Clinical trial NCT06126354: Dexamethasone/Pancreatic Clamp P&F
Official title: Role of Hyperinsulinemia in NAFLD: Dexamethasone-Pancreatic Clamp Pilot & Feasibility Study
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Insulin Resistance
Prediabetic State
Non-Alcoholic Fatty Liver Disease
Overweight and Obesity
Keywords: Insulin resistance
Hyperinsulinemia
Diabetes
Non-alcoholic fatty liver disease
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Albert Einstein College of Medicine
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2023-11-13
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: All participants will undergo (i.e., cross over between) both pancreatic clamp protocols (MH, RE) separated by 2-4 weeks. The order of the clamp protocols (i.e., MH \> RE, RE \> MH) will be randomized.
Primary purpose: BASIC_SCIENCE

Brief summary: This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study in the setting of dexamethasone-induced insulin resistance. The investigators will recruit participants with a history of overweight/obesity but no history of prediabetes or diabetes. Participants will be rendered temporarily insulin resistant by taking seven doses of dexamethasone. They will then undergo two pancreatic clamp procedures in which individualized basal IIR are identified, followed in one by maintenance of basal IIR (maintenance hyperinsulinemia, MH) and in the other by a stepped decline in IIR (reduction toward euinsulinemia, RE). In both clamps the investigators will closely monitor plasma glucose and various metabolic parameters. The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR.

Detailed description: Although high blood sugar and risk of heart disease are the most well-known health effects of type 2 diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, NAFLD can progress to severe liver inflammation, liver failure, and even liver cancer. The investigators suspect that high levels of the blood sugar-lowering hormone insulin leads to excessive fat production by the liver, and so lowering insulin levels might help to improve NAFLD. In order to answer this question, the investigators will temporarily render volunteers insulin resistant -- that is, simulating the risk of T2DM and NAFLD -- using seven doses of dexamethasone. They will then perform a "pancreatic clamp" - a procedure in which the body's production of insulin is temporarily shut off and then replaced at the same or lower levels. Again, the investigators expect that lowering insulin levels will lower fat production. Because this is a new research approach, the investigators first need to understand how lowering insulin levels affects blood sugar. Research participants in this pilot study will therefore undergo two pancreatic clamps, each following seven doses of dexamethasone, in random order: one roughly maintaining their own internal ("basal") insulin level and one in which the investigators lower that basal insulin level by 10%, 20%, and 40%. In each case, the investigators will observe the absolute and relative changes in blood sugar and the levels of certain fats as the investigators change the insulin level. Once the investigators have found a lower insulin level that they can safely maintain, the investigators will go on to study its effect on fat production in a later study.

Eligibility criteria: Inclusion Criteria:

1. Men and women (using highly effective contraception if of childbearing potential) aged 18-65 years
2. Body mass index of 25.0-39.9 kg/m2
3. Able to understand written and spoken English and/or Spanish
4. Evidence of normal glucose metabolism (euglycemia), represented by not meeting the American Diabetes Association's definitions for prediabetes, impaired fasting glucose (IFG), or diabetes on screening labs. Thus, participants must meet both of the following conditions on screening labs:

   i. Prediabetes: Hemoglobin A1c \< 5.7% ii. IFG: plasma glucose of \< 100 mg/dL after 8-h fast
5. Normal fasting serum insulin (fasting insulin level \< 12 μIU/mL) on screening labs
6. 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. Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the clamp ii. Unwillingness to fast (except water) for up to 24 hours iii. Documented weight loss of ≥ 5% of baseline within the previous 6 months iv. Abnormal blood pressure (including on treatment, if prescribed)
   * Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg, and/or
   * Diastolic blood pressure \< 60 mm Hg or \> 100 mm Hg v. Abnormal resting heart rate: \< 60 or ≥100 bpm
   * Sinus brady- or tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion vi. Abnormal screening electrocardiogram (or if on file, performed within previous 90 d):
   * Non-sinus rhythm
   * Significant QTc prolongation (≥ 480 ms)
   * New or previously unknown ischaemic changes that persist on repeat EKG: ST elevations, T-wave inversions vii. Laboratory evidence of impaired glucose metabolism:
   * Hemoglobin A1c ≥ 5.7%, and/or
   * Fasting plasma glucose ≥ 100 mg/dL viii. Positive qualitative human chorionic gonadotropin, beta subunit (β-hCG) in women of childbearing potential ix. Positive urine drug screen, except for lawfully prescribed medications and/or marijuana x. Liver function abnormalities (either of the following)
   * Transaminases (AST or ALT) \> 2.0 x the upper limit of normal
   * Total bilirubin \> 1.25 x the upper limit of normal xi. Abnormal fasting lipids at screening (either of the following)
   * Triglycerides ≥ 400 mg/dL
   * LDL-cholesterol ≥ 190 mg/dL xii. Abnormal screening serum electrolytes (any of the following)
   * Abnormal sodium, potassium, chloride, or bicarbonate levels that are considered potentially significant according to the clinical judgment of the PI.
   * Creatinine equating to estimated glomerular filtration rate \< 60 mL/min/1.73 m2 xiii. Abnormal complete blood count (CBC) (any of the following)
   * Hemoglobin \< 10 g/dL or hematocrit \< 30%
   * Platelet count \< 100,000/μL
   * Exempt from CBC requirement if previously obtained value within 2 months of screening is available
3. Unwillingness to comply with masking and COVID-19 testing requirements per hospital policy
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)
   * Oral contraceptive pills taken daily, including during the study
   * Intrauterine device (levonorgestrel-eluting or copper) active at the time of study
   * Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of study
   * Etonogestrel implants (e.g., Implanon®, etc.) active at the time of the study
   * Etonogestrel/ethinyl estradiol vaginal ring (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 ii. Women currently pregnant, measured by serum and/or urine β-hCG iii. Women currently breastfeeding
5. Concerns related to glucose metabolism i. Known, documented history of having met any of the American Diabetes Association's definitions of prediabetic state or of diabetes mellitus (i.e., overt diabetes):

   * Hemoglobin A1c ≥ 5.7%

     o Or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
   * Plasma glucose ≥ 100 mg/dL after 8-h fast
   * Plasma glucose of ≥ 140 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 within the previous 5 years iii. Use of most antidiabetic medications within the 90 days prior to screening
   * 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 used for weight control or polycystic ovarian syndrome is acceptable provided that recruits meet all of the inclusion criteria at screening iv. Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) v. Fasting plasma glucose \< 70 mg/dL at screening
6. Concerns related to lipid metabolism i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative ii. Use of certain lipid-lowering drugs within 90 d prior to screening visit:

   * Statins or PCSK9 inhibitors for secondary prevention or treatment of familial hypercholesterolemia

     o 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, 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 (or history of within the past 5 years)
   * Autoimmune pancreatitis
   * Surgical removal of any portion of the pancreas ii. Cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
   * Atherosclerotic cardiovascular disease
   * Stable or unstable angina
   * Myocardial infarction
   * Ischaemic or hemorrhagic stroke
   * Peripheral arterial disease (claudication)
   * Use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor) Heart rhythm abnormalities
   * Congestive heart failure of any New York Heart Association class
   * Severe valvular heart disease (e.g., aortic stenosis)
   * Pulmonary hypertension iii. Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate \< 60 mL/min/1.73 m2), of any cause iv. Advanced or severe liver disease, 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. Gallstone disease, including:
   * Biliary colic (active)
   * History of acute cholecystitis not treated with cholecystectomy
   * History of other gallstone complications (e.g., pancreatitis, cholangitis) vi.Chronic viral illness (N.B. diagnosis based only on medical history; we 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 d 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)
   * Active inflammatory bowel disease (quiescent and off medication is acceptable)
   * Celiac disease (in remission with 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 causing functional impairment that:
   * 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, or lithium x. Other endocrinopathies:
   * Cushing syndrome (okay if considered in remission after treatment, provided that no exogenous corticosteroids or other ongoing treatment are required)
   * Adrenal insufficiency
   * Primary aldosteronism xi. Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation xii. Bleeding disorders, including due to anticoagulation, or significant anemia (see above) xiii. Dysautonomia, including post-vagotomy xiv. 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, including due to medications and/or heart/liver/kidney problems, as listed above
9. Clinical concern for increased risk of hypokalemia, including low potassium on screening labs (i.e., below lower limit of normal)
10. Use of certain medications currently or within 30 d prior to screening:

    i. Prescribed medications used for any of the indications in the preceding list (§5.3.7) of excluded conditions, or their use within 90 d prior to screening, except allowances for:

    • Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitor \[ACEi\]/angiotensin receptor blocker \[ARB\] used for uncomplicated hypertension rather than for congestive heart failure, etc.)

    o Note, as above, that antidiabetic drugs except metformin within 90 d of screening are excluded ii. Oral or parenteral corticosteroids for more than 3 days within the previous 30 days; topical and inhaled formulations are permitted iii. Fludrocortisone iv. Beta blockers or non-dihydropyridine calcium channel blockers (verapamil or diltiazem)
11. History of certain weight-loss (bariatric) surgery, including:

    i. Roux-en-Y gastric bypass ii. Biliopancreatic diversion iii. Restrictive procedures (lap band, sleeve gastrectomy) performed within the past 6 months
12. Clinical concern for alcohol overuse, including recent documented history during screening and/or participant report of regularly consuming more than 2 drinks per day for males or 1 drink per day for females.
13. Positive urine drug screen, with exceptions for:

    * Lawfully prescribed medications
    * Marijuana/tetrahydrocannabinol positivity, provided that the participant agrees not to use it during the same period that they will abstain from alcohol)
14. History of severe infection or ongoing febrile illness within 30 days of screening
15. Any other disease, 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, foods (including soy, dairy, peanuts, tree nuts, or egg), 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 within 6 months prior to screening or within 5 half-lives of an investigational agent, whichever is longer.

Primary outcomes:
measure: Absolute values of plasma glucose
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in plasma glucose
timeFrame: Up to 425 minutes from the start of the procedure
measure: Absolute values of serum insulin
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum insulin
timeFrame: Up to 425 minutes from the start of the procedure
measure: Absolute values of serum C-peptide
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum C-peptide
timeFrame: Up to 425 minutes from the start of the procedure
Secondary outcomes:
measure: Absolute values of serum or plasma triglyceride (TG)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in absolute values of serum or plasma triglyceride (TG)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Absolute values of serum or plasma free fatty acid (FFA)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum or plasma free fatty acid (FFA)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Absolute values of serum or plasma apolipoprotein B (ApoB)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum or plasma apolipoprotein B (ApoB)
timeFrame: Up to 425 minutes from the start of the procedure
measure: Plasma glucose kinetics: rate of appearance
timeFrame: Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure
measure: Plasma glucose kinetics: rate of disappearance
timeFrame: Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure
measure: Plasma glucose kinetics: endogenous glucose production
timeFrame: Measured every 5 minutes x 4 at the end of each steady-state IIR period, up to 425 minutes from the start of the procedure
Other outcomes:
measure: Absolute values of serum/plasma glucagon
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum or plasma glucagon
timeFrame: Up to 425 minutes from the start of the procedure
measure: Absolute values of serum or plasma growth hormone
timeFrame: Up to 425 minutes from the start of the procedure
measure: Relative change in serum or plasma growth hormone
timeFrame: Up to 425 minutes from the start of the procedure
measure: Serum cortisol level
timeFrame: Up to 425 minutes from the start of the procedure
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Joshua R Cook, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: