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

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

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

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Etanercept; Drug: Vitamin D; Drug: GAD-Alum

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Helsingborg, Sweden
    • Helsingborg Hospital
  • Linköping, Sweden
    • Linkoping University Hospital
  • Lund, Sweden
    • Lund University Hospital
  • Malmö, Sweden
    • Skåne University Hospital, UMAS
  • Stockholm, Sweden
    • Sachsska, Södersjukhuset
  • Uddevalla, Sweden
    • Uddevalla Hospital
  • Västerås, Sweden
    • Västerås Hospital
  • Örebro, Sweden
    • Orebro University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Informed consent given by patients and parent(s)/legal guardian(s)
2. Type 1 diabetes according to the ADA classification, diagnosed within the previous 100 days at the time of screening
3. Age 8.00 -17.99 years at time of screening
4. Fasting C-peptide at time of screening ≥0.12 nmol/L
5. Positive for GADA but < 50 000 Units
6. Menarchal females must agree to avoid pregnancy and have a negative urine pregnancy test
7. Immunity against Varicella, either through previous infection or vaccination
8. Patients must follow the Swedish vaccination programme
9. 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:

1. oral (except low-dose gestagen (lynestrenol and norethisterone), injectable, or implanted hormonal contraceptives (females)
2. intrauterine device (females)
3. intrauterine system (for example, progestin-releasing coil) (females)
4. vasectomized male (with appropriate postvasectomy documentation of the absence of sperm in the ejaculate)

For males of childbearing potential:

a. Condom (male)

Exclusion Criteria:

1. Previous or current treatment with immunosuppressant therapy (although topical or inhaled steroids are accepted)
2. Continuous treatment with anti-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 (especially hypoglycemic agents) 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 hypercalcemia
6. A history of anaemia or significantly abnormal haematology results at screening
7. A history of epilepsy, head trauma or cerebro-vascular accident, or clinical features of continuous motor unit activity in proximal muscles
8. Clinically significant history of acute reaction to vaccines or other drugs in the past
9. 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
10. Participation in other clinical trials with a new chemical entity within the previous 3 months
11. Inability or unwillingness to comply with the provisions of this protocol
12. A history of alcohol or drug abuse
13. A significant illness other than diabetes within 2 weeks prior to first dosing
14. Known human immunodeficiency virus (HIV)
15. Prior or active viral hepatitis B or C infection
16. 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)
17. Males or females not willing to use adequate contraception, if sexually active, until 1 year after the last GAD-Alum and etanercept administration, respectively
18. 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.
19. Deemed by the investigator not being able to follow instructions and/or follow the study protocol
20. 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
21. Hypersensitivity to the active substance in Enbrel (etanercept) or other ingredients in Enbrel
22. Active or inactive (latent) tuberculosis (TBC) at screening
23. History of malignancy or significant cardiovascular disease
24. Current or history of leukopenia, anemia and/or thrombocytopenia
25. Liver disease (clinical or hepatic enzymes >3 times the upper limit of normal (ULN))
26. Renal insufficiency (clinical or creatinine >3 times the upper limit of normal (ULN))
27. MS, undefined neurologic condition or known SLE, or anti-nuclear or known doublestranded DNA antibody positivity
28. Arrhythmia
29. Pancreatitis
30. Vitamin D serum levels >100 nmol/L at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A; 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: Etanercept; Drug: Vitamin D; Other Names: Cholecalciferol; Drug: GAD-Alum; Recombinant Human Glutamic Acid Decarboxylase (rhGAD65); Other Names: Diamyd

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johnny Ludvigsson
• Collaborators: Ostergotland County Council, Sweden; Diamyd Medical AB; Swedish Child Diabetes Foundation

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (ACTUAL): February 25, 2019
• Study Completion (ACTUAL): February 25, 2019

Study Registration Dates

• First Submitted: May 19, 2015
• First Submitted That Met QC Criteria: June 4, 2015
• First Posted (ESTIMATE): June 8, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 29, 2021
• Last Update Submitted That Met QC Criteria: March 26, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Diabetes; Vitamin D; Diabetes Mellitus; Type 1 Diabetes; Diamyd; Diabetes Type 1; GAD65; GAD-Alum; Diabetes mellitus Type 1; Glucose Metabolism Disorders; Metabolic Diseases; rhGAD65; Etanercept; Autoimmune Diabetes; Juvenile Diabetes; Insulin Dependent Diabetes; Type 1 Diabetes MellitusType 1 Diabetes Mellitus
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Etanercept; Vitamin D; Cholecalciferol
• Other Study ID Numbers: EDCR IIa