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

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ClinicalTrials.gov Identifier: NCT02464033
Recruitment Status : Completed
First Posted : June 8, 2015
Results First Posted : September 25, 2019
Last Update Posted : September 25, 2019
Sponsor:
Collaborators:
Swedish Child Diabetes Foundation
Ostergotland County Council, Sweden
Diamyd Medical AB
Information provided by (Responsible Party):
Johnny Ludvigsson, Linkoeping University

Brief Summary:

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

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Drug: GAD-Alum Drug: Vitamin D Drug: Etanercept Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2015
Actual Primary Completion Date : February 25, 2019
Actual Study Completion Date : February 25, 2019

Resource links provided by the National Library of Medicine


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: GAD-Alum
Recombinant Human Glutamic Acid Decarboxylase (rhGAD65)
Other Name: Diamyd

Drug: Vitamin D
Other Name: Cholecalciferol

Drug: Etanercept



Primary Outcome Measures :
  1. Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability [ Time Frame: 1 months ]
    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. Number of Patients With Reactions of the Injection Site as an Assessment of the Tolerability [ Time Frame: 2 months ]
    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

  3. Number of Patients With Any Abnormal Findings From Physical Examinations After Baseline [ Time Frame: Month 1, 2, 3, 6, 9, 15 and 30 ]
    Number of patients with any abnormal findings from physical examinations after baseline, including neurological assessments as an assessment of tolerability.

  4. Number of Patients With Clinically Significant Laboratory Findings [ Time Frame: Month 1, 2, 3, 6, 9, 15 and 30 ]
    Number of patients with clinically significant laboratory findings, laboratory measurements as an assessment of the tolerability

  5. GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) [ Time Frame: 6 months ]
    GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000

  6. GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) [ Time Frame: 15 months ]
    GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000

  7. GAD65AB Titer Measured to Evaluate the Tolerability (Main Study Period) [ Time Frame: 30 months ]
    GAD65AB titer (GADA) change from baseline. GAD65AB = Antibodies to GAD with molecular mass 65000

  8. Number of Patients With an Infection Reported as Adverse Event Related to Study Treatment [ Time Frame: Month 1, 2, 3, 6, 9, 15 and 30 ]
    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


Secondary Outcome Measures :
  1. C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline [ Time Frame: Baseline and 6 months at 0, 30, 60, 90 and 120 minutes post-dose ]
    Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 6 months. MMTT=Mixed Meal Tolerance Test

  2. C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline [ Time Frame: Baseline and 15 months at 0, 30, 60, 90 and 120 minutes post-dose ]
    Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 15 months

  3. C-peptide: Area Under the Curve (AUC 0-120 Min) During an MMTT, Change From Baseline [ Time Frame: Baseline and 30 months at 0, 30, 60, 90 and 120 minutes post-dose ]
    Weighted mean C-peptide: (AUC mean 0-120 min) during an MMTT, change from baseline to 30 months

  4. Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L [ Time Frame: 6 months ]
    Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 6 months

  5. Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L [ Time Frame: 15 months ]
    Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 15 months

  6. Number of Patients With a Stimulated Maximum C-peptide Level Above 0.2 Nmol/L [ Time Frame: 30 months ]
    Number of patients with a stimulated maximum C-peptide level above 0.2 nmol/L at 30 months

  7. Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 6 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 6 months

  8. Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 15 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 15 months

  9. Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 30 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 30 months

  10. Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline [ Time Frame: Baseline and 6 months ]
    Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline

  11. Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline [ Time Frame: Baseline and 15 months ]
    Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline

  12. Exogenous Insulin Dose Per kg Body Weight and 24 Hours, Change From Baseline [ Time Frame: Baseline and 30 months ]
    Exogenous 24-hour insulin dose per kg body weight and 24 hours average, change from baseline

  13. C-peptide: Stimulated, 90 Minute Value, Change From Baseline [ Time Frame: Baseline and 6 months ]
    C-peptide: Stimulated, 90 minute value, change from baseline to 6 months

  14. C-peptide: Stimulated, 90 Minute Value, Change From Baseline [ Time Frame: Baseline and 15 months ]
    C-peptide: Stimulated, 90 minute value, change from baseline to 15 months

  15. C-peptide: Stimulated, 90 Minute Value, Change From Baseline [ Time Frame: Baseline and 30 months ]
    C-peptide: Stimulated, 90 minute value, change from baseline to 30 months

  16. C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 6 months ]
    C-peptide: Fasting concentration, change from baseline to 6 months

  17. C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 15 months ]
    C-peptide: Fasting, concentration, change from baseline to 15 months

  18. C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 30 months ]
    C-peptide: Fasting, concentration, change from baseline to 30 months

  19. Change in Immune System Markers From Baseline to Month 6 (Main Study Period) and Subsequent Visits During the Extension Study Period [ Time Frame: Baseline and 6, 9, 15 and 30 months ]
    Inflammatory markers, (e.g. TNF-alfa, IL-1 beta, IL-2, IL-17); Th2-deviation of cell-mediated immune response seen e.g. as increased ratio IL-5,10, 13 in comparison with IFN-gamma, TNF-alfa, IL-1 beta and IL-17; Regulatory T-cells. TNF=Tumor necrosis factor , IL=Interleukin, IFN=Interferon



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Ages Eligible for Study:   8 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02464033


Locations
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Sweden
Helsingborg Hospital
Helsingborg, Sweden
Linköping University Hospital
Linköping, Sweden
Lund University Hospital
Lund, Sweden
Skåne University Hospital, UMAS
Malmö, Sweden
Sachsska, Södersjukhuset
Stockholm, Sweden
Uddevalla Hospital
Uddevalla, Sweden
Västerås Hospital
Västerås, Sweden
Örebro University Hospital
Örebro, Sweden
Sponsors and Collaborators
Johnny Ludvigsson
Swedish Child Diabetes Foundation
Ostergotland County Council, Sweden
Diamyd Medical AB
Investigators
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Principal Investigator: Johnny Ludvigsson, MD,PhD,Prof Linkoeping University
  Study Documents (Full-Text)

Documents provided by Johnny Ludvigsson, Linkoeping University:
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Responsible Party: Johnny Ludvigsson, MD, PhD, Professor, Linkoeping University
ClinicalTrials.gov Identifier: NCT02464033    
Other Study ID Numbers: EDCR IIa
First Posted: June 8, 2015    Key Record Dates
Results First Posted: September 25, 2019
Last Update Posted: September 25, 2019
Last Verified: September 2019
Keywords provided by Johnny Ludvigsson, Linkoeping University:
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
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Vitamin D
Cholecalciferol
Etanercept
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors