Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03283566
• Collaborator: Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute) (Other), Stanford University (Other)
• Enrollment: 9
• Location: 1
• Arms: 2
• Actual Duration (Months): 31.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: open label, randomized, two-arm, single-blinded, placebo-controlled, parallelopen 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: Oct 3, 2017
• Actual Primary Completion Date: May 31, 2020
• Actual Study Completion Date: May 31, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

• Principal Investigator: Betul Hatipoglu, MD, Staff

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 25, 2016

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT03283566
• Other Study ID Numbers: 17-912
• First Posted: Sep 14, 2017
• Last Update Posted: Apr 8, 2022
• Last Verified: Apr 1, 2022

• 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: Pancreatitis; Pancreatitis, Chronic; Diabetes Mellitus, Type 1; Hydroxychloroquine

Study Results

Participant Flow

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	4	5
COMPLETED	3	3
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Hydroxychloroquine	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	3	3	6
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	3 100%	6 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50 (12)	37 (3)	43.5 (7.5)
Sex: Female, Male (Count of Participants)
Female	3 100%	1 33.3%	4 66.7%
Male	0 0%	2 66.7%	2 33.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%	3 100%	6 100%

Outcome Measures

1. Primary Outcome

Title	Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT
Description	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

Outcome Measure Data

Analysis Population Description

C-peptide/Glucose = ng/mg glucose/IEQ/kg - Primary 12-month endpoint

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	3	3
Mean (Standard Deviation) [ng/mg glucose/IEQ/kg]	.000000077 (.000000096)	0.000000079 (.00000012)

2. Secondary Outcome

Title	C-peptide AUC Response to MMTT
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	3	3
Mean (Standard Deviation) [ng/mL/min]	813 (463)	588 (391)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	Assuming a 20-30% difference in outcome (CP/G quotient) between study arms, which is equivalent to 0.08-0.12 CP/G difference and a 0.07 standard deviation, a sample size of 6 subjects (1:1 randomization) will detect a CP/G difference of at least 0.12, assuming 80% power, with a 0.05 significance level.
Statistical Test of Hypothesis	p-Value	0.739
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass
Description	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

Outcome Measure Data

Analysis Population Description

Treatment versus placebo

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	3	3
Mean (Standard Deviation) [ng/mL/min/IEQ/kg iAUC post-MMT]	0.00091 (0.0006)	0.00222 (0.0029)

Adverse Events

Time Frame	About 3 years total study time. Each patient was assessed during a period of 12 months.
Adverse Event Reporting Description	No difference from clinicaltrials.gov definitions
Arm/Group Title	Hydroxychloroquine		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Hydroxychloroquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)
Serious Adverse Events
	Hydroxychloroquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Hydroxychloroquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.