Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

NCT ID: NCT03283566

Last Updated: 2022-04-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-03
• Study Completion Date: 2020-05-31

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.

Conditions

Chronic Pancreatitis; Insulin Dependent Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Hydroxychloroquine

Administered pre-transplant through 3 months after surgery.

Group Type: ACTIVE_COMPARATOR

Hydroxychloroquine

Intervention Type: DRUG

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.

Placebo

Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.

Interventions

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.

Intervention Type: DRUG

Placebo

Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.

Intervention Type: DRUG

Other Intervention Names

Plaquenil

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Betul Hatipoglu, MD

Role: PRINCIPAL_INVESTIGATOR

Staff

Locations

Cleveland Clinic

Cleveland, Ohio, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

17-912

Identifier Type: -

Identifier Source: org_study_id