Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03444064 |
| Other study ID # |
Pro00071320 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2018 |
| Est. completion date |
May 15, 2024 |
Study information
| Verified date |
September 2023 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Islet transplantation is a relatively new procedure used in people with difficult to control
Type 1 diabetes. Patients who receive an islet transplant take medication that suppresses
their immune system and prevent rejection of the islet tissue. In spite of the strengths of
the current immunosuppression regimen, it has failed to enhance single-donor success rates,
and the majority of patients require 2 or more islet transplants to achieve insulin
independence. The need for life-long, high-dose immunosuppression is also associated with
substantial side effects, and continues to limit application of islet transplantation earlier
in the course of the disease.
The investigators have learned that Regulatory T cells (Tregs), a small subset of cluster of
differentiation 4+ (CD4+) T cells, have emerged as the major contributor to self-tolerance
through suppression of activation and effector function of other immune cells. Tregs function
by preventing the initiation of unwanted immune activation and by suppressing ongoing immune
response to limit bystander tissue destruction. It has been suggested that infusion of Tregs
before extensive graft damage may improve long-term graft outcomes.
This study is an open label, controlled, dose finding pilot study. Up to 18 participants will
be recruited including 12 participants receiving the investigational treatment and 6
participants being assigned to control group. All participants will undergo the routine
Standard of Care islet transplant procedure, and will be maintained on lower dose tacrolimus
and sirolimus immunosuppression.
The primary goal is to assess the safety and feasibility of intravenous infusion of ex
vivo-selected and ex vivo-expanded autologous PolyTregs in islet transplant patients. The
other goal is to assess the effect of Tregs on beta cell function in islet transplant
patients.
The control group (6) will receive the current Edmonton islet transplant induction therapy
(Alemtuzumab with Etanercept and Anakinra). The intervention group (up to 12) will receive
islet transplant with same induction therapy as control group and PolyTregs (400-1600
million) six weeks post- transplant and will be followed for 1 year to assess safety and
preliminary efficacy of Treg therapy. The Treg product will be administered via a peripheral
intravenous (IV) line primed with saline per established standard operating procedures in
approximately 20 to 30 minutes. The intravenous line will be maintained after the infusion
and the participant will be asked to remain in the hospital for 24 hours. All participants
will be maintained on low dose tacrolimus and sirolimus immunosuppression.
The investigators will also use retrospective data from the islet transplant cohort receiving
Tac/mycophenolate mofetil(MMF) with alemtuzumab (>100 patients).
All study participants will be followed up for 58 weeks. Tests and assessments will be
performed at each key study visit and will be allowed for +/- 2 weeks to accommodate
scheduling.
The following measurements will be recorded at each key study visit :
Blood work, including the following:
Complete blood count (CBC) and differential
Creatinine and electrolytes
Fasting glucose and c-peptide
Any adverse events
Physical examination
Body weight (kg)
Vital signs (BP, HR)
Glucose records for self-monitoring.
Hemoglobin A1c
Insulin use (total daily dose)
Autoantibodies and autoreactive T cell
MMTT
Immune profile
Description:
BACKGROUND:
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of
pancreatic beta (β)-cells, resulting in absolute deficiency of insulin. To date, clinical
islet transplantation is an accepted modality to treat select patients who exhibit frequent
hypoglycemic events and severe glycemic liability. The "Edmonton Protocol" became a milestone
by reporting sustained C-peptide production and high rates of insulin-independence after
transplant in patients with T1DM. Due to the challenges associated with allo- and
autoimmunity in islet transplantation, appropriate immunosuppression is necessary to prevent
acute and/or long-term rejection. Current immunosuppression protocols used in Edmonton and
many other international sites for islet transplantation consist of a combination of
induction, anti-inflammatory and maintenance therapy, accounting for higher success rates of
islet transplantation. In spite of the strengths of the current immunosuppression regimen
described above, it has failed to enhance single-donor success rates (15%), with the majority
of patients requiring 2 or more islet transplants to achieve insulin independence. In
Edmonton, clinical trials are designed to improve islet isolation, engraftment and long-term
graft survival. The need for life-long, high-dose immunosuppression is associated with
substantial side effects, and continues to limit application of islet transplantation earlier
in the course of the disease.
Regulatory T cells (Tregs) are a small subset of CD4+ T cells that depend on the FOXP3
transcription factor for their lineage differentiation and function. Tregs have emerged as
the major contributor to self-tolerance through suppression of activation and effector
function of other immune cells. Tregs function by preventing the initiation of unwanted
immune activation and by suppressing ongoing immune responses to limit bystander tissue
destruction. It has been suggested that infusion of Tregs before extensive graft damage may
improve long-term graft outcomes. Unlike generalized immunosuppressive regimens, Tregs are
long-lived and can function in a dominant and antigen-specific manner. Thus, therapeutic
infusion of Tregs has the potential to induce long-term donor-specific tolerance without
impeding desired immune responses to pathogens and tumors in transplant patients. In terms of
diabetes, both animal and human studies demonstrate the central role of Tregs in preserving
β-cell function. Infusion of Tregs prevents and even reverses diabetes in non-obese diabetic
(NOD) mice. It has been demonstrated in animal studies that infused Tregs migrate to the
allograft site shortly after transplantation and can induce stable islet graft survival
without immunosuppression. Recent human studies report functional defects of Tregs in T1DM,
which appear to be reversible.
This clinical trial is collaboration between Dr. Shapiro's Clinical Islet Transplantation
Program team in Edmonton, Alberta with Drs. Tang and Bluestone's teams at the University of
California San Francisco (UCSF). Drs. Tang and Bluestone have been instrumental in developing
PolyTreg technology, providing an opportunity for this exciting collaboration in a clinical
trial of Treg infusion in islet transplantation. Dr. Tang's team focuses on translating
knowledge on mechanisms of immune tolerance into novel therapeutics for treating autoimmune
diabetes and preventing transplant rejection. They have demonstrated the efficacy of Tregs at
multiple levels to halt tissue destruction in diabetic mouse models by subverting fully
differentiated effector T-cells. Dr. Bluestone's research over the past 25 years has focused
on understanding the basic processes that control T-cell activation and immune tolerance in
autoimmunity and organ transplantation including a special emphasis on Tregs. Dr. Bluestone
has demonstrated that PolyTreg immunotherapy can be safely administered in adult patients
with new onset T1DM. Drs. Tang and Bluestone have abundant experience in Treg isolation and
production and Treg immunotherapy, and bring strong technical and scientific support to this
project. The investigators expect that this collaboration will integrate the strengths of
both Treg immunotherapy and the standard treatment for islet transplant. Hence, this trial is
to investigate the safety and efficacy of Treg infusion incorporated into the current
protocol for islet transplantation, in the hope of finding more effective alternatives to the
current immunosuppression regimen in islet transplantation.
TRIAL DESIGN
Based on existing pre-clinical and clinical findings, the investigators hypothesize that
Tregs protect from both auto and allorejection of transplanted islets, thereby improving
insulin independent durability and C-peptide function over time in adults with T1DM.
Primary Objective
To assess the safety and feasibility of intravenous infusion of ex vivo-selected and ex
vivo-expanded autologous polyTregs in islet transplant patients.
Primary Outcome Measure/Endpoint
Adverse events
Laboratory abnormalities
Signs of toxicity
Infusion reactions
Complications related to infection
Secondary Objective
To assess effects on endogenous insulin secretion: Assess the effect of Tregs on b cell
function in islet transplant patients.
Secondary Outcome Measure/Endpoint
C-peptide response during MMTTs
Insulin use
HbA1C
Exploratory Objective
Surrogate markers of diabetes immune response: Measure the effect of PolyTregs on the
pathologic autoimmune and allo-immune responses.
Exploratory Outcome Measure/Endpoint Multicolor flow cytometry (MFC) to assess effect on
immune profile (pre- infusion, 1, 2, 4 weeks and 3, 6 and 12 months post-infusion)
Autoantibodies and autoreactive T cell using tetramer/or ELISA spot assay (pre-infusion, and
3, 6 and 12 months post infusion).
Persistence and stability of infused PolyTregs in blood using deuterium labelling (Days 1, 7,
14, 28, 3 months,6 months and 12 months after infusion)
This trial design will allow determination of the following specific aims:
To demonstrate the safety of PolyTreg immunotherapy in islet transplantation in Type 1
diabetic patients.
To assess the immunological impact of PolyTreg immunotherapy on patients receiving islet
transplant.
To assess the efficacy and to establish the optimal dose for PolyTreg immunotherapy.
The investigators propose that PolyTregs will protect/dampen both auto and allo-rejection,
thereby improving insulin independent durability and C-peptide function over time. In this
trial, the investigators propose low level Tac/Sirolimus immunosuppression, the investigators
hope that less early exposure and long-term exposure to high dose tacrolimus will lead to
marked improvement in Beta cell function, less renal dysfunction, less opportunistic
infections, less Posttransplant lymphoproliferative disease (PTLD). The long-term goal is to
develop and optimize PolyTreg dosing for a subsequent Phase 2 efficacy/safety randomized
controlled trial (RCT).
STUDY PROCEDURES
Study participants will undergo a screening evaluation for this study. This will include the
screening for standard of care islet transplant. For women of child bearing potential, the
investigators will ask to confirm they are not pregnant with a blood test. If the patient is
eligible and has consented to take part, he / she will be assigned into either the control
group or treatment group at the investigator's discretion. The only difference between the
two groups will be that the treatment group will receive PolyTregs infusion and the control
group will not receive PolyTregs infusion. The investigators will collect certain details
from his / her medical records, including age, sex, ethnicity and medical information. If the
patient is assigned into the treatment group, a blood sample of 400 mL will be collected for
PolyTregs manufacturing, which will be infused back to the patient at week 6 after islet
transplant. The investigators will enrol two participants in the control group at first and
will proceed with further enrolment for both groups if the procedure appears safe in the
first two patients.
For treatment group:
Study visit 1: Pre-islet transplant
Before initiation of islet transplant induction therapy, a total of 400 ml whole blood will
be collected and immediately transported to the UCSF for PolyTregs manufacturing.
Study visit 2: Islet transplant
At this visit, participants will undergo islet transplant according to the current standard
procedures at the University of Alberta Hospital. The only difference will be the use of
lower doses of Tacrolimus/Sirolimus for immunosuppression.
Study visit 3: 30 days ± 7 days post-islet transplant
At visit 2, participants will have standard of care metabolic testing and blood samples taken
in the Clinical Investigation Unit (CIU) at the University of Alberta Hospital (UAH). These
tests assess the function of transplanted islets and include an arginine-stimulated c-peptide
test and an Ensure test. Blood samples will be taken at various time intervals over
approximately 90 minutes and will test for: HbA1c, c-peptide, insulin and glucose. The
investigators may also ask to review participants' insulin usage /blood glucose records. In
addition, a blood sample will be collected for the testing of immune profiles, antibodies and
T cell function.
Study visit 4: PolyTreg infusion (6 weeks ± 7 days post-islet transplant)
The participant will be admitted to UAH at week 6 post-islet transplantation for PolyTregs
infusion. He / she will stay at the UAH for 24 hours for monitoring after the infusion. A
blood sample will be collected to assess the persistence and stability of infused PolyTregs
while the participant stays in the hospital.
Study visit 5: 1 week ± 2 days post-PolyTregs infusion
A blood sample will be collected at UAH at Day 7 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs and participants' immune profiles.
Study visit 6: 2 weeks ± 4 days post-PolyTregs infusion
A blood sample will be collected at UAH at Day 14 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs and participants' immune profiles.
Study visit 7: 4 weeks ± 7 days post-PolyTregs infusion
A blood sample will be collected at UAH at Day 28 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs and participants' immune profiles.
Study visit 8: 6 weeks ± 7 days post-PolyTregs infusion (12 weeks ± 7 days post-islet
transplant)
At this visit, participants will have standard of care metabolic testing and blood samples
taken in the CIU at the UAH. These tests assess the function of transplanted islets and
include an arginine-stimulated c-peptide test and an Ensure test. Blood samples will be taken
at various time intervals over approximately 90 minutes and will test for: HbA1c, c-peptide,
insulin and glucose. The investigators may also ask to review participants' insulin usage
/blood glucose records.
Study visit 9: 12 weeks ± 7 days post-PolyTregs infusion
A blood sample will be collected at UAH at week 12 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs, immune profiles and antibodies and T cell
function.
Study visit 10: 26 weeks ± 30 days post-PolyTregs infusion
A blood sample will be collected at UAH at week 26 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs, immune profiles and antibodies and T cell
function.
Study visit 11: 52 weeks ± 30 days post-PolyTregs infusion
A blood sample will be collected at UAH at week 52 after PolyTregs infusion to assess the
persistence and stability of infused PolyTregs, immune profiles and antibodies and T cell
function. Participants will also have standard of care metabolic testing and blood samples
taken in the CIU at UAH. These tests assess the function of transplanted islets and include
an arginine-stimulated c-peptide test and an Ensure test. Blood samples will be taken at
various time intervals over approximately 90 minutes and will test for: HbA1c, c-peptide,
insulin and glucose. The investigators may also ask to review participants' insulin usage
/blood glucose records.
Long-term Standard of Care Follow-up
After study visit 11, participants will be followed by the standard of care schedule for
islet transplant.
For control group:
Study visit 1: Islet transplant
At this visit, participants will undergo islet transplant according to the current standard
procedures at the University of Alberta Hospital. The only difference will be the use of
lower doses of Tacrolimus/ Sirolimus for immunosuppression.
Study visit 2: 30 days (± 7 days) post-islet transplant
At visit 2, participants will have standard of care metabolic testing and blood samples taken
in the Clinical Investigation Unit (CIU) at the University of Alberta Hospital (UAH). These
tests assess the function of transplanted islets and include an arginine-stimulated c-peptide
test and an Ensure test. Blood samples will be taken at various time intervals over
approximately 90 minutes and will test for: HbA1c, c-peptide, insulin and glucose. The
investigators may also ask to review patient's insulin usage /blood glucose records. In
addition, a blood sample will be collected for the testing of immune profiles, antibodies and
T cell function.
Study visit 3: 7 weeks ± 7 days post-islet transplant
At visit 3, a blood sample will be collected at UAH to assess participants' immune profiles.
Study visit 4: 8 weeks ± 7 days post-islet transplant
At visit 4, a blood sample will be collected at UAH to assess participants' immune profiles.
Study visit 5: 10 weeks ± 7 days post-islet transplant
At visit 5, a blood sample will be collected at UAH to assess participants' immune profiles.
Study visit 6: 12 weeks ± 7 days post-islet transplant
At this visit, participants will have standard of care metabolic testing and blood samples
taken in the Clinical Investigation Unit (CIU) at the University of Alberta Hospital (UAH).
These tests assess the function of transplanted islets and include an arginine-stimulated
c-peptide test and an Ensure test. Blood samples will be taken at various time intervals over
approximately 90 minutes and will test for: HbA1c, c-peptide, insulin and glucose. The
investigators may also ask to review patient's insulin usage /blood glucose records.
Study visit 7: 18 weeks ± 7 days post-islet transplant
At visit 7, a blood sample will be collected at UAH to assess participants' immune profiles
and antibodies and T cell function.
Study visit 8: 32 weeks ± 30 days post-islet transplant
At visit 8, a blood sample will be collected at UAH to assess participants' immune profiles
and antibodies and T cell function.
Study visit 9: 58 weeks ± 30 days post-islet transplant
At visit 9, a blood sample will be collected at UAH to assess participants' immune profiles
and antibodies and T cell function. Study participants will also have standard of care
metabolic testing and blood samples taken in the CIU at UAH. These tests assess the function
of transplanted islets and include an arginine-stimulated c-peptide test and an Ensure test.
Blood samples will be taken at various time intervals over approximately 90 minutes and will
test for: HbA1c, c-peptide, insulin and glucose. The investigators may also ask to review
participants' insulin usage /blood glucose records.
Long-term Standard of Care Follow-up
After study visit 9, participants will be followed by the standard of care schedule for islet
transplant.
