Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Type 1 Diabetes (PARADIGM)
Primary Purpose
Type 1 Diabetes
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Co-transplantation of PTG with pancreatic islets
Sponsored by
About this trial
This is an interventional treatment trial for Type 1 Diabetes
Eligibility Criteria
Inclusion Criteria:
- Male and female subjects age 18 or older.
- Subjects who are able to provide written informed consent and to comply with study procedures.
- Clinical history compatible with Type 1 diabetes (onset < 40 yrs old and insulin dependent for > 5 yrs at enrollment, c-peptide negative).
- Recipients should have absent stimulated c-peptide (< 0.3 ng/mL) in response to a (Boost® 6 mL/kg BW to a maximum of 360 mL; another equivalent product), measured at 60 and 90 min after start of consumption.
- Subjects who are > 6 months post-renal transplant or >6 months post-liver transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic ± Prednisone ≤ 10 mg/day).
- Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 6 previous months prior to islet transplant, as well as absence of a rejection episode in the 6 months prior to islet transplant
- Stable liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values < 1.5, or total bilirubin < 1.5 times normal upper limits at time of study entry, as well as absence of a rejection episode in the 6 months prior to islet transplant
Exclusion Criteria:
- Presence of donor specific anti-HLA antibodies detected by Luminex Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross match
- Insulin requirement of >1.0 IU/kg/day
- Weight more than 100 kg or body mass index (BMI) > 30 kg/m2.
- Primary hyperparathyroidism OR secondary hyperparathyroidism
- Untreated or unstable proliferative diabetic retinopathy.
- Blood Pressure: SBP > 180 mmHg or DBP >100 mmHg despite treatment with antihypertensive agents.
- Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation, as well as presence of a rejection episode in the 6 months prior to islet transplant
- Elevated liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values > 1.5, or total bilirubin >1.5 times normal upper limits at time of study entry, as well as presence of a rejection episode in the 6 months prior to islet transplant
- Proteinuria (albumin/creatinine ratio or ACr > 300mg/g) of new onset since kidney transplantation.
- 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 subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
- Active infection including hepatitis B, hepatitis C, HIV, or TB. Quantiferon gold assay will be used to determine TB infection.
- Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within 1 year prior to study entry.
- Any history of malignancy following receiving either the kidney or liver transplant, except for completely resected squamous or basal cell carcinoma of the skin
- Known active alcohol or substance abuse.
Severe co-existing cardiac disease, characterized by any one of these conditions:
- Recent MI (within past 6 months),
- Evidence of ischemia on functional cardiac exam within the last year,
- Left ventricular ejection fraction < 30%,
- Valvular disease requiring replacement with prosthetic valve.
- Active infections (except mild skin and nail fungal infections).
- Active peptic ulcer disease or gastritis, symptomatic gallstones, or portal hypertension.
- Use of any investigational agents within 4 weeks of enrollment.
- 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 study completion.
- Positive screen for BK viremia at time of screening.
- Untreated hyperlipidemia - TC > 200 mg/dL, TGC > 200 mg/dL, LDL > 130 mg/dL
Sites / Locations
- University of CaliforniaRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
PTG with adult pancreatic islet co-transplantation
Arm Description
People with Type 1 (c-peptide negative) diabetes with stable kidney or liver allografts on chronic immunosuppression who receive study intervention, which is co-transplantation of allogeneic parathyroid (PTG) with adult pancreatic islets in people with Type 1 diabetes in the intramuscular (IM) site
Outcomes
Primary Outcome Measures
Incidence of adverse events
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Incidence of post-transplant infections and malignancies
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Incidence of de novo sensitization
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Incidence of Insulin independence
Efficacy: Incidence of participants no longer using insulin
Secondary Outcome Measures
Glycemic control
Assessed by measuring HbA1c using high-performance liquid chromatography
Glycemic lability
Assessed with the Mean Amplitude of Glycemic Excursions (MAGE) test
Hypoglylcemic episodes: Clarke Survey Score
The Clarke survey will be used to assess the frequency and severity of hypoglycemic episodes
Hypoglylcemic episodes: Hypo Score
The HYPO score will be used to assess the frequency and severity of hypoglycemic episodes
Beta cell function as assessed by Mixed Meal Tolerance Test (MMTT)
Results from both MMTT and FSIGT will be used to assess beta cell function
Beta cell function as assessed by Insulin-Modified Frequently-Sampled Intravenous Glucose ToleranceTest (FSIGT)
Results from both MMTT and FSIGT will be used to assess beta cell function
Full Information
NCT ID
NCT03977662
First Posted
May 24, 2019
Last Updated
May 15, 2023
Sponsor
Peter Stock
Collaborators
California Institute for Regenerative Medicine (CIRM)
1. Study Identification
Unique Protocol Identification Number
NCT03977662
Brief Title
Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Type 1 Diabetes
Acronym
PARADIGM
Official Title
Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Diabetes in the Intra-Muscular Site
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2019 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
January 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Peter Stock
Collaborators
California Institute for Regenerative Medicine (CIRM)
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 primary objective is to test the hypothesis that co-transplantation of allogeneic PTG with adult pancreatic islets (derived from same deceased donor) in the IM site in people with Type 1 diabetes with functioning kidney and/or liver transplants is safe, allows islet engraftment, and leads to insulin independence.
Detailed Description
Single-center, open label, non-randomized safety and efficacy trial to evaluate co-transplantation of allogeneic parathyroid glands (PTG) with adult pancreatic islets (both PTG and pancreatic islets obtained from same deceased donor) in people with Type 1 diabetes in the intramuscular (IM) site with stable function of liver or kidney allografts on chronic immunosuppression.
A total of 8 patients will be enrolled in the study and followed for a minimum of 1 year up to 2 years after the last islet transplant, depending on enrollment date.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
PTG with adult pancreatic islet co-transplantation
Arm Type
Experimental
Arm Description
People with Type 1 (c-peptide negative) diabetes with stable kidney or liver allografts on chronic immunosuppression who receive study intervention, which is co-transplantation of allogeneic parathyroid (PTG) with adult pancreatic islets in people with Type 1 diabetes in the intramuscular (IM) site
Intervention Type
Combination Product
Intervention Name(s)
Co-transplantation of PTG with pancreatic islets
Intervention Description
Co-transplantation of allogeneic parathyroid glands (PTG) with adult pancreatic islets (both PTG and pancreatic islets obtained from same deceased donor) in people with Type 1 diabetes in the intramuscular (IM) site with stable function of liver or kidney allografts on chronic immunosuppression
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Time Frame
Minimum of 1 year up to 2 years depending on transplant date
Title
Incidence of post-transplant infections and malignancies
Description
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Time Frame
Minimum of 1 year up to 2 years depending on transplant date
Title
Incidence of de novo sensitization
Description
Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.
Time Frame
Minimum of 1 year up to 2 years depending on transplant date
Title
Incidence of Insulin independence
Description
Efficacy: Incidence of participants no longer using insulin
Time Frame
Minimum of 1 year up to 2 years depending on transplant date
Secondary Outcome Measure Information:
Title
Glycemic control
Description
Assessed by measuring HbA1c using high-performance liquid chromatography
Time Frame
Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2
Title
Glycemic lability
Description
Assessed with the Mean Amplitude of Glycemic Excursions (MAGE) test
Time Frame
Day 75, Day 180, Day 270, Year 1
Title
Hypoglylcemic episodes: Clarke Survey Score
Description
The Clarke survey will be used to assess the frequency and severity of hypoglycemic episodes
Time Frame
Day 75, Day 180, Day 270, Year 1
Title
Hypoglylcemic episodes: Hypo Score
Description
The HYPO score will be used to assess the frequency and severity of hypoglycemic episodes
Time Frame
Day 75, Day 180, Day 270, Year 1
Title
Beta cell function as assessed by Mixed Meal Tolerance Test (MMTT)
Description
Results from both MMTT and FSIGT will be used to assess beta cell function
Time Frame
Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2
Title
Beta cell function as assessed by Insulin-Modified Frequently-Sampled Intravenous Glucose ToleranceTest (FSIGT)
Description
Results from both MMTT and FSIGT will be used to assess beta cell function
Time Frame
Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male and female subjects age 18 or older.
Subjects who are able to provide written informed consent and to comply with study procedures.
Clinical history compatible with Type 1 diabetes (onset < 40 yrs old and insulin dependent for > 5 yrs at enrollment, c-peptide negative).
Recipients should have absent stimulated c-peptide (< 0.3 ng/mL) in response to a (Boost® 6 mL/kg BW to a maximum of 360 mL; another equivalent product), measured at 60 and 90 min after start of consumption.
Subjects who are > 6 months post-renal transplant or >6 months post-liver transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic ± Prednisone ≤ 10 mg/day).
Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 6 previous months prior to islet transplant, as well as absence of a rejection episode in the 6 months prior to islet transplant
Stable liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values < 1.5, or total bilirubin < 1.5 times normal upper limits at time of study entry, as well as absence of a rejection episode in the 6 months prior to islet transplant
Exclusion Criteria:
Presence of donor specific anti-HLA antibodies detected by Luminex Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross match
Insulin requirement of >1.0 IU/kg/day
Weight more than 100 kg or body mass index (BMI) > 30 kg/m2.
Primary hyperparathyroidism OR secondary hyperparathyroidism
Untreated or unstable proliferative diabetic retinopathy.
Blood Pressure: SBP > 180 mmHg or DBP >100 mmHg despite treatment with antihypertensive agents.
Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation, as well as presence of a rejection episode in the 6 months prior to islet transplant
Elevated liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values > 1.5, or total bilirubin >1.5 times normal upper limits at time of study entry, as well as presence of a rejection episode in the 6 months prior to islet transplant
Proteinuria (albumin/creatinine ratio or ACr > 300mg/g) of new onset since kidney transplantation.
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 subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
Active infection including hepatitis B, hepatitis C, HIV, or TB. Quantiferon gold assay will be used to determine TB infection.
Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within 1 year prior to study entry.
Any history of malignancy following receiving either the kidney or liver transplant, except for completely resected squamous or basal cell carcinoma of the skin
Known active alcohol or substance abuse.
Severe co-existing cardiac disease, characterized by any one of these conditions:
Recent MI (within past 6 months),
Evidence of ischemia on functional cardiac exam within the last year,
Left ventricular ejection fraction < 30%,
Valvular disease requiring replacement with prosthetic valve.
Active infections (except mild skin and nail fungal infections).
Active peptic ulcer disease or gastritis, symptomatic gallstones, or portal hypertension.
Use of any investigational agents within 4 weeks of enrollment.
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 study completion.
Positive screen for BK viremia at time of screening.
Untreated hyperlipidemia - TC > 200 mg/dL, TGC > 200 mg/dL, LDL > 130 mg/dL
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Patricia Brennan, RN, PhD
Phone
415-476-3229
Email
Patricia.Brennan@ucsf.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Rodney Rogers
Phone
415-514-6454
Email
Rodney.Rogers@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Stock, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patricia Brennan, RN, PhD
Phone
415-476-3229
Email
Patricia.Brennan@ucsf.edu
12. IPD Sharing Statement
Learn more about this trial
Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Type 1 Diabetes
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