Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing Total Pancreatectomy and Autologous Islet Transplantation: A Clinical, Molecular, and Genomic Study

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.

Study Overview

• Status: Completed
• Conditions: Chronic Pancreatitis; Insulin Dependent Diabetes
• Intervention / Treatment: Drug: Hydroxychloroquine; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychloroquine; Administered pre-transplant through 3 months after surgery.	Drug: 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.; Other Names: Plaquenil
Placebo Comparator: Placebo; Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).	Drug: Placebo; Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months
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.	12 months

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: Stanford University; Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
• Investigators: Principal Investigator: Betul Hatipoglu, MD, staff

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2017
• Primary Completion (Actual): May 31, 2020
• Study Completion (Actual): May 31, 2020

Study Registration Dates

• First Submitted: September 13, 2017
• First Submitted That Met QC Criteria: September 13, 2017
• First Posted (Actual): September 14, 2017

Study Record Updates

• Last Update Posted (Actual): April 8, 2022
• Last Update Submitted That Met QC Criteria: April 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Diabetes; Pancreatectomy; Hydroxychloroquine; Pancreatitis; Autologous Islet Transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Pancreatic Diseases; Diabetes Mellitus, Type 1; Pancreatitis; Pancreatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 17-912

Drug and device information, study documents

• 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