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

NCT03685773 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 2018-9506
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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).

Conditions

Diabetes Mellitus, Type 2; Glucose, High Blood; Glucose Metabolism Disorders

Keywords

diabetes; type 2 diabetes; diazoxide; insulin resistance; MRI; liver transplant

Outcome Measures

Primary Outcomes (1)

• Endogenous glucose production (EGP)

  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.

  7-7.5 hours

Secondary Outcomes (1)

• Change in Arterial Spin Labeling (ASL) signal

  Baseline, 2 hours post dosing, 4 hours post dosing

Study Arms (12)

MRI: Non-diabetic transplant (Diazoxide)

EXPERIMENTAL

Diazoxide (up to 7 mg/kg)

Drug: Diazoxide

MRI: Non-diabetic transplant (Placebo)

PLACEBO COMPARATOR

Taste-matched placebo for diazoxide

Drug: Placebo (for diazoxide)

MRI: T2D transplant (Diazoxide)

EXPERIMENTAL

Diazoxide (up to 7 mg/kg)

Drug: Diazoxide

MRI: T2D transplant (Placebo)

PLACEBO COMPARATOR

Taste-matched placebo for diazoxide

Drug: Placebo (for diazoxide)

Clamp: Non-diabetic transplant (Diazoxide)

EXPERIMENTAL

Diazoxide (up to 7 mg/kg) before pancreatic clamp study

Drug: Diazoxide

Clamp: Non-diabetic transplant (Placebo)

PLACEBO COMPARATOR

Taste-matched placebo (for diazoxide) before pancreatic clamp study

Drug: Placebo (for diazoxide)

Clamp: T2D transplant (Diazoxide)

EXPERIMENTAL

Diazoxide (up to 7 mg/kg) before pancreatic clamp study

Drug: Diazoxide

Clamp: T2D transplant (Placebo)

PLACEBO COMPARATOR

Taste-matched placebo (for diazoxide) before pancreatic clamp study

Drug: Placebo (for diazoxide)

Clamp: T2D transplant (Diazoxide + Nicotinic Acid)

EXPERIMENTAL

Nicotinic acid infusion and diazoxide (up to 7 mg/kg) before pancreatic clamp study

Drug: Diazoxide; Drug: Nicotinic acid

Clamp: T2D transplant (Placebo + Nicotinic Acid)

EXPERIMENTAL

Nicotinic acid infusion and placebo (for diazoxide) before pancreatic clamp study

Drug: Placebo (for diazoxide); Drug: Nicotinic acid

MRI: T2D transplant (Diazoxide + Nicotinic Acid)

EXPERIMENTAL

Nicotinic acid infusion and diazoxide (up to 7 mg/kg)

Drug: Diazoxide; Drug: Nicotinic acid

MRI: T2D transplant (Placebo + Nicotinic Acid)

EXPERIMENTAL

Nicotinic acid infusion and placebo (for diazoxide)

Drug: Placebo (for diazoxide); Drug: Nicotinic acid

Interventions

Diazoxide DRUG

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.

Also known as: Proglycem

Clamp: Non-diabetic transplant (Diazoxide); Clamp: T2D transplant (Diazoxide + Nicotinic Acid); Clamp: T2D transplant (Diazoxide); MRI: Non-diabetic transplant (Diazoxide); MRI: T2D transplant (Diazoxide + Nicotinic Acid); MRI: T2D transplant (Diazoxide)

Placebo (for diazoxide) DRUG

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.

Also known as: Placebo

Clamp: Non-diabetic transplant (Placebo); Clamp: T2D transplant (Placebo + Nicotinic Acid); Clamp: T2D transplant (Placebo); MRI: Non-diabetic transplant (Placebo); MRI: T2D transplant (Placebo + Nicotinic Acid); MRI: T2D transplant (Placebo)

Nicotinic acid DRUG

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.

Also known as: Niacin

Clamp: T2D transplant (Diazoxide + Nicotinic Acid); Clamp: T2D transplant (Placebo + Nicotinic Acid); MRI: T2D transplant (Diazoxide + Nicotinic Acid); MRI: T2D transplant (Placebo + Nicotinic Acid)

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Albert Einstein College of Medicine: lead

Study Sites (1)

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Diabetes Mellitus; Insulin Resistance

Interventions

Diazoxide; Niacin

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Meredith Hawkins, M.D., M.S.

  Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: The subject will be blinded to which study drug is received first (Drug or Placebo).
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2018
• First Posted: September 26, 2018
• Study Start: April 21, 2019
• Primary Completion: April 21, 2023
• Study Completion: April 21, 2023
• Last Updated: June 5, 2023

Record last verified: 2023-06

Locations

US (1)