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Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy

Primary Purpose

Islet Transplantation

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Infusion of recipient T regulatory cell
Infusion of concomitant Donor Derived Vertebral Bone Marrow
Sponsored by
Stanford University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Islet Transplantation

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Male and female patients age 18 to 70 years of age. Ability to provide written informed consent. Mentally stable and able to comply with the procedures of the study protocol. Clinical history compatible with T1D with onset of disease at < 45 years of age, insulin- dependence for ≥ 5 years at the time of enrollment, or a sum of patient age and insulin dependent diabetes duration of ≥ 28. Absence of stimulated C peptide (< 0.3 ng/mL) in response to a mixed meal tolerance test measured at 60 and 90 minutes after the start of consumption Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the 12 months prior to study enrollment. At least two episodes of severe hypoglycemia in the 12 months prior to study enrollment. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR a HYPO score greater than or equal to the 90th percentile (1047) during the screening period and within the last 6 months prior to randomization. Women of childbearing potential may be enrolled if a pregnancy test is negative, and they agree to the use of 2 forms of contraception from Screening to the end of the study. Males must agree to use 2 forms of contraception from Screening to the end of the study if their partners are of childbearing potential. Acceptable methods of birth control which must be used together are: Oral contraceptive and condom (combination oral contraceptives containing the second- generation progestin (levonorgestrel) and <30 μg of estrogen should be utilized), IUD and condom, Diaphragm with spermicide and condom Subject must complete training on how to use the Tandem X2 pump with Control IQ technology by a certified Diabetes Educator or physician. Patients must complete at least 2 hour training to the satisfaction of the educator and show proficiency and understanding in its use as judged by the educator. Patients with prior kidney transplantation on immunosuppressive medications are eligible provided they meet all eligibility criteria above excluding the need for hypoglycemia unawareness. Patients should not be candidates for solid organ pancreas transplant or have declined the surgical option. Exclusion Criteria: Body mass index (BMI) >30 kg/m2 or patient weight ≤50kg. Insulin requirement of >1.0 IU/kg/day or <15 U/day. 3. HbA1c >10%. Treatment with any anti-diabetic medication other than insulin within 4 weeks of Screening Untreated proliferative diabetic retinopathy. Blood Pressure: SBP >180 mmHg or DBP >100 mmHg on optimal treatment. Estimated glomerular filtration rate of <50 mL/min/1.73m2. Presence or history of macroalbuminuria (>500mg/g creatinine). Presence or history of panel-reactive anti-HLA antibodies >50%. Negative cross- match by flow cytometry and no DSA to organ donor by standard methods. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male participants: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception Presence of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection. Negative screen for Epstein-Barr Virus (EBV) by IgG determination. Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin. Known active alcohol or substance abuse. Baseline Hb below the lower limits of normal; neutropenia (<1,500/7L), or thrombocytopenia (platelets <100,000/7L). Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after islet transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) >1.5. Severe co-existing cardiac disease, characterized by any one of these conditions: recent myocardial infarction (within past 6 months). evidence of uncorrectable ischemia on functional cardiac exam within the last year. left ventricular ejection fraction <30%. Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT]), or total bilirubin, with values > 1.5 times normal upper limits will exclude a patient. Acute or chronic pancreatitis. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. Use of any investigational agents within 4 or more weeks of enrollment, depending upon the pharmacokinetics of the investigational agent and durability of changes with treatment in immune function or glycemic regulation. Administration of live attenuated vaccine(s) within 2 months of enrollment. Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial. A previous islet transplant. History of medical non-adherence or poor social support. Individuals with selective IgA deficiencies (IgA level less than 15 mg/dL) who have known antibody against IgA.

Sites / Locations

  • Stanford University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Recipient T Regulatory Cell

Donor Derived Vertebral Bone Marrow

Arm Description

T regulatory cells prior to islet transplantation, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).

Deceased donor vertebral bone marrow (VBM) cells, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).

Outcomes

Primary Outcome Measures

Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
Occurrence of grade 4 or greater adverse events of islet transplantation
Adverse event grade 4 or greater
Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)
Number of patients who received planned Treg or Donor Bone Marrow

Secondary Outcome Measures

HbA1c ≤6.5%
HbA1c ≤6.5%
Absence of severe hypoglycemic events
Absence of severe hypoglycemic event , requiring intervention by other person than the patient
Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose
Reduction of exogenous insulin requirement by 50% from baseline
Clarke hypoglycemia severity (HYPO) score less than 2 (0 to >4, >4 indicate severe hypoglycemia unawareness)
Improvement of Clarke score to less than 2
Basal C-peptide at levels e >0.5 ng/mL (>0.17 nmol/L) fasting or stimulated.
C-petide production from islet transplant assessment
Target of glucose variability and hypoglycemia duration derived from the CGMS <Standard Deviation and Coefficient targets>
Monitoring of glucose control 24h sensor monitoring
Measurement of donor Specific Antibody, cPRA
Single bead luminex anti HLA class 1 and 2 assay
Quality of life (QOL) assessment
QOL questionnaire SF-12 (0-100, higher score is better outcome)

Full Information

First Posted
June 14, 2023
Last Updated
August 18, 2023
Sponsor
Stanford University
Collaborators
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT05973734
Brief Title
Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy
Official Title
Clinical Islet Transplantation With Apheresis, Isolation and Reintroduction of Recipient Regulatory T Cells or Administration of Deceased Donor Vertebral Bone Marrow in Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 1, 2023 (Anticipated)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
May 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University
Collaborators
University of California, San Francisco

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to learn if patients who have brittle type 1 diabetes receiving an islet transplantation will have better control of their sugars if they also receive one of 2 types of immune cells along with the islet transplant. The participants will receive either their own immune cells, called regulatory T cells, or immune cells from the bone marrow of the islet donor.
Detailed Description
Islet transplantation success remains limited by the immediate loss of islet after transplantation, rejection, and side effect from immunosuppression. Preclinical animal models provide evidence that donor bone marrow cells OR regulatory T cells infused at the time of islet transplantation can improve the survival of islets after transplantation and reduce the need for immunosuppression. The purpose of this study is to evaluate the feasibility and safety of combining an islet transplant with the recipient's Tregs OR deceased donor bone marrow cells in patients with brittle type 1 diabetes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Islet Transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
All patients are planned to receive an islet transplantation. The patients will also receive either Arm 1) recipient T regulatory cell infusion or arm 2) same donor vertebral body derived bone marrow cell infusion. Attribution to either arm will be based on the availability of either cell product in specific cases.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Recipient T Regulatory Cell
Arm Type
Experimental
Arm Description
T regulatory cells prior to islet transplantation, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).
Arm Title
Donor Derived Vertebral Bone Marrow
Arm Type
Experimental
Arm Description
Deceased donor vertebral bone marrow (VBM) cells, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).
Intervention Type
Biological
Intervention Name(s)
Infusion of recipient T regulatory cell
Intervention Description
Patients will undergo a single apheresis collection with a target total blood volume of 20-30 L and the collected cells used as the source of purified Tregs to be infused following the islet transplantation. In the event a patient is unable to meet the collection target, a second collection may be performed.
Intervention Type
Biological
Intervention Name(s)
Infusion of concomitant Donor Derived Vertebral Bone Marrow
Intervention Description
The cells from the donor VB and spleen are processed under cGMP conditions and released for infusion after the respective recipient has undergone transplant and conditioning. Under this protocol, the donor's VB will be obtained at the same time as the pancreatic islets and will be the source of HSC for infusion with the intent to establish immune tolerance to the donor's pancreatic islet cells. Subjects will receive one infusion of allogeneic cadaveric islets. Subjects will receive induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF). After islet transplantation, the VBM cells will be infused in one time window: on day 0-1. Subjects will undergo closed-loop insulin pump glucose control peri-transplant.
Primary Outcome Measure Information:
Title
Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
Description
Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
Time Frame
within 3 months
Title
Occurrence of grade 4 or greater adverse events of islet transplantation
Description
Adverse event grade 4 or greater
Time Frame
Within two years
Title
Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)
Description
Number of patients who received planned Treg or Donor Bone Marrow
Time Frame
Within two years
Secondary Outcome Measure Information:
Title
HbA1c ≤6.5%
Description
HbA1c ≤6.5%
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Absence of severe hypoglycemic events
Description
Absence of severe hypoglycemic event , requiring intervention by other person than the patient
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose
Description
Reduction of exogenous insulin requirement by 50% from baseline
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Clarke hypoglycemia severity (HYPO) score less than 2 (0 to >4, >4 indicate severe hypoglycemia unawareness)
Description
Improvement of Clarke score to less than 2
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Basal C-peptide at levels e >0.5 ng/mL (>0.17 nmol/L) fasting or stimulated.
Description
C-petide production from islet transplant assessment
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Target of glucose variability and hypoglycemia duration derived from the CGMS <Standard Deviation and Coefficient targets>
Description
Monitoring of glucose control 24h sensor monitoring
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Measurement of donor Specific Antibody, cPRA
Description
Single bead luminex anti HLA class 1 and 2 assay
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation
Title
Quality of life (QOL) assessment
Description
QOL questionnaire SF-12 (0-100, higher score is better outcome)
Time Frame
assessed at 6, 12 and 24 months post-islet transplantation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female patients age 18 to 70 years of age. Ability to provide written informed consent. Mentally stable and able to comply with the procedures of the study protocol. Clinical history compatible with T1D with onset of disease at < 45 years of age, insulin- dependence for ≥ 5 years at the time of enrollment, or a sum of patient age and insulin dependent diabetes duration of ≥ 28. Absence of stimulated C peptide (< 0.3 ng/mL) in response to a mixed meal tolerance test measured at 60 and 90 minutes after the start of consumption Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the 12 months prior to study enrollment. At least two episodes of severe hypoglycemia in the 12 months prior to study enrollment. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR a HYPO score greater than or equal to the 90th percentile (1047) during the screening period and within the last 6 months prior to randomization. Women of childbearing potential may be enrolled if a pregnancy test is negative, and they agree to the use of 2 forms of contraception from Screening to the end of the study. Males must agree to use 2 forms of contraception from Screening to the end of the study if their partners are of childbearing potential. Acceptable methods of birth control which must be used together are: Oral contraceptive and condom (combination oral contraceptives containing the second- generation progestin (levonorgestrel) and <30 μg of estrogen should be utilized), IUD and condom, Diaphragm with spermicide and condom Subject must complete training on how to use the Tandem X2 pump with Control IQ technology by a certified Diabetes Educator or physician. Patients must complete at least 2 hour training to the satisfaction of the educator and show proficiency and understanding in its use as judged by the educator. Patients with prior kidney transplantation on immunosuppressive medications are eligible provided they meet all eligibility criteria above excluding the need for hypoglycemia unawareness. Patients should not be candidates for solid organ pancreas transplant or have declined the surgical option. Exclusion Criteria: Body mass index (BMI) >30 kg/m2 or patient weight ≤50kg. Insulin requirement of >1.0 IU/kg/day or <15 U/day. 3. HbA1c >10%. Treatment with any anti-diabetic medication other than insulin within 4 weeks of Screening Untreated proliferative diabetic retinopathy. Blood Pressure: SBP >180 mmHg or DBP >100 mmHg on optimal treatment. Estimated glomerular filtration rate of <50 mL/min/1.73m2. Presence or history of macroalbuminuria (>500mg/g creatinine). Presence or history of panel-reactive anti-HLA antibodies >50%. Negative cross- match by flow cytometry and no DSA to organ donor by standard methods. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male participants: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception Presence of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection. Negative screen for Epstein-Barr Virus (EBV) by IgG determination. Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin. Known active alcohol or substance abuse. Baseline Hb below the lower limits of normal; neutropenia (<1,500/7L), or thrombocytopenia (platelets <100,000/7L). Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after islet transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) >1.5. Severe co-existing cardiac disease, characterized by any one of these conditions: recent myocardial infarction (within past 6 months). evidence of uncorrectable ischemia on functional cardiac exam within the last year. left ventricular ejection fraction <30%. Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT]), or total bilirubin, with values > 1.5 times normal upper limits will exclude a patient. Acute or chronic pancreatitis. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. Use of any investigational agents within 4 or more weeks of enrollment, depending upon the pharmacokinetics of the investigational agent and durability of changes with treatment in immune function or glycemic regulation. Administration of live attenuated vaccine(s) within 2 months of enrollment. Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial. A previous islet transplant. History of medical non-adherence or poor social support. Individuals with selective IgA deficiencies (IgA level less than 15 mg/dL) who have known antibody against IgA.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kevin Ly, BS
Phone
650-497-6057
Email
kevinly@stanford.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Stephan Busque, MD
Phone
650-498-6189
Email
sbusque@stanford.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephan Busque, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kevin Ly, BS
Phone
650-497-6057
Email
kevinly@stanford.edu
First Name & Middle Initial & Last Name & Degree
Stephan Busque, MD
First Name & Middle Initial & Last Name & Degree
Stephan Busque, MD
First Name & Middle Initial & Last Name & Degree
Everett Meyer, MD
First Name & Middle Initial & Last Name & Degree
Marina Basina, MD
First Name & Middle Initial & Last Name & Degree
Avnesh S Thakor, MD, PhD
First Name & Middle Initial & Last Name & Degree
Thomas A Pham, MD
First Name & Middle Initial & Last Name & Degree
Kent P Jensen, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
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Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy

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