Glycemic Effect of Diazoxide in NAFLD

• Status: Recruiting
• Trial end date: 2025-01-01
• Target enrollment: 0
• Participant gender: All

Summary

The goal of this clinical trial is to compare a two-week course of diazoxide (at two different doses) and placebo in people with insulin resistance-associated non-alcoholic fatty liver disease (IR-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-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

• Have blood drawn after an overnight fast on six 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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Columbia University
• Treatments: Diazoxide

Criteria

Inclusion Criteria:

1. Adults aged 18-65 years (using highly effective contraception if of childbearing potential)

2. Body mass index of 27.0-35.0 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 14 days of informed consent

5. Diagnosed with non-alcoholic fatty liver disease (NAFLD), also known as metabolic-associated fatty liver disease (MAFLD), by hepatologist or other qualified specialist physician and the condition is listed as an active problem in the electronic medical record

6. Meeting either of the American Diabetes Association's definitions for prediabetes or impaired fasting glucose (IFG) on screening labs:

i. Prediabetes: Hemoglobin A1c (HbA1c) 5.7-6.4%

ii. IFG: plasma glucose of 100-125 mg/dL after ≥ 8-h fast

7. Fasting hyperinsulinemia (fasting insulin level ≥ 15 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.

Exclusion Criteria:

1. Unable to provide informed consent in English or Spanish

2. Concerns arising at screening visit (any of the following):

i. Weight loss of ≥ 3.0% of baseline within the previous 6 months

ii. Abnormal blood pressure (including on treatment, if prescribed)

• Systolic blood pressure < 95 mm Hg or > 160 mm Hg, and/or

• Diastolic blood pressure < 65 mm Hg or > 100 mm Hg

iii. Abnormal resting heart rate ≤ 60 bpm or ≥ 100 bpm

• Sinus brady- or tachycardia that has been appropriately evaluated and considered benign by the recruit's personal physician may be permitted at PI's discretion

iv. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d) • Non-sinus rhythm • Significant corrected QT segment (QTc) prolongation (≥ 480 ms)

• New or previously unknown ischaemic changes that persist on repeat EKG:

•• ST segment elevations

•• T-wave inversions

v. Laboratory evidence of diabetes mellitus:

• Hemoglobin A1c ≥ 6.5%, and/or

• Fasting plasma glucose ≥ 126 mg/dL

vi. Positive qualitative serum β-hCG (human chorionic gonadotropin, beta subunit; i.e., pregnancy test) in women of childbearing potential

vii. Liver function abnormalities

• Transaminases (AST or ALT) > 2.0 x the upper limit of normal, and/or

• Total bilirubin > 1.25 x the upper limit of normal

viii. Abnormal screening lipids

• Triglycerides > 400 mg/dL, and/or

• LDL-cholesterol > 190 mg/dL

ix. Abnormal screening serum electrolytes (any of the following)

• Sodium, potassium, chloride, or bicarbonate outside of the reference range

• Creatinine equating to estimated glomerular filtration rate < 60 mL/min/1.73 m2

x. Abnormal screening thyroid-stimulating hormone (TSH) level (≥10 mIU/L or < LLN)

• Exempt from TSH screening if previously obtained value within 2 months of screening is available

xi. Uric acid level > upper limit of normal

xii. Glucose-6-phosphate dehydrogenase < lower limit of normal

3. COVID-19 precautions

i. Not fully vaccinated against COVID-19 (4 doses if age ≥ 50, 3 doses if ages 18-49)

ii. Unwillingness to comply with masking requirements per hospital policy

iii. Active, documented COVID-19 at any time after screening

4. Reproductive concerns

i. Women of childbearing potential not using highly effective contraception, defined as:

• 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

• Norelgestromin/ethinyl estradiol transdermal system (e.g., Ortho-Evra®) active at the time of the study

ii. Women currently pregnant (tested by serum and/or urine β-hCG)

iii. Women currently breastfeeding

5. Concerns related to glucose metabolism

i. History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):

• 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

ii. History of gestational diabetes mellitus

iii. Use of antidiabetic medications within the 90 days prior to screening, including those prescribed for other indications (e.g., weight control, restoration of ovulation in of polycystic ovarian syndrome), including: • Metformin, 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

iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)

6. Concerns related to lipid metabolism

i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia

ii. Use of lipid-lowering drugs other than statins for primary prevention within the 90 days prior to screening, including:

• Statins for secondary prevention or treatment of familial hypercholesterolemia

• PCSK9 inhibitors (alirocumab, evolocumab, inclisiran) (for inclisiran, use within the previous year is exclusionary)

• Fibrates (e.g., fenofibrate, clofibrate, gemfibrozil)

• High-dose niacin (>100 mg daily)

• Fish oils or purified supplements of omega-3 fatty acids

• Vitamin E supplements

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:

i. Pancreatic pathology, including but not limited to:

• Pancreatic neoplasia

• Chronic pancreatitis

• Acute pancreatitis within the previous 5 years

• Autoimmune pancreatitis

• Surgical removal of any portion of the pancreas

ii. Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary)

• Atherosclerotic cardiovascular disease

• Stable or unstable angina

• Myocardial infarction

• Ischaemic or hemorrhagic stroke, or transient ischaemic attack

• Carotid artery stenosis on imaging

• 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

• Valvular heart disease (e.g., aortic stenosis)

• Pulmonary hypertension

iii. Chronic kidney disease, Stage 2 or higher (estimated glomerular filtration rate < 60 mL/min/1.73 m2), of any cause

iv. Chronic liver disease other than uncomplicated NAFLD, including but not limited to:

• 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)

v. Gout

vi. Chronic viral illness (N.B. diagnosis based only on medical history; the investigators will not test for any of these viruses at any point in this study)

• 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

vii. Malabsorptive conditions

• 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

viii. Active seizure disorder (including controlled with antiepileptic drugs)

ix. Psychiatric diseases that…

• Are or have been decompensated within 1 year of screening, and/or

• Require use of anti-dopaminergic antipsychotic drugs, monoamine oxidase inhibitors, tricyclic antidepressants, or lithium

x. Glucose-6-phosphate dehydrogenase (G6PD) deficiency

• Due to presence of quinine in tonic water placebo

xi. Other endocrinopathies:

• Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids are required)

• Adrenal insufficiency

• Primary aldosteronism

• Thyroid disease

• Hypothyroidism if thyroid-stimulating hormone (TSH) ≥ 10 mIU/L, with or without treatment

• Hyperthyroidism (TSH < lower limit of normal), with or without treatment

xii. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation

xiii. Active malignancy, or hormonally active benign neoplasm, except allowances for:

• 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 <90 and/or diastolic blood pressure <60 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:

i. Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 90 d prior to screening, except allowances for:

• Levothyroxine treatment of hypothyroidism, if TSH < 10 mIU/L at 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 within 90 d of screening are excluded

ii. Thiazide diuretics, loop diuretics, or beta blockers for any indication

• Note, as above, that other antihypertensive drugs (e.g., ACEi/ARB, calcium channel blockers, pure alpha blockers) are permitted

iii. Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral)

iv. Phenytoin or fosphenytoin for any indication

v. Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted

vi. Fludrocortisone

vii. Opioids

10. History of weight-loss (bariatric) surgery, including:

i. Adjustable lap banding

ii. Vertical sleeve gastrectomy

iii. Roux-en-Y gastric bypass

iv. Biliopancreatic diversion

11. Clinical concern for alcohol overuse, including phosphatidylethanol ≥ 0.05 µmol/L at screening 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

13. Tobacco smoking currently or within the previous 6 months

14. History of severe infection or ongoing febrile illness within 30 days of screening

15. 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.

16. 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.

17. 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.