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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02464033
Recruitment Status : Completed
First Posted : June 8, 2015
Results First Posted : September 25, 2019
Last Update Posted : March 29, 2021
Sponsor:
Collaborators:
Swedish Child Diabetes Foundation
Ostergotland County Council, Sweden
Diamyd Medical AB
Information provided by (Responsible Party):
Johnny Ludvigsson, Linkoeping University

Tracking Information
First Submitted Date  ICMJE May 19, 2015
First Posted Date  ICMJE June 8, 2015
Results First Submitted Date  ICMJE June 10, 2019
Results First Posted Date  ICMJE September 25, 2019
Last Update Posted Date March 29, 2021
Study Start Date  ICMJE May 2015
Actual Primary Completion Date February 25, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 24, 2019)
  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: June 4, 2015)
  • Reactions of the injection site as an assessment of the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Reactions of the injection site (Erythema, Oedema, Haematoma, Tenderness, Pain, Itching)
  • To Evaluate the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Incidence of infection as an assessment of the tolerability of a combination therapy
  • Number of adverse events and number of participants with adverse events as an assessment of the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Number of adverse events and number of participants with adverse events
  • Number of serious adverse events and number of participants with serious adverse events as an assessment of the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Number of serious adverse events and number of participants with serious adverse events
  • Physical examinations, including neurological assessments as an assessment of the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Physical examinations, including neurological assessments
  • Laboratory measurements as an assessment of the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    Laboratory measurements (biochemistry and haematology), including Calcium and Vitamin D in serum
  • GAD65AB titer measured to Evaluate the tolerability of a combination therapy with Diamyd, Vitamin D and etanercept at Month 6 (main study Period) [ Time Frame: 6 months ]
    GAD65AB titer (GADA)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2021)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 6 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 6 months
  • Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 15 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 15 months
  • Hemoglobin A1c (HbA1c), Change From Baseline [ Time Frame: Baseline and 30 months ]
    Hemoglobin A1c (HbA1c), change from baseline to 30 months
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 6 months ]
    C-peptide: Fasting concentration, change from baseline to 6 months
  • C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 15 months ]
    C-peptide: Fasting, concentration, change from baseline to 15 months
  • C-peptide Fasting Concentration, Change From Baseline [ Time Frame: Baseline and 30 months ]
    C-peptide: Fasting, concentration, change from baseline to 30 months
  • Spontaneous IL-17a Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months and 30 months ]
    Spontaneous IL-17a secretion at baseline, 6 months, 9 months, 15 months and 30 months
  • GAD65-induced IL-4 Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced IL-4 secretion at baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced IL-13 Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced IL-13 secretion at baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced IFN-gamma Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced IFN-gamma secretion at baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced TNF-alpha Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced TNF-alpha secretion at baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced GM-CSF Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced GM-CSF secretion baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced MIP-1b Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced MIP-1b secretion at baseline, 6 months, 9 months, 15 months, 30 months
  • GAD65-induced MCP-1 Secretion [ Time Frame: Baseline, 6 months, 9 months, 15 months, 30 months ]
    GAD65-induced MCP-1 secretion at baseline, 6 months, 9 months, 15 months, 30 months
Original Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2015)
  • Change in immune system markers from baseline to Month 6 (main study period) and subsequent visits during the extension study period [ Time Frame: 6 months, 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
  • C-peptide: Area Under the Curve (mean 0-120 min) during an MMTT, change from baseline [ Time Frame: 6 months, 9, 15 and 30 months ]
  • Proportion of patients with a stimulated maximum C-peptide level above 0.2 nmol/L [ Time Frame: 6 months, 9, 15 and 30 months ]
  • Hemoglobin A1c (HbA1c), change from baseline [ Time Frame: 6 months, 9, 15 and 30 months ]
  • Exogenous insulin dose per kg body weight and 24 hours, change from baseline [ Time Frame: 6 months, 9, 15 and 30 months ]
  • C-peptide: Fasting, 90 minute value, change from baseline [ Time Frame: 6 months, 9, 15 and 30 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE EDCR Study - Etanercept Diamyd Combination Regimen -Open Trial to Evaluate Safety in Children With Type 1 Diabetes
Official Title  ICMJE 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
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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE
  • Drug: GAD-Alum
    Recombinant Human Glutamic Acid Decarboxylase (rhGAD65)
    Other Name: Diamyd
  • Drug: Vitamin D
    Other Name: Cholecalciferol
  • Drug: Etanercept
Study Arms  ICMJE 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.
Interventions:
  • Drug: GAD-Alum
  • Drug: Vitamin D
  • Drug: Etanercept
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 4, 2015)		 20
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 25, 2019
Actual Primary Completion Date February 25, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02464033
Other Study ID Numbers  ICMJE EDCR IIa
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Johnny Ludvigsson, Linkoeping University
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Johnny Ludvigsson
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Swedish Child Diabetes Foundation
  • Ostergotland County Council, Sweden
  • Diamyd Medical AB
Investigators  ICMJE
Principal Investigator: Johnny Ludvigsson, MD,PhD,Prof Linkoeping University
PRS Account Linkoeping University
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP