Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

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Brief Title

Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Quotient of stimulated C-peptide/glucose level normalized for IEQ/Kg infused in response to MMTT

Secondary Outcome

 C-peptide AUC in response to MMTT

Condition

Chronic Pancreatitis

Intervention

Hydroxychloroquine

Study Arms / Comparison Groups

 Hydroxychloroquine
Description:  Administered pre-transplant through 3 months after surgery.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

9

Start Date

October 3, 2017

Completion Date

May 31, 2020

Primary Completion Date

May 31, 2020

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
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Betul Hatipoglu, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03283566

Organization ID

17-912


Responsible Party

Sponsor

Study Sponsor

The Cleveland Clinic

Collaborators

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

Study Sponsor

Betul Hatipoglu, MD, Principal Investigator, Staff


Verification Date

December 2020