An Immunotherapy Vaccine (PIpepTolDC) for the Treatment of Patients With Type 1 Diabetes
Primary Purpose
Type 1 Diabetes Mellitus
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tolerogenic Dendritic Cell Vaccine
Sponsored by
About this trial
This is an interventional treatment trial for Type 1 Diabetes Mellitus
Eligibility Criteria
Inclusion Criteria:
- Willingness to undergo leukapheresis
- Willingness to be followed for about 2 years post-prime dose
- For participants who have a personal continuous glucose monitoring device (CGMD): Willingness to wear a second CGMD during mandated study CGMD visits
- Diagnosis of type 1 diabetes based on American Diabetes Association (ADA) criteria
Historical presence of at least one type-1 diabetes associated autoantibody
- GAD specific autoantibodies (glutamic acid decarboxylase autoantibodies [GADA])
- Islet cell cytoplasmic autoantibodies (ICA)
- Islet-antigen 2 specific autoantibody (IA-2A)
- Zinc transporter 8 specific autoantibody (ZNT8A); and/or
- Insulin autoantibody (IAA) (must have been obtained within 7 days of initiating exogenous insulin replacement therapy)
- Time from diagnosis to screening mixed meal tolerance test (MMTT) must be >= 1 year but =< 4 years
- Stable glycemic control per participant's physician
- HbA1c =< 7.5% (=< 58 mmol/mol)
- Non-fasting C-peptide > 0.017 nmol/L
- Stimulated peak C-peptide levels > 0.2 nmol/L from a 2-hour screening MMTT
- Positive for *04:01 allele, *04:02 allele and/or *04:04 allele at the human leukocyte antigen (HLA)-DRB1 gene locus
- Does not possess the protective HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype
- Adequate self-assessment of blood glucose values and recording of glucose values, and administered insulin doses as deemed sufficient by the participant's physician
- No diagnosis of type 1 diabetes related microvascular/macrovascular complications (e.g. nephropathy, retinopathy and neuropathy)
- Deemed acceptable for autologous cell collection (i.e. leukapheresis)
- Only for those who are naive to CGMD use: Deemed able to correctly use a CGM device following training session with a certified diabetes educator and manufacturer representative
- Must meet organ function criteria
Exclusion Criteria:
- Other investigational agents, biologics
Anti-inflammatory therapy
- Exception: Over-the-counter (OTC) anti-inflammatory agents (e.g. ibuprofen, Tylenol) are generally allowed. However, those requiring chronic OTC anti-inflammatory agents and unable to stop during mandated CGMD study visits will be excluded
- Systemic corticosteroids within 28 days prior to leukapheresis
- Systemic immunosuppressive therapy (e.g. cyclosporine-A, cyclophosphamide)
- Monoclonal antibody therapy
- Allergen immunotherapy within 28 days prior to leukapheresis
- Vaccine(s) within 28 days prior to leukapheresis
- Prior allogeneic organ transplant
- Beta-cell stimulants (e.g. sulfonylureas such as glimepiride), glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors (exception: Those with acute exposure to these agents during T1D misdiagnosis may be permitted per PI discretion)
- Insulin sensitizers (e.g. metformin, thiazolidinediones) within 2 months of leukapheresis
- History of insulin sensitizer use (e.g. metformin, thiazolidinediones) ≥ 2 months
- Other autoimmune/inflammatory disorders (exceptions: (i) Type 1 diabetes. (ii) Asymptomatic patients with incidental autoantibody titres may be permitted per PI discretion)
- Other autoimmune/inflammatory disorders (exception type 1 diabetes)
- Active infection requiring antibiotics and/or anti-virals
- Known history of HIV, HBV, HCV, HTLV, syphilis
- History of positive purified protein derivative (PPD) skin test
- History of atopy requiring systemic treatment and/or history of severe allergic reactions
- History or current malignancy
- Unstable cardiac disease
- History of vascular disease (e.g. deep vein thrombosis, stroke)
- Clinically significant uncontrolled illness
- Females only: pregnant or breastfeeding
Sites / Locations
- City of Hope Medical CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Autologous Tolerogenic Dendritic Cell with Proinsulin Peptide (PIpepTolDC)
Arm Description
After completion of leukapheresis, patients receive a prime dose of PIpepTolDC intradermally (ID) on Day 0, followed by a boost dose of PIpepTolDC ID on Day 28.
Outcomes
Primary Outcome Measures
Incidence of adverse events
Toxicity and adverse events (except hypoglycemia and diabetic ketoacidosis [DKA]) will be recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Hypoglycemia events and DKA will be defined per American Diabetes Association (ADA) grading systems.Observed toxicities will be summarized by type, severity (by CTCAE v 5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.
Apheresis duration
Measured in hours.
Number of CD14+ monocytes
Number of CD14+ monocytes collected during apheresis
TolDC recovery after culture
Number of TolDC generated from CD14+ monocytes
Number of successful manufactured products
Number of manufactured products that meet the required cell dose/day, sterility (e.g. endotoxin and gram staining), and viability compared to the total number of products manufactured.
Secondary Outcome Measures
Change in stimulated C-peptide area under the curve
Assessed via 2-hr mixed meal tolerance test (MMTT). C-peptide preservation is defined as the maintenance of baseline C-peptide levels.
Change in interferon (IFN)-gamma and IL-10 producing CD4+ T cells
Will be assessed in response to pro-insulin peptide C19-A3, and assessed via cytokine enzyme-linked immunosorbent spot assay.
Change in T cell responsiveness
Will assess for changes in T cell responsiveness to pro-insulin peptide C19-A3 compared to other antigens. Assessed via Lymphocyte Simulation Test.
Change in the number of CD8+ autoreactive T cells
Assessed via quantum dot (Q-DOT) nanotechnology assay.
Change in immune phenotype
Will analyze for changes in immune cell populations via flow cytometry
Change in islet autoantibodies
Will analyze for changes in IAA, GAA, IA-2A, ZnT8A via enzyme-linked immunosorbent assay.
Change in glycosylated hemoglobin A1c (HbA1c) levels
HbA1c levels will be assessed via blood test
Change in exogenous insulin use (units/kg)
Insulin usage will be recorded daily from the insulin pump and/or participant insulin use logs. The mean daily insulin usage over the 10 consecutive days (IU units/kg body weight/day) preceding the clinic visit will be calculated for each participant.
Change in blood glucose levels
Will include clinically important/severe hypoglycemia, hyperglycemia and DKA events as assessed by ADA grading systems. Levels of glucose will be assessed from bloods samples taken during the MMTT and from insulin pump/participant insulin logs
Full Information
NCT ID
NCT04590872
First Posted
October 6, 2020
Last Updated
June 14, 2023
Sponsor
City of Hope Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT04590872
Brief Title
An Immunotherapy Vaccine (PIpepTolDC) for the Treatment of Patients With Type 1 Diabetes
Official Title
A Pilot Study to Evaluate the Safety and Feasibility of Autologous Tolerogenic Dendritic Cells Loaded With Proinsulin Peptide (C19-A3) in Patients With Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 16, 2022 (Actual)
Primary Completion Date
October 10, 2024 (Anticipated)
Study Completion Date
October 10, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase I trial investigates the side effects of PIpepTolDC vaccine in treating patients with type 1 diabetes who use insulin and don't have any other diabetes-related health complications. Type 1 diabetes is an autoimmune disease. This means that the immune system, which usually protects against foreign invaders like bacteria and viruses, attacks the body's insulin-producing betacells in the pancreas (autoimmune response). Overtime, the beta cells are destroyed by the immune system. To stay alive, people with type 1 diabetes must use insulin. PIpepTolDC vaccine is a type of immunotherapy (a treatment that uses a person's own immune system) that works like an allergy shot. The vaccine is made using one's own immune cells (dendritic cells) and a beta cell protein. The vaccine may teach the immune system to stop attacking the beta cells, which may help the beta cells recover and make enough insulin to control blood sugar levels. The vaccine may also help reduce future type 1 diabetes related complications.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes Mellitus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Autologous Tolerogenic Dendritic Cell with Proinsulin Peptide (PIpepTolDC)
Arm Type
Experimental
Arm Description
After completion of leukapheresis, patients receive a prime dose of PIpepTolDC intradermally (ID) on Day 0, followed by a boost dose of PIpepTolDC ID on Day 28.
Intervention Type
Biological
Intervention Name(s)
Tolerogenic Dendritic Cell Vaccine
Intervention Description
PIpepTolDCs
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Toxicity and adverse events (except hypoglycemia and diabetic ketoacidosis [DKA]) will be recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Hypoglycemia events and DKA will be defined per American Diabetes Association (ADA) grading systems.Observed toxicities will be summarized by type, severity (by CTCAE v 5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.
Time Frame
Up to 2 years
Title
Apheresis duration
Description
Measured in hours.
Time Frame
up to 2 years
Title
Number of CD14+ monocytes
Description
Number of CD14+ monocytes collected during apheresis
Time Frame
up to 2 years
Title
TolDC recovery after culture
Description
Number of TolDC generated from CD14+ monocytes
Time Frame
up to 2 years
Title
Number of successful manufactured products
Description
Number of manufactured products that meet the required cell dose/day, sterility (e.g. endotoxin and gram staining), and viability compared to the total number of products manufactured.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Change in stimulated C-peptide area under the curve
Description
Assessed via 2-hr mixed meal tolerance test (MMTT). C-peptide preservation is defined as the maintenance of baseline C-peptide levels.
Time Frame
Baseline up to 2 years of follow up
Title
Change in interferon (IFN)-gamma and IL-10 producing CD4+ T cells
Description
Will be assessed in response to pro-insulin peptide C19-A3, and assessed via cytokine enzyme-linked immunosorbent spot assay.
Time Frame
Baseline up to 2 years of follow up
Title
Change in T cell responsiveness
Description
Will assess for changes in T cell responsiveness to pro-insulin peptide C19-A3 compared to other antigens. Assessed via Lymphocyte Simulation Test.
Time Frame
Baseline up to 2 years of follow up
Title
Change in the number of CD8+ autoreactive T cells
Description
Assessed via quantum dot (Q-DOT) nanotechnology assay.
Time Frame
Baseline up to 2 years of follow up
Title
Change in immune phenotype
Description
Will analyze for changes in immune cell populations via flow cytometry
Time Frame
Baseline up to 2 years of follow up
Title
Change in islet autoantibodies
Description
Will analyze for changes in IAA, GAA, IA-2A, ZnT8A via enzyme-linked immunosorbent assay.
Time Frame
Baseline up to 2 years of follow up
Title
Change in glycosylated hemoglobin A1c (HbA1c) levels
Description
HbA1c levels will be assessed via blood test
Time Frame
Baseline up to 2 years of follow up
Title
Change in exogenous insulin use (units/kg)
Description
Insulin usage will be recorded daily from the insulin pump and/or participant insulin use logs. The mean daily insulin usage over the 10 consecutive days (IU units/kg body weight/day) preceding the clinic visit will be calculated for each participant.
Time Frame
Baseline up to 2 years of follow up
Title
Change in blood glucose levels
Description
Will include clinically important/severe hypoglycemia, hyperglycemia and DKA events as assessed by ADA grading systems. Levels of glucose will be assessed from bloods samples taken during the MMTT and from insulin pump/participant insulin logs
Time Frame
Baseline up to 2 years of follow up
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Willingness to undergo leukapheresis
Willingness to be followed for about 2 years post-prime dose
For participants who have a personal continuous glucose monitoring device (CGMD): Willingness to wear a second CGMD during mandated study CGMD visits
Diagnosis of type 1 diabetes based on American Diabetes Association (ADA) criteria
Historical presence of at least one type-1 diabetes associated autoantibody
GAD specific autoantibodies (glutamic acid decarboxylase autoantibodies [GADA])
Islet cell cytoplasmic autoantibodies (ICA)
Islet-antigen 2 specific autoantibody (IA-2A)
Zinc transporter 8 specific autoantibody (ZNT8A); and/or
Insulin autoantibody (IAA) (must have been obtained within 7 days of initiating exogenous insulin replacement therapy)
Time from diagnosis to screening mixed meal tolerance test (MMTT) must be >= 1 year but =< 4 years
Stable glycemic control per participant's physician
HbA1c =< 7.5% (=< 58 mmol/mol)
Non-fasting C-peptide > 0.017 nmol/L
Stimulated peak C-peptide levels > 0.2 nmol/L from a 2-hour screening MMTT
Positive for *04:01 allele, *04:02 allele and/or *04:04 allele at the human leukocyte antigen (HLA)-DRB1 gene locus
Does not possess the protective HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype
Adequate self-assessment of blood glucose values and recording of glucose values, and administered insulin doses as deemed sufficient by the participant's physician
No diagnosis of type 1 diabetes related microvascular/macrovascular complications (e.g. nephropathy, retinopathy and neuropathy)
Deemed acceptable for autologous cell collection (i.e. leukapheresis)
Only for those who are naive to CGMD use: Deemed able to correctly use a CGM device following training session with a certified diabetes educator and manufacturer representative
Must meet organ function criteria
Exclusion Criteria:
Other investigational agents, biologics
Anti-inflammatory therapy
Exception: Over-the-counter (OTC) anti-inflammatory agents (e.g. ibuprofen, Tylenol) are generally allowed. However, those requiring chronic OTC anti-inflammatory agents and unable to stop during mandated CGMD study visits will be excluded
Systemic corticosteroids within 28 days prior to leukapheresis
Systemic immunosuppressive therapy (e.g. cyclosporine-A, cyclophosphamide)
Monoclonal antibody therapy
Allergen immunotherapy within 28 days prior to leukapheresis
Vaccine(s) within 28 days prior to leukapheresis
Prior allogeneic organ transplant
Beta-cell stimulants (e.g. sulfonylureas such as glimepiride), glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors (exception: Those with acute exposure to these agents during T1D misdiagnosis may be permitted per PI discretion)
Insulin sensitizers (e.g. metformin, thiazolidinediones) within 2 months of leukapheresis
History of insulin sensitizer use (e.g. metformin, thiazolidinediones) ≥ 2 months
Other autoimmune/inflammatory disorders (exceptions: (i) Type 1 diabetes. (ii) Asymptomatic patients with incidental autoantibody titres may be permitted per PI discretion)
Other autoimmune/inflammatory disorders (exception type 1 diabetes)
Active infection requiring antibiotics and/or anti-virals
Known history of HIV, HBV, HCV, HTLV, syphilis
History of positive purified protein derivative (PPD) skin test
History of atopy requiring systemic treatment and/or history of severe allergic reactions
History or current malignancy
Unstable cardiac disease
History of vascular disease (e.g. deep vein thrombosis, stroke)
Clinically significant uncontrolled illness
Females only: pregnant or breastfeeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Coordinator
Phone
866-444-7538
Email
DL-TolDC@coh.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Behrouz Salehian-Dardashti, MD
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Behrouz Salehian-Dardashti
Phone
866-444-7538
Email
DL-TolDC@coh.org
First Name & Middle Initial & Last Name & Degree
Behrouz Salehian-Dardashti
12. IPD Sharing Statement
Learn more about this trial
An Immunotherapy Vaccine (PIpepTolDC) for the Treatment of Patients With Type 1 Diabetes
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