Clinical trial NCT02801942: Immune Profile in Subjects With New Onset Type 1 Diabetes
Official title: Exploration of the Peripheral Immune System in Subjects With New Onset T1 Diabetes (NOT1D)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: Biomarker
Immune Profile
Biopsy
Leukocyte subsets
Inguinal lymph nodes
Type 1 Diabetes Mellitus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-06-16
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility 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.

Primary outcomes:
measure: Percentage of Leukocyte Subsets Including B Lymphocytes, Classical B Lymphocytes, Double Negative B Lymphocytes, Naive B Lymphocytes, Plasmablast and Transitional B Lymphocytes in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including B Lymphocytes, Classical B Lymphocytes, Double Negative B Lymphocytes, Naive B Lymphocytes, Plasmablast and Transitional B Lymphocytes in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including B-cells, Clusters of Differentiation 56 Positive (CD56+) CD16+ , CD56bright Natural Killer (NK) Cells, CD56lo CD16+, CD56lo CD16 Negative (CD56lo CD16-), Dendritic Cells, NK Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including B-cells, CD56+ CD16+, CD56bright NK Cells, CD56lo CD16+, CD56lo CD16-, Dendritic Cells, NK Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD56+CD16+, CD56bright NK Cells, CD56lo CD16+ and CD56lo CD16- in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD56+CD16+, CD56bright NK Cells CD56lo CD16+ and CD56lo CD16- in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Myeloid Dendritic Cells and Plasmacytoid Dendritic Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Myeloid Dendritic Cells and Plasmacytoid Dendritic Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD14+ CD16+ Monocytes, CD14+ Monocytes, and CD16+ Monocytes in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD14+ CD16+ Monocytes, CD14+ Monocytes and CD16+ Monocytes in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD45RA+ Effector Memory CD8, Central Memory CD8, Effector Memory CD8, Naive CD8 and Stem Cell Memory-like CD8 Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD45RA+ Effector Memory CD8, Central Memory CD8, Effector Memory CD8, Naive CD8 and Stem Cell Memory-like CD8 Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Programmed Death 1 (PD-1)+ Inducible Costimulator (ICOS)+ Follicular Helper T (TFH) Cell-like Regulatory (Reg) T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including PD-1+ ICOS+ TFH Cell-like Reg T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including PD-1+ ICOS+ TFH Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including PD-1+ ICOS+ TFH Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Central Memory Conventional (Conv) T Cells, Effector Memory Conv T Cells, Naive Conv T Cells and Stem Cell Memory-like Conv T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Central Memory Conv T Cells, Effector Memory Conv T Cells, Naive Conv T Cells and Stem Cell Memory-like Conv T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, Type 17 T Helper (TH17) Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 T Cells, TH1 TH2 Cells, TH2 Cells, and TH22 Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, Type 17 T Helper (TH17) Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 T Cells, TH1 TH2 Cells, TH2 Cells, and TH22 Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 Cells, TH1 TH2 Cells, TH17 Cells, TH2 Cells and TH22 Cells-like Reg T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 Cells, TH1 TH2 Cells, TH17 Cells, TH2 Cells and TH22 Cells-like Reg T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Reg T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Reg T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD69+ CD8 and Antigen Ki67 (Ki67)+ CD8 in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD69+ CD8 and Antigen Ki67 (Ki67)+ CD8 in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Reg T Cells, CD69+ Reg T Cells, Helios+ Reg T Cells, Ki67+ T Reg Cells, Memory Reg T Cells and Resting Reg T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Reg T Cells, CD69+ Reg T Cells, Helios+ Reg T Cells, Ki67+ T Reg Cells, Memory Reg T Cells and Resting Reg T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Conv T Cells, CD69+ Conv T Cells, Helios+ Conv T Cells and Ki67+ Conv T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Conv T Cells, CD69+ Conv T Cells, Helios+ Conv T Cells and Ki67+ Conv T Cells in iLN
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Memory Conv T Cells, CD69+ Memory Conv T Cells, Helios+ Memory Conv T Cells and Ki67+ Memory Conv T Cells in Blood
timeFrame: Pre Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Memory Conv T Cells, CD69+ Memory Conv T Cells, Helios+ Memory Conv T Cells and Ki67+ Memory Conv T Cells in iLN
timeFrame: Biopsy session on Day 1
Secondary outcomes:
measure: Percentage of Leukocyte Subsets Including B Lymphocytes, Classical B Lymphocytes, Double Negative B Lymphocytes, Naive B Lymphocytes, Plasmablast and Transitional B Lymphocytes in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including B-cells, CD56+ CD16+, CD56bright NK Cells, CD56lo CD16+, CD56lo CD16, Dendritic Cells, NK Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD56+CD16+, CD56br NK Cells CD56lo CD16+ and CD56lo CD16- in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Myeloid Dendritic Cells and Plasmacytoid Dendritic Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD14+ CD16+ Monocytes, CD14+ Monocytes and CD16+ Monocytes in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD45RA+ Effector Memory CD8, Central Memory CD8, Effector Memory CD8, Naive CD8 and Stem Cell Memory-like CD8 in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including PD-1+ ICOS+ TFH Cell-like Reg T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including PD-1+ ICOS+ TFH Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Central Memory Conv T Cells, Effector Memory Conv T Cells, Naive Conv T Cells and Stem Cell Memory-like Conv T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, TH17 Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 T Cells, TH1 TH2 Cells, TH2 Cells, and TH22 Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including TFH Cells, PD-1+ ICOS+ TFH Cells, TH1 Cells, TH1 TH17 Cells, TH1 TH17 TH2 Cells, TH1 TH2 Cells, TH17 Cells, TH2 Cells and TH22 Cells-like Reg T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including Reg T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD69+ CD8 and Antigen Ki67 (Ki67)+ CD8 in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Reg T Cells, CD69+ Reg T Cells, Helios+ Reg T Cells, Ki67+ T Reg Cells, Memory Reg T Cells and Resting Reg T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Conv T Cells, CD69+ Conv T Cells, Helios+ Conv T Cells and Ki67+ Conv T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Percentage of Leukocyte Subsets Including CD15s+ Memory Conv T Cells, CD69+ Memory Conv T Cells, Helios+ Memory Conv T Cells and Ki67+ Memory Conv T Cells in iLN Core Biopsies and iLN FNA
timeFrame: Biopsy session on Day 1
measure: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs
timeFrame: Up to Day 14
measure: Number of Participants Undergoing Procedure Under Local Anesthetics
timeFrame: Up to Day 4
measure: Number of Participants Undergoing iLN Biopsy Under Local Anesthetics
timeFrame: Up to Day 4
measure: Number of Participants With Different Reasons for Participating in the Study
timeFrame: Up to Day 4
measure: Number of Participants With Extreme Anxiety Towards the Lymph Node Biopsy
timeFrame: Up to Day 4
measure: Number of Participants Looking Forward to Undergo the Procedure
timeFrame: Up to Day 4
measure: Number of Participants With Aspects Better Explained About the Lymph Node Biopsy Procedure
timeFrame: Up to Day 4
measure: Number of Participants Who Considered to Undergo Lymph Node Biopsy Procedure Another Time
timeFrame: Up to Day 4
measure: Number of Participants Who Were Encouraged to be Included in Study for iLN Biopsy
timeFrame: Up to Day 4
measure: Number of Participants Who Appreciated Receiving Study Feedback
timeFrame: Up to Day 4
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Cardiff
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: