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GAD-Alum (Diamyd) Administered Into Lymph Nodes in Combination With Vitamin D in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT03345004
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : September 27, 2018
Sponsor:
Information provided by (Responsible Party):
Diamyd Medical AB

Study Description
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Brief Summary:
The objective of DIAGNODE-2 is to evaluate the efficacy of Diamyd compared to Placebo, upon administration directly into a lymph node in combination with an oral vitamin D/Placebo regimen, in terms of preserving endogenous insulin secretion as measured by C-peptide.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Diabetes Mellitus Autoimmune Diseases Metabolic Disease Glucose Metabolism Disorders Immune System Diseases Endocrine System Diseases Juvenile Diabetes Insulin Dependent Diabetes Autoimmune Diabetes Vitamin D Physiological Effects of Drugs Biological: GAD-alum Dietary Supplement: Vitamin D Biological: Placebo for Diamyd (GAD-alum) Dietary Supplement: Placebo for Vitamin D Phase 2

Detailed Description:
The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial. Eligible patients will receive injections of Diamyd/placebo into an inguinal lymph gland at three occasions, with one month intervals in combination with an oral vitamin D/placebo regimen (starting 1 month ahead of injections) during 4 months. All patients will continue to receive intensive insulin treatment from their personal physicians during the whole study period. The patients will be followed in a blinded manner for a total of 15 months.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study is a 2-arm, randomized, double-blind, placebo-controlled, multicenter, clinical trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase IIb, 2-Arm, Randomized, Double-blind, Placebo-Controlled, Multicentre Study to Optimize Diamyd® Therapy Administered Into Lymph Nodes Combined With Oral Vitamin D to Investigate the Impact on the Progression of Type 1 Diabetes
Actual Study Start Date : December 20, 2017
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Active arm
Patients will be assigned to receive i) three (3) intralymphatic injections with 4µg Diamyd (GAD-alum) on Days 30, 60, and 90 and; ii) oral vitamin D 2000 IU/daily for 4 months (from Day 1 through Day 120)
 Biological: GAD-alum
Alhydrogel®-formulated recombinant human glutamic acid decarboxylase (rhGAD)
Other Name: Diamyd

Dietary Supplement: Vitamin D
Oil suspension of Vitamin D
Placebo Comparator: Placebo arm
Patients will be assigned to receive i) three (3) intralymphatic injections of Placebo for Diamyd (GAD-alum) on Days 30, 60, and 90 and; ii) oral Placebo for vitamin D once a day for 4 months (from Day 1 through Day 120)
 Biological: Placebo for Diamyd (GAD-alum)
Alhydrogel® only

Dietary Supplement: Placebo for Vitamin D
Placebo oil suspension for Vitamin D


Outcome Measures
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Primary Outcome Measures :
  1. Change in stimulated C-peptide during a MMTT [ Time Frame: Baseline and 15 months ]
    Change in C-peptide (Area Under the Curve [AUC]mean 0-120 min) during a Mixed Meal Tolerance Test (MMTT) between baseline to 15 months.


Secondary Outcome Measures :
  1. Stimulated maximum C-peptide above 0.2 nmol/L [ Time Frame: 15 months ]
    • Proportion of patients with a stimulated maximum C-peptide level above 0.2 nmol/L (0.6 ng/ml)

  2. Stimulated C-peptide above 0.2 nmol/L at 90 min [ Time Frame: 15 months ]
    • Proportion of patients with a stimulated 90min C-peptide level above 0.2 nmol/L (0.6 ng/ml)

  3. • Change in maximum C-peptide [ Time Frame: Baseline and 15 months ]
    • Change in maximum C-peptide during MMTT (nmol/L)

  4. C-peptide levels during a MMTT [ Time Frame: 15 months ]
    • C-peptide measured at 30, 60, 90, and 120 minutes during MMTT (nmol/L) at 15 months

  5. • Change in Fasting C-peptide [ Time Frame: Baseline and 15 months ]
    • Change in Fasting C-peptide (nmol/L)

  6. Change in HbA1c [ Time Frame: Baseline and 15 months ]
    • Change in HbA1c (mmol/mol)

  7. Change in insulin consumption [ Time Frame: Baseline and 15 months ]
    • Change in daily exogenous insulin consumption (IU)

  8. Change in IDAA1c [ Time Frame: Baseline and 15 months ]
    • Change in insulin-dose-adjusted HbA1c (IDAA1c)

  9. Proportion of patients with IDAA1c ≤ 9 [ Time Frame: 15 months ]
    • Proportion of patients with IDAA1c ≤ 9

  10. Change in glycemic variability/fluctuations [ Time Frame: Screening and 15 months ]
    • Change in glycemic variability/fluctuations (evaluated from data from continuous glucose monitoring FreeStyle LibrePro, FGM) over 14 day period.

  11. Number of hypoglycemias [ Time Frame: Baseline and 15 months ]
    • Number of self-reported episodes of severe hypoglycemia (Severe hypoglycemia defined as needing help from others and/or seizures and/or unconscious) (counts)

  12. Number of patients having at least 1 severe hypoglycemic event [ Time Frame: Baseline and 15 months ]
    • Number of patients having at least 1 severe hypoglycemic event (counts)

  13. Change in Rate of hypoglycemic events [ Time Frame: Baseline and 15 months ]
    • Change in Rate of hypoglycemic events

  14. Injection site reactions [ Time Frame: 15 months ]
    • Injection site reactions

  15. Adverse Events [ Time Frame: 15 months ]
    • Occurrence of AEs

  16. Laboratory analysis of safety parameters [ Time Frame: 15 months ]
    • Laboratory measurements (hematology and clinical chemistry)

  17. Urine analysis [ Time Frame: 15 months ]
    • Urine analysis (microalbuminuria, creatinine)

  18. Physical examination [ Time Frame: 15 months ]
    • Physical examinations, including neurological assessments

  19. GAD65A titer [ Time Frame: 15 months ]
    • GAD65A titer (IU/ml)

  20. Vital signs [ Time Frame: 15 months ]
    • Vital signs (blood pressure) (mmHg)

  21. Total serum Immunoglobulin E [ Time Frame: 15 months ]
    • Total serum Immunoglobulin E (IgE) (IU/ml).

  22. Concentrations of serum autoantibodies [ Time Frame: 15 months ]
    • Concentrations of serum autoantibodies towards GAD65 and IA 2 (IU/ml).

  23. Concentrations of serum autoantibodies isotypes [ Time Frame: 15 months ]
    • Concentrations of serum autoantibody isotypes towards GAD65 (IU/ml).

  24. Cytokine secretion patterns of PBMCs [ Time Frame: 15 months ]
    • Secretion of cytokines interleukin (IL)-1, IL-2, IL-5, IL-13, IL-10, IL-17, interferon (IFN)γ, and tumour necrosis factor (TNF)α by peripheral blood mononuclear cells (PBMCs) upon stimulation with GAD65.

  25. Number of PMBCs secreting specific cytokines [ Time Frame: 15 months ]
    • Number of PBMCs secreting IL-10, IL-4 and/or IFNγ upon stimulation with GAD65 measured by enzyme linked immunosorbent spot forming cell assay (ELISPOT)

  26. Proliferation of PBMCs [ Time Frame: 15 months ]
    • Proliferation of PBMCs upon stimulation with GAD65.

  27. Flow cytometric analysis of PBMC subsets [ Time Frame: 15 months ]
    • FACS analysis of PBMC subsets.

  28. Exploratory immunological characterization [ Time Frame: 15 months ]
    • Further exploratory immunological characterization.

  29. Change in Quality of Life [ Time Frame: Baseline and 15 months ]
    • Change in QoL as measured by questionnaire EQ-5D-5L between baseline and Month 15.

  30. Quality adjusted life years [ Time Frame: 15 months ]
    • Quality adjusted life years (QALYs) based on the EQ-5D-5L questionnaire.


Eligibility Criteria
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Ages Eligible for Study:   12 Years to 24 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Informed consent given by patients and/or patient's parent(s) or legal acceptable representative(s) (guardian(s)) according to national regulations
  2. T1D according to the ADA classification diagnosed ≤6 months at the time of screening
  3. Age: ≥12 and <25 years old
  4. Fasting C-peptide ≥0.12 nmol/L (0.36 ng/ml) on at least one occasion (maximum 2 tests on different days within a period of 2 weeks)
  5. Positive for GAD65A but < 50 000 IU/ml
  6. Females must agree to avoid pregnancy and 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 Diamyd. Adequate contraception is as follows:

For females of childbearing potential:

  1. oral (except low‐dose gestagen (lynestrenol and norestisteron)), injectable, or implanted hormonal contraceptives
  2. combined (estrogen and progestogen containing)
  3. oral, intravaginal or transdermal progesterone hormonal contraception associated with inhibition of ovulation
  4. intrauterine device
  5. intrauterine hormone-releasing system (for example, progestin‐releasing coil)
  6. bilateral tubal occlusion
  7. vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate)
  8. male partner using condom
  9. abstinence from heterosexual intercourse

For males of childbearing potential:

  1. condom (male)
  2. abstinence from heterosexual intercourse

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 other than insulin
  4. A history of anemia or significantly abnormal hematology results at screening
  5. A history of epilepsy, head trauma or cerebrovascular accident, or clinical features of continuous motor unit activity in proximal muscles
  6. Clinically significant history of acute reaction to vaccines or other drugs in the past
  7. Treatment with any vaccine, including influenza vaccine, within 4 months prior to planned first study drug dose or planned treatment with any vaccine up to 4 months after the last injection with study drug.
  8. Participation in other clinical trials with a new chemical entity within the previous 3 months
  9. Inability or unwillingness to comply with the provisions of this protocol
  10. A history of alcohol or drug abuse
  11. A significant illness other than diabetes within 2 weeks prior to first dosing
  12. Known HIV or hepatitis
  13. Females who are lactating or pregnant (the possibility of pregnancy must be excluded by urine βHCG on-site within 24 hours prior to the Diamyd/placebo treatment)
  14. 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
  15. Deemed by the investigator not being able to follow instructions and/or follow the study protocol
Contacts and Locations
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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): NCT03345004


Contacts
Contact: Johnny Ludvigsson, MD, Prof +46 13 28 68 54 johnny.ludvigsson@regionostergotland.se

Locations
Czechia
Diabetes Centre, Institute of Clinical and Experimental Medicine Recruiting
Praha, Czechia, 14021
Department of Paediatrics, University Hospital Motol Recruiting
Praha, Czechia, 15006
Spain
Adult and Pediatrics Endocrinology and Diabetology, Hospital Universitario Cruces Recruiting
Barakaldo, Spain, 48903
Adult Endocrinology and Diabetology, Hospital vall D' Hebrón Recruiting
Barcelona, Spain, 08035
Pediatrics Endocrinology and Diabetology, Hospital Vall D'Hebrón Recruiting
Barcelona, Spain, 08035
Adult Endocrinology and Diabetology, Hospital Ramón y Cajal Recruiting
Madrid, Spain, 28033
Pediatrics Endocrinology and Diabetology, Hospital Ramón y Cajal Recruiting
Madrid, Spain, 28033
Adult Endocrinology and Diabetology, Hospital Carlos Haya Recruiting
Málaga, Spain, 29009
Pediatrics Endocrinology and Diabetology, Hospital Materno-Ifantil Recruiting
Málaga, Spain, 29011
Adult Endocrinology and Diabetology, Hospital Macarena Recruiting
Sevilla, Spain, 41009
Pediatrics Endocrinology and Diabetology, Hospital Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Adult and Pediatrics Endocrinology and Diabetology, Hospital Miguel Servet Recruiting
Zaragoza, Spain, 50009
Sweden
Barn- och Ungdomskliniken, Universitetssjukhuset Recruiting
Linköping, Sweden, 58185
Endokrinmedicinska kliniken. Universitetssjukhuset Recruiting
Linköping, Sweden, 58185
Barn-och Ungdomsmedicinmottagningen and Endokrinmottagningen, Skånes Universitetssjukhus Recruiting
Malmö, Sweden, 20502
Barn- och ungdomskliniken, Uddevalla Sjukhus Recruiting
Uddevalla, Sweden, 45180
Diabetesmottagningen, Uddevalla Sjukhus Recruiting
Uddevalla, Sweden, 45180
Barnmottagningen, Norrlands Universitetssjukhus Recruiting
Umeå, Sweden, 901 85
Sponsors and Collaborators
Diamyd Medical AB
Investigators
Principal Investigator: Johnny Ludvigsson, MD, Prof Universitetssjukhuset i Linköping
More Information
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Additional Information:
Information regarding the clinical trial  This link exits the ClinicalTrials.gov site

Publications:

Responsible Party: Diamyd Medical AB
ClinicalTrials.gov Identifier: NCT03345004     History of Changes
Other Study ID Numbers: DIAGNODE-2 (D/P2/17/6)
2017-001861-25 ( EudraCT Number )
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Diamyd Medical AB:
Diamyd
Diabetes
Juvenile Diabetes
Diabetes Type 1
Type 1 Diabetes
Autoimmune Diabetes
Insulin Dependent Diabetes
Type 1 Diabetes Mellitus
rhGAD65
GAD65
 GAD-Alum
Diabetes Mellitus
Diabetes Mellitus Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Vitamin D
Vitamins
Micronutrients
Cholecalciferol
Ergocalciferols

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Autoimmune Diseases
Metabolic Diseases
Glucose Metabolism Disorders
Immune System Diseases
Endocrine System Diseases
Vitamins
Vitamin D
 Ergocalciferols
Aluminum sulfate
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Adjuvants, Immunologic
Immunologic Factors