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Immune Profile in Subjects With New Onset Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT02801942
Recruitment Status : Completed
First Posted : June 16, 2016
Last Update Posted : August 2, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
It is hypothesized that early changes in the immune system in New Onset Type 1 Diabetes Mellitus (NOT1D) subjects can be detected in immune cells from the inguinal lymph nodes (iLN), which will be distinct from changes observed in peripheral blood derived immune cells. Therefore this study will assess and compare the molecular immune profile of cells derived from the iLN in healthy and NOT1D subjects, to understand the immunological processes that may lead to beta cell destruction. It is a multi-center, non-drug treatment study. Up to 15 subjects in each group, namely healthy subjects and NOT1D subjects, will be evaluated in the study. A data look will be carried out after the recruitment of a cohort of up to 5 healthy subjects, to determine if the quality and quantity of cells derived from aspirate or core biopsy or from peripheral blood are likely to be sufficient to continue the study to meet its primary objective. An interim analysis will be carried out after the recruitment of 5 evaluable healthy subjects and 5 evaluable NOT1D subjects. The primary purpose of this interim analysis will be to facilitate decision making and study design for a potential follow-up interventional study.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Procedure: Inguinal lymph node fine needle aspirate biopsy Procedure: Inguinal lymph node core biopsy Procedure: Peripheral blood collection Other: Pre- and post-biopsy questionnaire Not Applicable

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Exploration of the Peripheral Immune System in Subjects With New Onset T1 Diabetes (NOT1D)
Actual Study Start Date : July 25, 2016
Actual Primary Completion Date : December 21, 2017
Actual Study Completion Date : December 21, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Healthy subjects
Up to 30 mL of blood sample will be collected from healthy subjects. Inguinal lymph node fine needle aspirate biopsy and core biopsy will be performed. Leukocyte subset phenotyping will be carried out on iLN-derived cells by assessing expression of (but not restricted to) the following antigens: CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD24, CD25, CD38, CD45RA, CD56, Human Leukocyte antigen D related (HLA-DR) and forkhead box P3 protein also called scurfin (FOXP3).
Procedure: Inguinal lymph node fine needle aspirate biopsy
Inguinal lymph node will be localized by ultrasonography and sampled by 21-gauge needle and a 5 mL syringe using to and fro needle movement while applying 1 mL suction with the syringe. Up to 2 fine needle aspirate passages will be obtained, to derive immune cells.

Procedure: Inguinal lymph node core biopsy
Inguinal lymph node will be localized by ultrasonography and following fine needle aspirate, an incision will be made. Up to five core biopsies will be obtained, to derive immune cells.

Procedure: Peripheral blood collection
Blood sample (30 mL) will be collected, to derive immune cells.

Other: Pre- and post-biopsy questionnaire
All subjects will be asked to complete a questionnaire about their expectations/experiences of undergoing the biopsy procedures.

Experimental: Subjects with NOT1D
Up to 30 mL of blood sample will be collected from subjects with NOT1D. Inguinal lymph node fine needle aspirate biopsy and core biopsy will be performed. Leukocyte subset phenotyping will be carried out on iLN-derived cells by assessing expression of (but not restricted to) the following antigens: CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD24, CD25, CD38, CD45RA, CD56, HLA-DR and FOXP3.
Procedure: Inguinal lymph node fine needle aspirate biopsy
Inguinal lymph node will be localized by ultrasonography and sampled by 21-gauge needle and a 5 mL syringe using to and fro needle movement while applying 1 mL suction with the syringe. Up to 2 fine needle aspirate passages will be obtained, to derive immune cells.

Procedure: Inguinal lymph node core biopsy
Inguinal lymph node will be localized by ultrasonography and following fine needle aspirate, an incision will be made. Up to five core biopsies will be obtained, to derive immune cells.

Procedure: Peripheral blood collection
Blood sample (30 mL) will be collected, to derive immune cells.

Other: Pre- and post-biopsy questionnaire
All subjects will be asked to complete a questionnaire about their expectations/experiences of undergoing the biopsy procedures.




Primary Outcome Measures :
  1. Absolute number of leukocyte subsets in iLN as a candidate biomarker [ Time Frame: Biopsy session on Day 1 ]
    Up to two fine needle aspirate passages of iLN and up to five core biopsies of iLN samples will be collected at the indicated time point from both healthy and NOT1D subjects. Inguinal lymph node will be localized by ultrasonography. Candidate biomarkers associated with either location of cells (that is, iLNs derived leukocytes versus peripheral blood derived cells) and/or disease-status will be identified using flow cytometry technique.

  2. Absolute number of leukocyte subsets in peripheral blood as a candidate biomarker [ Time Frame: Pre biopsy session on Day 1 ]
    Blood samples of volume up to 30 milliliters (mL) will be collected at the indicated time point from both healthy and NOT1D subjects. Candidate biomarkers associated with either location of cells (that is, iLNs derived leukocytes versus peripheral blood derived cells) and/or disease-status will be identified using flow cytometry technique.

  3. Percentage of leukocyte subsets in iLN as a candidate biomarker [ Time Frame: Biopsy session on Day 1 ]
    Candidate biomarkers associated with either location of cells (that is, iLNs derived leukocytes versus peripheral blood derived cells) and/or disease-status will be identified using flow cytometry technique.

  4. Percentage of leukocyte subsets in peripheral blood as a candidate biomarker [ Time Frame: Pre biopsy session on Day 1 ]
    Candidate biomarkers associated with either location of cells (that is, iLNs derived leukocytes versus peripheral blood derived cells) and/or disease-status will be identified using flow cytometry technique.


Secondary Outcome Measures :
  1. Absolute number of leukocyte subsets in iLN core biopsies [ Time Frame: Biopsy session on Day 1 ]
    Up to five lymph node core biopsy samples will be collected at the indicated time point from both healthy and NOT1D subjects. Candidate biomarkers associated with type of biopsy (core biopsy versus fine needle aspirate) will be identified using flow cytometry technique.

  2. Absolute number of leukocyte subsets in iLN fine needle aspirates [ Time Frame: Biopsy session on Day 1 ]
    Up to two fine needle aspirate passages will be collected at the indicated time point from both healthy and NOT1D subjects. Candidate biomarkers associated with type of biopsy (core biopsy versus fine needle aspirate) will be identified using flow cytometry technique.

  3. Percentage of leukocyte subsets in iLN core biopsies [ Time Frame: Biopsy session on Day 1 ]
    Candidate biomarkers associated with type of biopsy (core biopsy versus fine needle aspirate) will be identified using flow cytometry technique.

  4. Percentage of leukocyte subsets in iLN fine needle aspirates [ Time Frame: Biopsy session on Day 1 ]
    Candidate biomarkers associated with type of biopsy (core biopsy versus fine needle aspirate) will be identified using flow cytometry technique.

  5. Number of subjects with adverse events (AEs) and serious adverse events (SAEs) following lymph node biopsy procedure [ Time Frame: Up to Day 14 ]
    In this study, an AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with study procedures. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgement will be categorized as SAE.

  6. Descriptive data obtained by a questionnaire on the acceptability of iLN biopsy in research setting [ Time Frame: Up to Day 4 ]
    Subjects will be asked to complete a questionnaire about their expectations/experiences of undergoing the biopsy procedures. Subjects will be required to fill the questionnaire before biopsy and after biopsy.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Between 18 and 40 years of age inclusive, at the time of signing the informed consent.
  • Healthy subjects will be as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination and laboratory tests.
  • Subjects will be considered healthy if values for the following parameters: fasted glucose, glycated hemoglobin (HbA1c), International normalized ratio (INR), activated partial thromboplastin time (APTT), platelet count, red blood cells and total lymphocyte count are within the normal range at screening.
  • NOT1D subject with documented diagnosis of diabetes mellitus according to American Diabetes Association (ADA) and World Health Organization (WHO) criteria and consistent with Type 1a (autoimmune) Diabetes Mellitus, with an interval of up to 8 weeks between the initial diagnosis and day 1 of the study (Day 1 = "iLN biopsy" day).
  • NOT1D subject, who currently requires insulin treatment for type 1 diabetes (T1D) and has received insulin therapy for at least 7 days prior to screening.
  • NOT1D subject positive, at screening, for at least one autoantibody associated with T1D: anti- Glutamic Acid Decarboxylase (GAD), anti-Islet antigen 2 (IA-2), anti- islet cell antibodies (ICA), anti-Indole 3 acetic acid (IAA), anti- Zinc transporter 8 (ZnT8).
  • NOT1D subject with evidence, at screening, of residual functioning beta cells as measured by fasted C-peptide levels >=0.15 nanomole per liter (nmol/L).
  • NOT1D subject having values for the following parameters: INR, APTT, platelet count, red blood cells and total lymphocyte count within the normal range at screening.
  • Both, male or female subjects are eligible to participate in this study. A female subject is only eligible to participate if she is not pregnant [as confirmed by a negative urine human chorionic gonadotropin (hCG) test], not lactating at screening and study visit(s) or has documented evidence to not be of child bearing potential.
  • Capable of giving signed informed consent which includes compliance with the study requirements and study restrictions.
  • A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator, in consultation with the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

Exclusion Criteria:

  • Healthy subjects having family history of T1D (that is, first degree relative has been diagnosed with T1D)
  • Healthy subjects with presence of one or more of serum autoantibodies, such as anti-GAD, anti-IA2, anti-ICA, anti-IAA, anti-ZnT8, anti-thyroid peroxidase antibodies, anti-tissue transglutaminase antibodies and anti-nuclear antibodies.
  • NOT1D subjects with history of autoimmune disease other than T1D
  • NOT1D subjects with presence of one or more of serum autoantibodies of the following: anti-thyroid peroxidase antibodies, anti-tissue transglutaminase antibodies or anti-nuclear antibodies
  • Allergy or intolerance to local anesthetic agents
  • Any localized groin condition which would contraindicate biopsy procedure including but not limited to: Active infection/inflammation at the intended puncture site, previous surgery/scarring or any other anatomical abnormality as deemed relevant to the procedure by the investigator, in consultation with the Medical Monitor if required.
  • History of bleeding disorders, current or anticipated continuous use of anticoagulant (including but not limited to warfarin, rivaroxaban) and antiplatelet agents (including but not limited to Nonsteroidal anti-inflammatory drugs [NSAIDS], clopidogrel, etc.)
  • Active or unresolved bacterial infection, viral infection, fungal infection within 4 weeks prior to day 1.
  • Known febrile episode over 38 degrees Celsius within 4 weeks prior to day 1.
  • Active organ dysfunction or previous organ allograft.
  • History of malignancy (with the exception of resected basal carcinoma of the skin or cervical carcinoma in situ).
  • Has undergone any major surgical procedure within 30 days before screening, and/or is planning to undergo any such surgery during the period of the study (i.e. from screening until the last follow-up telephone call)
  • Present or previous treatment with any cell depleting therapies or immune-modulating or suppressive agents (e.g., oral steroids), including investigational agents such as the following but not limited to e.g., Interleukin (IL)-2, alemtuzumab, anti- Cluster of Differentiation (CD) 4, anti-CD5, anti-CD3, anti-CD19, anti-CD20.
  • Vaccination =<28 days before day 1 of the study or planned during the study period
  • Current participation in an interventional clinical trial. Subjects, who participated in an interventional clinical trial previously, must wait for 3 months after completing the previous interventional clinical trial before participating in this study.
  • Any medical history or clinically relevant abnormality that is deemed by the investigator and/or medical monitor to make the subject ineligible for inclusion because of a safety concern or any situation that, in the investigator's judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures or to complete all scheduled assessments.
  • A positive pre-study drug/alcohol screen (unless positive due to prescription medication). A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • Inability to access the groin area to perform the biopsy procedure as judged by the investigator.

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): NCT02801942


Locations
United Kingdom
GSK Investigational Site
Cambridge, United Kingdom, CB2 0QQ
GSK Investigational Site
Cardiff, United Kingdom, CF14 4XN
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] March 6, 2017
Statistical Analysis Plan  [PDF] June 9, 2017


Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02801942     History of Changes
Other Study ID Numbers: 203158
First Posted: June 16, 2016    Key Record Dates
Last Update Posted: August 2, 2018
Last Verified: July 2018

Keywords provided by GlaxoSmithKline:
Biomarker
Immune Profile
Biopsy
Leukocyte subsets
Inguinal lymph nodes
Type 1 Diabetes Mellitus

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases