 and 30 | 
| GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) | GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000 | 6 months | 
| GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) | GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000 | 15 months | 
| GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) | GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000 | 30 months | 
| Number of Patients With an Infection Reported as Adverse Event Related to Study Treatment | Number of patients with an infection reported as Adverse Event related to study treatment (GAD-Alum and/or Etanercept),as an assessment of the tolerability | Month 1, 2, 3, 6, 9, 15 and 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline | Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 6 months. MMTT=Mixed Meal Tolerance Test | Baseline and 6 months at 0, 30, 60, 90 and 120 minutes post-dose | 
| C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline | Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 15 months | Baseline and 15 months at 0, 30, 60, 90 and 120 minutes post-dose | 
| C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline | Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 30 months | Baseline and 30 months at 0, 30, 60, 90 and 120 minutes post-dose | 
| Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L | Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 6 months | 6 months | 
| Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L | Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 15 months | 15 months | 
| Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L | Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 30 months | 30 months | 
| Hemoglobin A1c (HbA1c), Change From Baseline | Hemoglobin A1c (HbA1c), change from baseline to 6 months | Baseline and 6 months | 
| Hemoglobin A1c (HbA1c), Change From Baseline | Hemoglobin A1c (HbA1c), change from baseline to 15 months | Baseline and 15 months | 
| Hemoglobin A1c (HbA1c), Change From Baseline | Hemoglobin A1c (HbA1c), change from baseline to 30 months | Baseline and 30 months | 
| Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline | Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline | Baseline and 6 months | 
| Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline | Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline | Baseline and 15 months | 
| Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline | Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline | Baseline and 30 months | 
| C-peptide: Stimulated, 90 Minute Value, Change From Baseline | C-peptide: Stimulated, 90 minute value, change from baseline to 6 months | Baseline and 6 months | 
| C-peptide: Stimulated, 90 Minute Value, Change From Baseline | C-peptide: Stimulated, 90 minute value, change from baseline to 15 months | Baseline and 15 months | 
| C-peptide: Stimulated, 90 Minute Value, Change From Baseline | C-peptide: Stimulated, 90 minute value, change from baseline to 30 months | Baseline and 30 months | 
| C-peptide Fasting Concentration, Change From Baseline | C-peptide: Fasting concentration, change from baseline to 6 months | Baseline and 6 months | 
| C-peptide Fasting Concentration, Change From Baseline | C-peptide: Fasting, concentration, change from baseline to 15 months | Baseline and 15 months | 
| C-peptide Fasting Concentration, Change From Baseline | C-peptide: Fasting, concentration, change from baseline to 30 months | Baseline and 30 months | 
| Spontaneous IL-17a Secretion | Spontaneous IL-17a secretion at baseline, 6 months, 9 months, 15 months and 30 months | Baseline, 6 months, 9 months, 15 months and 30 months | 
| GAD65-induced IL-4 Secretion | GAD65-induced IL-4 secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced IL-13 Secretion | GAD65-induced IL-13 secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced IFN-gamma Secretion | GAD65-induced IFN-gamma secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced TNF-alpha Secretion | GAD65-induced TNF-alpha secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced GM-CSF Secretion | GAD65-induced GM-CSF secretion baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced MIP-1b Secretion | GAD65-induced MIP-1b secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 
| GAD65-induced MCP-1 Secretion | GAD65-induced MCP-1 secretion at baseline, 6 months, 9 months, 15 months, 30 months | Baseline, 6 months, 9 months, 15 months, 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diamyd, Diabetes, Juvenile Diabetes, Diabetes Type 1, Type 1 Diabetes, Autoimmune Diabetes, Insulin Dependent Diabetes, Type 1 Diabetes MellitusType 1 Diabetes Mellitus, rhGAD65, GAD65, GAD-Alum, Diabetes Mellitus, Diabetes mellitus Type 1, Glucose Metabolism Disorders, Metabolic Diseases, Vitamin D, Etanercept