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The Role of Hepatic Denervation in the Dysregulation of Glucose Metabolism in Liver Transplant Recipients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03685773
Recruitment Status : Suspended (Temporarily paused due to COVID-19 and expected to resume. This is not a suspension of IRB approval.)
First Posted : September 26, 2018
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Meredith Hawkins, Albert Einstein College of Medicine

Tracking Information
First Submitted Date  ICMJE September 24, 2018
First Posted Date  ICMJE September 26, 2018
Last Update Posted Date July 9, 2020
Estimated Study Start Date  ICMJE January 2021
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 24, 2018)
Endogenous glucose production (EGP) [ Time Frame: 7-7.5 hours ]
Rates of EGP (a measure of the body's production of sugar) will be measured during pancreatic clamp studies, with suppression of pancreatic hormones by somatostatin infusion and basal hormone replacement.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2018)
Change in Arterial Spin Labeling (ASL) signal [ Time Frame: Baseline, 2 hours post dosing, 4 hours post dosing ]
Change in Arterial Spin Labeling (ASL) signal measured using 3T MRI from baseline to 2 hours post dosing, and 2 hours post dosing to 4 hours post dosing. ASL is a measure of brain blood flow, and an increase in ASL is interpreted as an increase in brain activity. Data is collected at three time points during each of the two visits (pre dosing, 2 hours post dosing, 4 hours post dosing). Response to diazoxide is compared between 3 time points for each group, and this response is then compared between non-diabetic and type 2 diabetic liver transplant subjects.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Role of Hepatic Denervation in the Dysregulation of Glucose Metabolism in Liver Transplant Recipients
Official Title  ICMJE The Role of Hepatic Denervation in the Dysregulation of Glucose Metabolism in Liver Transplant Recipients
Brief Summary It is believed that important brain centers send signals through the vagus nerve to the liver to suppress the amount of glucose (sugar) that gets produced. People who have received liver transplants have had their vagus nerve cut during transplantation, and many of these individuals have diabetes at one year post-transplant. The goals of this study are: to see whether metabolic control centers in the brain can still be activated normally with the medication diazoxide in patients who have had a liver transplant, and to understand whether disrupting the vagus nerve would result in excess glucose being produced by the liver (ie. a potential mechanism for why these patients develop diabetes).
Detailed Description

In this study, investigators will study both diabetic and non-diabetic individuals who are otherwise healthy more than one year after receiving a liver transplant. They will participate in at least one of the following two parts of this study: The first involves functional magnetic resonance imaging (fMRI), and the second is using a day-long infusion study called a "pancreatic clamp."

Functional magnetic resonance imaging (fMRI) is a technique for measuring and mapping brain activity that is noninvasive and safe. This technique relies on the fact that blood flow in the brain and the activity of brain cells are coupled. Investigators will observe the activity of metabolically-relevant areas of the brain by activating potassium channels with diazoxide at baseline and at 2-hour intervals vs when given placebo.

In the pancreatic clamp study, glucose (a sugar) and insulin (a hormone produced in the pancreas that regulates the amount of sugar in the blood) are infused with an intravenous catheter. Blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body which are related to glucose metabolism. The rates of endogenous glucose production (a measure of the body's production of sugar) will be measured as the main measurement of the study.

All participants will be screened prior to study enrollment. For the fMRI studies, eligible participants will come on two separate occasions for day-long study visits (one day in which the brain will be imaged before and after receiving diazoxide (a potassium channel activator), and one day in which the brain will be imaged before and after placebo. For the pancreatic clamp studies, eligible participants will come on two separate occasions for day-long study visits (one study with diazoxide, and one study with placebo). All studies in participants with type 2 diabetes will include overnight admissions prior to the study day for gradual normalizing of blood glucose through the infusion of insulin. Participants without diabetes will not have to stay for an overnight admission. Study participants with type 2 diabetes will also be eligible for an additional study in which Nicotinic Acid will be infused overnight to lower free fatty acid (FFA) levels. It will be determined whether FFA lowering will impact the fMRI studies and clamp studies that will be performed the next day.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Masking Description:
The subject will be blinded to which study drug is received first (Drug or Placebo).
Primary Purpose: Basic Science
Condition  ICMJE
  • Diabetes Mellitus, Type 2
  • Glucose, High Blood
  • Glucose Metabolism Disorders
Intervention  ICMJE
  • Drug: Diazoxide

    MRI studies: Non-diabetic and T2D participants will receive diazoxide (up to 7 mg/kg) between baseline MRI scan and second MRI scan.

    Clamp studies: Non-diabetic participants will not require an overnight admission. They will receive diazoxide (up to 7 mg/kg) and undergo the pancreatic clamp study. Type 2 diabetic participants will be admitted the evening before the study day to normalize blood sugar levels. They will then receive diazoxide (up to 7 mg/kg) the next morning and undergo the pancreatic clamp study.

    Other Name: Proglycem
  • Drug: Placebo (for diazoxide)

    MRI studies: Non-diabetic and T2D participants will receive placebo (for diazoxide) between baseline MRI scan and second MRI scan.

    Clamp studies: Non-diabetic participants will not require an overnight admission. They will receive a taste-matched placebo (for diazoxide) and undergo the pancreatic clamp study. Type 2 diabetic participants will be admitted the evening before the study day to normalize blood sugar levels. They will then receive a taste-matched placebo (for diazoxide) the next morning and undergo the pancreatic clamp study.

  • Drug: Nicotinic acid
    Type 2 diabetic participants in this arm will receive a nicotinic acid infusion to lower free fatty acid levels. They will then receive diazoxide (up to 7 mg/kg) the next morning and undergo the MRI or pancreatic clamp study.
    Other Name: Niacin
Study Arms  ICMJE
  • Experimental: MRI: Non-diabetic transplant (Diazoxide)
    Diazoxide (up to 7 mg/kg)
    Intervention: Drug: Diazoxide
  • Placebo Comparator: MRI: Non-diabetic transplant (Placebo)
    Taste-matched placebo for diazoxide
    Intervention: Drug: Placebo (for diazoxide)
  • Experimental: MRI: T2D transplant (Diazoxide)
    Diazoxide (up to 7 mg/kg)
    Intervention: Drug: Diazoxide
  • Placebo Comparator: MRI: T2D transplant (Placebo)
    Taste-matched placebo for diazoxide
    Intervention: Drug: Placebo (for diazoxide)
  • Experimental: Clamp: Non-diabetic transplant (Diazoxide)
    Diazoxide (up to 7 mg/kg) before pancreatic clamp study
    Intervention: Drug: Diazoxide
  • Placebo Comparator: Clamp: Non-diabetic transplant (Placebo)
    Taste-matched placebo (for diazoxide) before pancreatic clamp study
    Intervention: Drug: Placebo (for diazoxide)
  • Experimental: Clamp: T2D transplant (Diazoxide)
    Diazoxide (up to 7 mg/kg) before pancreatic clamp study
    Intervention: Drug: Diazoxide
  • Placebo Comparator: Clamp: T2D transplant (Placebo)
    Taste-matched placebo (for diazoxide) before pancreatic clamp study
    Intervention: Drug: Placebo (for diazoxide)
  • Experimental: Clamp: T2D transplant (Diazoxide + Nicotinic Acid)
    Nicotinic acid infusion and diazoxide (up to 7 mg/kg) before pancreatic clamp study
    Interventions:
    • Drug: Diazoxide
    • Drug: Nicotinic acid
  • Experimental: Clamp: T2D transplant (Placebo + Nicotinic Acid)
    Nicotinic acid infusion and placebo (for diazoxide) before pancreatic clamp study
    Interventions:
    • Drug: Placebo (for diazoxide)
    • Drug: Nicotinic acid
  • Experimental: MRI: T2D transplant (Diazoxide + Nicotinic Acid)
    Nicotinic acid infusion and diazoxide (up to 7 mg/kg)
    Interventions:
    • Drug: Diazoxide
    • Drug: Nicotinic acid
  • Experimental: MRI: T2D transplant (Placebo + Nicotinic Acid)
    Nicotinic acid infusion and placebo (for diazoxide)
    Interventions:
    • Drug: Placebo (for diazoxide)
    • Drug: Nicotinic acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: September 24, 2018)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Liver Transplant at least one year ago
  • Age: 21-70

Exclusion Criteria:

  • BP > 150/90 or <90/60 on more than one occasion, unless there is a documented history of white coat hypertension by treating physician.
  • Triglycerides > 400 mg/dl and/or Total Cholesterol >300 mg/dl
  • Clinically significant liver dysfunction
  • Clinically significant kidney dysfunction, GFR: <60 mg/dL
  • Anemia: HgB <12.5 for men and <11.0 for women
  • Positive urine drug test. Occasional use of cannabis (once or twice per week) will not be a basis for exclusion.
  • Urinalysis: Clinically significant abnormalities
  • Clinically significant electrolyte abnormalities
  • Smoking >10 cig/day
  • Alcohol: Men >14 drinks/wk or >4 drinks/day, Women >7 drinks/wk or >3 drinks/day
  • History of active hepatitis infection, HIV/AIDS, chronic kidney disease (stage 3 or greater), active cancer, cardiovascular disease or other heart disease, systemic rheumatologic conditions, seizures, bleeding disorders, muscle disease
  • Surgeries that involve removal of endocrine glands except for thyroidectomy (if euthyroid on thyroid hormone replacement - if such history T4 and TSH will be checked)
  • Pregnant women
  • Subject enrolled in another study less than one month prior to the anticipated start date in the proposed study, besides those done by our group
  • Family history: family history of premature cardiac death
  • Allergies to medication administered during study
  • Uncontrolled psychiatric disorders
  • Any condition which in the opinion of the PI makes the subject ill-suited for participation in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03685773
Other Study ID Numbers  ICMJE 2018-9506
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Meredith Hawkins, Albert Einstein College of Medicine
Study Sponsor  ICMJE Albert Einstein College of Medicine
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Meredith Hawkins, MD, MS Albert Einstein College of Medicine
PRS Account Albert Einstein College of Medicine
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP