Glycemic Effect of Diazoxide in NAFLD

NCT05729282 | Completed Phase 1 FDA Drug FDA Device

• 2 other identifiers: AAAU2570K12DK133995
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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 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).

Conditions

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

Keywords

Insulin resistance; Hyperinsulinemia; Non-Alcoholic Fatty Liver Disease; Triglycerides

Outcome Measures

Primary Outcomes (4)

• Fasting plasma glucose (absolute values)

  Measurement of fasting plasma glucose levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: mg/dL).

  Up to Study Day 15

• Fasting plasma glucose (relative/change)

  Measurement of fasting plasma glucose during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: fold difference and/or Δmg/dL versus other groups).

  Up to Study Day 15

• Fasting plasma/serum insulin (absolute values)

  Measurement of fasting endogenous insulin levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: micro-international units \[µIU\] per mL).

  Up to Study Day 15

• Fasting plasma/serum insulin (relative change)

  Measurement of fasting endogenous insulin levels during treatment with diazoxide 1 mpk vs 2 mpk vs placebo (units: fold difference and/or ΔµIU/mL versus other groups).

  Up to Study Day 15

Secondary Outcomes (7)

• Fasting serum or plasma triglycerides (TG) (absolute values)

  Up to Study Day 15

• Fasting serum/plasma triglycerides (TG) (relative/change)

  Up to Study Day 15

• Fasting serum or plasma free fatty acids (FFA) (absolute values)

  Up to Study Day 15

• Fasting serum or plasma free fatty acids (FFA) (relative/change)

  Up to Study Day 15

• Fasting serum/plasma apolipoprotein B (ApoB) (absolute values)

  Up to Study Day 15

Other Outcomes (4)

• Hepatic de novo lipogenesis (absolute values)

  Up to Study Day 15

• Hepatic de novo lipogenesis (relative/change)

  Up to Study Day 15

• Deuterium tracer enrichment in body water (measured in blood)

  Up to Study Day 15

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Participants will ingest a placebo solution (27 doses over 14 days) formulated to approximate the taste of diazoxide oral suspension. Blinding will occur by completely covering single-dose oral syringes with labels.

Drug: Placebo; Device: FreeStyle Libre Pro; Drug: Deuterated water (2H2O/D2O)

Diazoxide oral suspension, 1 mg per kg per dose

EXPERIMENTAL

Participants will ingest diazoxide oral suspension at 1 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.

Drug: Diazoxide oral suspension, 1 mg per kg per dose; Device: FreeStyle Libre Pro; Drug: Deuterated water (2H2O/D2O)

Diazoxide oral suspension, 2 mg per kg per dose

EXPERIMENTAL

Participants will ingest diazoxide oral suspension at 2 mg per kg body weight per dose (27 doses over 14 days). Blinding will occur by completely covering single-dose oral syringes with labels.

Drug: Diazoxide oral suspension, 2 mg per kg per dose; Device: FreeStyle Libre Pro; Drug: Deuterated water (2H2O/D2O)

Interventions

Diazoxide oral suspension, 1 mg per kg per dose DRUG

Diazoxide oral suspension provided in label-obscured single-use oral syringes at 1 mg per kg per dose (total of 27 doses over 14 days).

Also known as: Proglycem

Diazoxide oral suspension, 1 mg per kg per dose

Diazoxide oral suspension, 2 mg per kg per dose DRUG

Diazoxide oral suspension provided in label-obscured single-use oral syringes at 2 mg per kg per dose (total of 27 doses over 14 days).

Also known as: Proglycem

Diazoxide oral suspension, 2 mg per kg per dose

Placebo DRUG

Flavor-approximate placebo consisting of peppermint extract in diet tonic water, thickened with xanthan gum, provided in label-obscured single-use oral syringes at 2 mg per kg per dose (total of 27 doses over 14 days).

Also known as: Placebo solution

Placebo

FreeStyle Libre Pro DEVICE

All participants will wear a FreeStyle Libre Pro continuous glucose monitor (CGM) to track glycemic trends in response to study treatments. Investigators and participants will be blinded to CGM readings until after each participant has completed the trial.

Diazoxide oral suspension, 1 mg per kg per dose; Diazoxide oral suspension, 2 mg per kg per dose; Placebo

Deuterated water (2H2O/D2O) DRUG

All participants will consume 32 aliquots of deuterated water (2H2O/D2O) 50 mL over 14 days to assess hepatic de novo lipogenesis. Tracer enrichment will be determined in blood and saliva.

Also known as: Heavy water

Diazoxide oral suspension, 1 mg per kg per dose; Diazoxide oral suspension, 2 mg per kg per dose; Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18-70 years (using highly effective contraception if of childbearing potential)
• Body mass index of 27-50 kg/m2
• Able to understand written and spoken English and/or Spanish
• Able to have pre-randomization screening labs drawn and study protocol initiated within 30 days of informed consent
• 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
• Evidence of insulin resistance, represented by any or all of the following criteria:
• i. Meeting either of the American Diabetes Association's definitions for prediabetes or IFG on screening labs:
• Prediabetes: Hemoglobin A1c 5.7-6.4%
• IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast
• and/or
• ii. Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73
• Fasting hyperinsulinemia (fasting insulin level ≥ 13 µIU/mL) on screening labs
• 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.

You may not qualify if:

• Unable to provide informed consent in English or Spanish
• Concerns arising at screening visit (any of the following):
• i. Documented weight loss of ≥ 5.0% 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

Sponsors & Collaborators

• Columbia University: lead
• University of California, Berkeley: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Hyperinsulinism; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Prediabetic State

Interventions

Diazoxide; Deuterium Oxide

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Water; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Deuterium; Hydrogen; Elements; Gases

Study Officials

• Joshua R Cook, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Both investigators and participants will be blinded to the assigned treatment group. Routine unblinding will occur to investigators only after all of a participant's samples have been submitted for laboratory analysis. It should be noted that investigators may get a sense of group allocation based on changes in blood glucose. However, due to interindividual variability in extent of insulin resistance and body mass index, it will not be possible to assuredly decode the randomization prior to unblinding. The blinding of the study Principal Investigator (PI) will be repealed only in the case of early withdrawal and/or medical emergency (e.g., severe hyperglycemia), which in most cases will result in study termination anyway. Participants will be notified of their group assignment once all relevant data are collected and analyzed if opted in.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: February 6, 2023
• First Posted: February 15, 2023
• Study Start: August 1, 2023
• Primary Completion: September 10, 2025
• Study Completion: September 10, 2025
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Indefinitely following study completion.

Locations

US (1)