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Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

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ClinicalTrials.gov Identifier: NCT03283566
Recruitment Status : Completed
First Posted : September 14, 2017
Last Update Posted : December 29, 2020
Sponsor:
Collaborators:
Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
Stanford University
Information provided by (Responsible Party):
The Cleveland Clinic

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.

Condition or disease Intervention/treatment Phase
Chronic Pancreatitis Insulin Dependent Diabetes Drug: Hydroxychloroquine Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open label, randomized, two-arm, single-blinded, placebo-controlled, parallel
Masking: Triple (Participant, 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.
Primary Purpose: Treatment
Official Title: Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing Total Pancreatectomy and Autologous Islet Transplantation: A Clinical, Molecular, and Genomic Study
Actual Study Start Date : October 3, 2017
Actual Primary Completion Date : May 31, 2020
Actual Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pancreatitis

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 Name: 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.




Primary Outcome Measures :
  1. Quotient of stimulated C-peptide/glucose level normalized for IEQ/Kg infused in response to MMTT [ Time Frame: 12 months ]
    HCQ-treated compared to placebo arm


Secondary Outcome Measures :
  1. C-peptide AUC in response to MMTT [ Time Frame: 12 months ]
    HCQ-treated compared to placebo arm

  2. Ratio of C-peptide AUC to glucose AUC in response to MMTT [ Time Frame: 12 months ]
    HCQ-treated compared to placebo arm



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03283566


Locations
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United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
The Cleveland Clinic
Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
Stanford University
Investigators
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Principal Investigator: Betul Hatipoglu, MD Staff
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Responsible Party: The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT03283566    
Other Study ID Numbers: 17-912
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: December 29, 2020
Last Verified: December 2020

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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
Keywords provided by The Cleveland Clinic:
Pancreatectomy
Autologous Islet Transplantation
Pancreatitis
Diabetes
Hydroxychloroquine
Additional relevant MeSH terms:
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Pancreatitis
Pancreatitis, Chronic
Diabetes Mellitus, Type 1
Pancreatic Diseases
Digestive System Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents