Chronic Pancreatitis, Insulin Dependent Diabetes
Conditions
Keywords
Pancreatectomy, Autologous Islet Transplantation, Pancreatitis, Diabetes, Hydroxychloroquine
Brief summary
This will be a pilot, 12-month phase II, open label, randomized, two-arm, single-blinded, placebo-controlled, parallel clinical trial of individuals undergoing TPAIT (Total Pancreatectomy and Autologous Islet Transplantation) for treatment of chronic pancreatitis (CP). The two study arms consist of HCQ-treated (Hydroxychloroquine) and placebo-treated individuals. The purpose of this study is to investigate the effects of HCQ administration compared to placebo on islet cell function post-autologous transplantation.
Detailed description
A compelling level of evidence exists on the effects of the innate immunity-driven inflammation on the decline of functional beta cell mass in the autologous transplant setting. The investigators hypothesize that HCQ administration during the peri-transplant period will preserve islet mass and improve islet cell function in TPAIT by reducing inflammation. The investigators specifically aim to demonstrate a higher stimulated C-peptide level as well as greater glucose control in response to mixed meal tolerance testing (MMTT) at 6 and 12 months following TPAIT in patients treated with HCQ compared to placebo. A better response in the HCQ arm suggests improved islet survival and metabolic performance, potentially facilitating higher rates of insulin independence. HCQ administration: Arm 1 (n=5): Subjects will receive a pre-transplant HCQ 200 mg daily dose 30 days prior TPAIT followed by HCQ use for an additional 3 months post-surgery. Arm 2 (n=5) subjects will receive placebo treatment following the same schedule as in Arm 1. Exploratory mechanistic studies: All subjects will undergo a MMTT to assess islet cell function at 6 and 12 months following TPAIT (in addition to MMTT pre-surgery performed as standard of care, and whose results will be used for pre-randomization in this pilot). Baseline metabolic tests obtained too early after surgery may not be indicative of islet function, due to insulin supporting therapy administered for several weeks after transplantation. Also, compelling data indicate that stabilization of islet function may require up to 1 year to occur. Blood glucose and C-peptide serum levels will be measured in peripheral blood samples immediately prior and subsequent to MMTT. The research coordinator will contact the subjects at 3, 6 and 12 months for interview on the course of follow up and will assist in scheduling the 6 and 12-month appointments for MMTT. Mitochondrial Function and Metabolic Outcomes in TPAIT: Mitochondrial efficiency is important in the setting of TPAIT, where increase in metabolic demand and decrease in oxygenation have been established. The investigators will assess mitochondrial efficiency by measuring rates of mitochondrial respiration and glycolysis. These measures will be obtained on islets procured for donation and after islet isolation. Small amounts of digest left after islet isolation, that would normally be discarded, will be used for this portion of the study. The islets from the digest will be collected and will undergo extracellular efflux analysis through the Seahorse XF analyzer for mitochondrial function assessment. Commercially available normal human islet cells for experiments will be used as control. Controls will be compared simultaneously with islets isolated from study subjects. Genome-wide Gene Expression in TPAIT Patients: On the genomic level, several genetic pathways have been implicated in islet cell function and survival. The genetic profiles of islet cells from CP patients undergoing TPAIT have not been evaluated yet. The investigators aim to build an RNA-gene sequence database for islet cells of CP patients undergoing TPAIT, specifically targeting genes previously identified as key players in islet function. Small amounts of digest from the procedure used for isolating islets, and what remains in the circuit after the isolation process is complete, that would normally be discarded, will also be used for islet gene expression assessment.
Interventions
DRUGHydroxychloroquine
Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.
DRUGPlacebo
Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.
Sponsors
Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
Stanford University
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The study will be single-blinded. The PI, biostatistician who will analyze the data, consultants, and technicians running assays will be blinded to the study arm into which the subjects have been randomized. An alphanumeric identifier that refers to the study subject without any indicators of study arm allocation will be used. Only the surgeons and the research coordinator, but not the personnel conducting the metabolic studies, will be un-blinded as to the study arm randomization.
Intervention model description
open label, randomized, two-arm, single-blinded, placebo-controlled, parallel
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Clinically confirmed diagnosis of chronic pancreatitis (CP) * Intractable abdominal pain * History of failed operation(s) for CP * Recurrent acute pancreatitis * HbA1c \<8.0% * Sustained alcohol remission * Chronic narcotic use
Exclusion criteria
* Insulin dependence * Pancreatic carcinoma * Pancreatic mass suspicious for carcinoma * Cirrhosis * Portal hypertension * Continued alcohol abuse * Manufacturer's product label-contraindicated use of HCQ * History of retinopathy * Actual weight at enrollment \<40 Kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT | 12 months | HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| C-peptide AUC Response to MMTT | 12 months | HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion. |
| Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass | 12 months | C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydroxychloroquine Administered pre-transplant through 3 months after surgery.
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery. | 3 |
| Placebo Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery. | 3 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Hydroxychloroquine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 6 Participants | 3 Participants |
| Age, Continuous | 37 years STANDARD_DEVIATION 3 | 43.5 years STANDARD_DEVIATION 7.5 | 50 years STANDARD_DEVIATION 12 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
Primary
Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT
HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient.
Time frame: 12 months
Population: C-peptide/Glucose = ng/mg glucose/IEQ/kg - Primary 12-month endpoint
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxychloroquine | Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT | .000000077 ng/mg glucose/IEQ/kg | Standard Deviation 9.6e-8 |
| Placebo | Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT | 0.000000079 ng/mg glucose/IEQ/kg | Standard Deviation 1.2e-7 |
Secondary
C-peptide AUC Response to MMTT
HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxychloroquine | C-peptide AUC Response to MMTT | 813 ng/mL/min | Standard Deviation 463 |
| Placebo | C-peptide AUC Response to MMTT | 588 ng/mL/min | Standard Deviation 391 |
p-value: 0.739ANOVA
Secondary
Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass
C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms.
Time frame: 12 months
Population: Treatment versus placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxychloroquine | Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass | 0.00091 ng/mL/min/IEQ/kg iAUC post-MMT | Standard Deviation 0.0006 |
| Placebo | Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass | 0.00222 ng/mL/min/IEQ/kg iAUC post-MMT | Standard Deviation 0.0029 |