COMPLETED

Glycemic Effect of Diazoxide in NAFLD

Conditions

Hyperinsulinemia Insulin Resistance Non-Alcoholic Fatty Liver Disease Prediabetic State Triglycerides

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with overweight/obesity and insulin resistance (IR) with, or at high risk for, non-alcoholic fatty liver disease (NAFLD). The main questions it aims to answer are how mitigation of compensatory hyperinsulinemia with diazoxide affects parameters of glucose and lipid metabolism (how people with IR and NAFLD respond to lowering high insulin levels so that the investigators can see what happens to how the liver handles fat and sugar). Participants will: * Take 27 doses of diazoxide (at 1 mg per kg of body weight per dose \[mpk\] or 2 mpk) or of placebo, over 14 days * Take 32 doses of heavy (deuterated) water (50 mL each) over 14 days * Have blood drawn and saliva collected after an overnight fast on four mornings over the two-week study period * Consume their total calculated daily caloric needs as divided into three meals per day * Wear a continuous glucose monitor for the two-week study period Researchers will compare fasting blood tests at intervals during the study period in participants randomized (like the flip of a coin) to diazoxide 1 mpk, diazoxide 2 mpk, or placebo, to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B). They will also consume heavy (deuterated) water to assess de novo lipogenesis (building of new fatty acids by the liver).

Official Title

Role of Hyperinsulinemia in Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis: Diazoxide Pilot & Feasibility Study

Quick Facts

Study Start:2023-08-01

Study Completion:2025-09-10

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:COMPLETED

Study ID

NCT05729282

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 70 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Adults aged 18-70 years (using highly effective contraception if of childbearing potential) 2. Body mass index of 27-50 kg/m2 3. Able to understand written and spoken English and/or Spanish 4. Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent 5. Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified physician 6. Evidence of insulin resistance, represented by any or all of the following criteria: 1. Prediabetes: Hemoglobin A1c 5.7-6.4% 2. IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast 7. Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs 8. Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.	1. Unable to provide informed consent in English or Spanish 2. Concerns arising at screening visit (any of the following): * Non-sinus rhythm * Significant corrected QT segment (QTc) prolongation (≥ 480 ms) * New or previously unknown ischaemic changes that persist on repeat EKG: * Hemoglobin A1c ≥ 6.5%, and/or * Fasting plasma glucose ≥ 126 mg/dL * Transaminases (AST or ALT) \> 3.0 x the upper limit of normal, and/or * Total bilirubin \> 1.25 x the upper limit of normal 3. COVID-19 precautions 4. Reproductive concerns * Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy) * Combined oral contraceptive pills taken daily, including during the study * Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study * Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study * Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study * Etonogestrel/ethinyl estradiol vaginal rings (e.g., Nuvaring®, etc.) active at the time of the study * Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study 5. Concerns related to glucose metabolism * Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency * Plasma glucose ≥ 126 mg/dL after 8-h fast * Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load * Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state * Excluded: thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin * Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening 6. Concerns related to lipid metabolism * Statins or PCSK9 inhibitors for secondary prevention or for treatment of familial hypercholesterolemia. Statins or PCSK9 inhibitors for primary prevention of ASCVD are acceptable. * Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil) * High-dose niacin (\>100 mg daily) 7. Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions: * Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones * Chronic pancreatitis * Acute pancreatitis within the previous 5 years * Autoimmune pancreatitis * Surgical removal of any portion of the pancreas * Atherosclerotic cardiovascular disease * Stable or unstable angina * Myocardial infarction * Ischaemic or hemorrhagic stroke, or transient ischaemic attack * Peripheral arterial disease (claudication) * Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor) * History of percutaneous coronary intervention * Heart rhythm abnormalities * Congestive heart failure of any New York Heart Association class * Symptomatic valvular heart disease (e.g., aortic stenosis) * Pulmonary hypertension * Advanced liver fibrosis, as determined by non-invasive testing * Cirrhosis of any etiology * Autoimmune hepatitis or other rheumatologic disorder affecting the liver * Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis) * Chronic liver infection (e.g., viral hepatitis, parasitic infestation) * Hepatocellular carcinoma * Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease) * Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 days prior to screening * Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening * Human immunodeficiency virus (HIV) infection * Active inflammatory bowel disease (quiescent and off medication is acceptable) * Celiac disease (in remission on gluten-free diet is acceptable) * Surgical removal of a significant length of intestine * Are or have been decompensated within 1 year of screening, and/or * Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium * Due to presence of quinine in tonic water placebo * Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required) * Adrenal insufficiency * Primary aldosteronism * Non-melanoma skin cancer * Differentiated thyroid cancer (AJCC Stage I only) 8. Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure \<95 and/or diastolic blood pressure \<65 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above 9. Use of certain medications currently or within 90 d prior to screening: * Statins for primary prevention of cardiovascular disease * Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.) •• Note, as above, that antidiabetic drugs for any indication (except metformin) within 90 d of screening are excluded 10. History of certain weight-loss (bariatric) surgeries, including: 11. Clinical concern for alcohol overuse, including based on chart review and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females 12. Positive urine drug screen, except for: * Lawfully prescribed medication * Marijuana/THC positivity is okay, provided that the participant agrees not to use it during the same period that they will abstain from alcohol 13. History of severe infection or ongoing febrile illness within 30 days of screening 14. Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data. 15. Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. 16. Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.

Inclusion Criteria

Exclusion Criteria

1. Adults aged 18-70 years (using highly effective contraception if of childbearing potential)
2. Body mass index of 27-50 kg/m2
3. Able to understand written and spoken English and/or Spanish
4. Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent
5. Diagnosed with, or clinically judged to be at high risk for, non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified physician
6. Evidence of insulin resistance, represented by any or all of the following criteria:
1. Prediabetes: Hemoglobin A1c 5.7-6.4%
2. IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast
7. Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs
8. Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.

1. Unable to provide informed consent in English or Spanish
2. Concerns arising at screening visit (any of the following):
* Non-sinus rhythm
* Significant corrected QT segment (QTc) prolongation (≥ 480 ms)
* New or previously unknown ischaemic changes that persist on repeat EKG:
* Hemoglobin A1c ≥ 6.5%, and/or
* Fasting plasma glucose ≥ 126 mg/dL
* Transaminases (AST or ALT) \> 3.0 x the upper limit of normal, and/or
* Total bilirubin \> 1.25 x the upper limit of normal
3. COVID-19 precautions
4. Reproductive concerns
* Surgical sterilization (e.g., bilateral tubal occlusion, bilateral oophorectomy and/or salpingectomy, hysterectomy)
* Combined oral contraceptive pills taken daily, including during the study
* Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study
* Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study
* Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
* Etonogestrel/ethinyl estradiol vaginal rings (e.g., Nuvaring®, etc.) active at the time of the study
* Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study
5. Concerns related to glucose metabolism
* Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
* Plasma glucose ≥ 126 mg/dL after 8-h fast
* Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load
* Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state
* Excluded: thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, amylin mimetics, acarbose, insulin
* Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening
6. Concerns related to lipid metabolism
* Statins or PCSK9 inhibitors for secondary prevention or for treatment of familial hypercholesterolemia. Statins or PCSK9 inhibitors for primary prevention of ASCVD are acceptable.
* Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)
* High-dose niacin (\>100 mg daily)
7. Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions:
* Pancreatic neoplasia, unless appropriately evaluated and considered benign and not producing hormones
* Chronic pancreatitis
* Acute pancreatitis within the previous 5 years
* Autoimmune pancreatitis
* Surgical removal of any portion of the pancreas
* Atherosclerotic cardiovascular disease
* Stable or unstable angina
* Myocardial infarction
* Ischaemic or hemorrhagic stroke, or transient ischaemic attack
* Peripheral arterial disease (claudication)
* Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor)
* History of percutaneous coronary intervention
* Heart rhythm abnormalities
* Congestive heart failure of any New York Heart Association class
* Symptomatic valvular heart disease (e.g., aortic stenosis)
* Pulmonary hypertension
* Advanced liver fibrosis, as determined by non-invasive testing
* Cirrhosis of any etiology
* Autoimmune hepatitis or other rheumatologic disorder affecting the liver
* Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis)
* Chronic liver infection (e.g., viral hepatitis, parasitic infestation)
* Hepatocellular carcinoma
* Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease)
* Hepatitis B virus (HBV), unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 days prior to screening
* Hepatitis C virus (HCV) infection, unless previously successfully eradicated with antiviral drugs that have been discontinued for at least 90 d prior to screening
* Human immunodeficiency virus (HIV) infection
* Active inflammatory bowel disease (quiescent and off medication is acceptable)
* Celiac disease (in remission on gluten-free diet is acceptable)
* Surgical removal of a significant length of intestine
* Are or have been decompensated within 1 year of screening, and/or
* Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium
* Due to presence of quinine in tonic water placebo
* Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required)
* Adrenal insufficiency
* Primary aldosteronism
* Non-melanoma skin cancer
* Differentiated thyroid cancer (AJCC Stage I only)
8. Clinical concern for increased risk of volume overload or hypotension (systolic blood pressure \<95 and/or diastolic blood pressure \<65 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above
9. Use of certain medications currently or within 90 d prior to screening:
* Statins for primary prevention of cardiovascular disease
* Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) used for uncomplicated hypertension rather than for congestive heart failure, etc.) •• Note, as above, that antidiabetic drugs for any indication (except metformin) within 90 d of screening are excluded
10. History of certain weight-loss (bariatric) surgeries, including:
11. Clinical concern for alcohol overuse, including based on chart review and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females
12. Positive urine drug screen, except for:
* Lawfully prescribed medication
* Marijuana/THC positivity is okay, provided that the participant agrees not to use it during the same period that they will abstain from alcohol
13. History of severe infection or ongoing febrile illness within 30 days of screening
14. Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data.
15. Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, IV infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
16. Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.

Contacts and Locations

Principal Investigator

Joshua R Cook, MD, PhD

PRINCIPAL_INVESTIGATOR

Columbia University

Study Locations (Sites)

Columbia University Irving Medical Center

New York, New York, 10032

United States

Collaborators and Investigators

Sponsor: Columbia University

Joshua R Cook, MD, PhD, PRINCIPAL_INVESTIGATOR, Columbia University

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-08-01

Study Completion Date2025-09-10

Study Record Updates

Study Start Date2023-08-01

Study Completion Date2025-09-10

Terms related to this study

Keywords Provided by Researchers

Insulin resistance
Hyperinsulinemia
Non-Alcoholic Fatty Liver Disease
Triglycerides

Additional Relevant MeSH Terms

Hyperinsulinemia
Insulin Resistance
Non-Alcoholic Fatty Liver Disease
Prediabetic State