Dexamethasone/Pancreatic Clamp P&F

NCT06126354 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: AAAU76803P30DK063608
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Insulin Resistance; Prediabetic State; Non-Alcoholic Fatty Liver Disease; Overweight and Obesity

Keywords

Insulin resistance; Hyperinsulinemia; Diabetes; Non-alcoholic fatty liver disease

Outcome Measures

Primary Outcomes (6)

• Absolute values of plasma glucose

  Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the glucose levels that result from altering the basal IIR. Units: mg/dL

  Up to 425 minutes from the start of the procedure

• Relative change in plasma glucose

  Goal is first to clamp insulin infusion rate to maintain mean basal fasting plasma glucose during the basal titration phase, and then during the intervention phase to observe the impact of altering the basal IIR on glycemia. Units: fold difference and/or ∆mg/dL relative to previous time points

  Up to 425 minutes from the start of the procedure

• Absolute values of serum insulin

  Investigators will assess the insulin levels attained at the basal IIR, and at each stepwise reduction in IIR during the intervention phase. Units: micro-international units per milliliter (µIU/mL)

  Up to 425 minutes from the start of the procedure

• Relative change in serum insulin

  Investigators will compare the baseline insulin level to that attained at the basal IIR, as well as comparing to the change in insulin level that occurs with alterations in the IIR during the intervention phase. Units: fold difference and/or ∆ µIU/mL relative to previous time points

  Up to 425 minutes from the start of the procedure

• Absolute values of serum C-peptide

  Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero. Units: ng/mL

  Up to 425 minutes from the start of the procedure

• Relative change in serum C-peptide

  Suppression of endogenous insulin by octreotide during pancreatic clamp is expected to result in a fall in C-peptide levels to near zero. Units: fold difference and/or ∆ µIU/mL relative to previous time points

  Up to 425 minutes from the start of the procedure

Secondary Outcomes (9)

• Absolute values of serum or plasma triglyceride (TG)

  Up to 425 minutes from the start of the procedure

• Relative change in absolute values of serum or plasma triglyceride (TG)

  Up to 425 minutes from the start of the procedure

• Absolute values of serum or plasma free fatty acid (FFA)

  Up to 425 minutes from the start of the procedure

• Relative change in serum or plasma free fatty acid (FFA)

  Up to 425 minutes from the start of the procedure

• Absolute values of serum or plasma apolipoprotein B (ApoB)

  Up to 425 minutes from the start of the procedure

Other Outcomes (5)

• Absolute values of serum/plasma glucagon

  Up to 425 minutes from the start of the procedure

• Relative change in serum or plasma glucagon

  Up to 425 minutes from the start of the procedure

• Absolute values of serum or plasma growth hormone

  Up to 425 minutes from the start of the procedure

Study Arms (2)

Maintenance hyperinsulinemia (MH) protocol

ACTIVE COMPARATOR

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will remain at 100% of basal for the full duration (225 min). The IIR and resulting insulin levels are expected to be relatively high (cf. hyperinsulinemia) because of dexamethasone-induced insulin resistance.

Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Human Growth Hormone; Drug: Dexamethasone Oral; Other: [6,6-2H2] D-glucose; Drug: 20% D-glucose (aq); Dietary Supplement: BOOST Plus; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer; Other: Normal saline; Other: Human albumin

Reduction toward euinsulinemia (RE) protocol

EXPERIMENTAL

The basal insulin infusion rate (IIR) necessary to maintain participants' mean basal fasting plasma glucose (mbFPG) will be determined during the basal titration period. Then, during the intervention period, the IIR will be reduced progressively, at 75-min intervals, to 90%, 75%, and 60% of basal IIR. Thus, the basal hyperinsulinemia expected due to underlying insulin resistance will be reduced toward euinsulinemia.

Drug: Insulin human; Drug: Octreotide Acetate; Drug: Glucagon; Drug: Human Growth Hormone; Drug: Dexamethasone Oral; Other: [6,6-2H2] D-glucose; Drug: 20% D-glucose (aq); Dietary Supplement: BOOST Plus; Device: Harvard Apparatus PHD ULTRA CP syringe pump; Device: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer; Other: Normal saline; Other: Human albumin

Interventions

Insulin human DRUG

Insulin infusion rate (IIR) will be determined empirically first to maintain mean basal fasting plasma glucose, and then either maintained at the basal rate (MH protocol) or be reduced stepwise toward euinsulinemia (RE protocol).

Also known as: Novolin-R, Humulin-R

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Octreotide Acetate DRUG

Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.

Also known as: Octreotide Acetate IV

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Glucagon DRUG

Glucagon will be replaced at a constant rate of up to 0.65 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and rhGH.

Also known as: Glucagon IV

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Human Growth Hormone DRUG

Recombinant human growth hormone (rhGH) will be replaced at a constant rate of up to 3 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and glucagon.

Also known as: Omnitrope

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Dexamethasone Oral DRUG

Synthetic pure glucocorticoid used to induce temporary insulin resistance, administered orally as seven 1-mg doses over 72 hours.

Also known as: Dexamethasone

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

[6,6-2H2] D-glucose OTHER

Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp. (Non-investigational)

Also known as: D2-glucose, D2G

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

20% D-glucose (aq) DRUG

20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed. (Non-investigational)

Also known as: D20W

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

BOOST Plus DIETARY_SUPPLEMENT

Nutritional supplement will be administered to provide three standardized "mixed meals" on the day before the pancreatic clamp. (Non-investigational)

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Harvard Apparatus PHD ULTRA CP syringe pump DEVICE

Device: Harvard Apparatus PHD ULTRA CP syringe pump Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates. (Non-investigational)

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer DEVICE

Glucose oxidase analyzer used to detect plasma glucose levels at the point of care. YSI have been the gold standard in clamp studies for many years. Two machines will run in parallel to ensure accuracy of results. (Non-investigational)

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Normal saline OTHER

Normal saline (0.9% NaCl, aq), variable rate (as needed)

Also known as: NaCl IV

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Human albumin OTHER

Human albumin (5%, aq), 0.4 g per 100 mL of infusion (0.4% (w/v) in insulin and OCT/GCG/GH bags)

Also known as: Human albumin IV

Maintenance hyperinsulinemia (MH) protocol; Reduction toward euinsulinemia (RE) protocol

Eligibility Criteria

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

You may qualify if:

• Men and women (using highly effective contraception if of childbearing potential) aged 18-65 years
• Body mass index of 25.0-39.9 kg/m2
• Able to understand written and spoken English and/or Spanish
• 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
• Normal fasting serum insulin (fasting insulin level \< 12 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. 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)

Sponsors & Collaborators

• Columbia University: lead
• Albert Einstein College of Medicine: 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

Insulin Resistance; Prediabetic State; Non-alcoholic Fatty Liver Disease; Overweight; Obesity; Hyperinsulinism; Diabetes Mellitus

Interventions

Insulin; Octreotide; Glucagon; Human Growth Hormone; Dexamethasone; Glucose; Saline Solution; Serum Albumin, Human

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Fatty Liver; Liver Diseases; Digestive System Diseases; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Proglucagon; Growth Hormone; Pituitary Hormones, Anterior; Pituitary Hormones; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Hexoses; Monosaccharides; Sugars; Carbohydrates; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Serum Albumin; Albumins; Proteins; Blood Proteins

Study Officials

• Joshua R Cook, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participant will be blinded to study group assignment.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: 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.

Study Record Dates

• First Submitted: November 6, 2023
• First Posted: November 13, 2023
• Study Start: July 1, 2024
• Primary Completion: November 30, 2025
• Study Completion: March 31, 2026
• Last Updated: July 10, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Indefinitely following study completion.
• Access Criteria: All requests will be reviewed by the PI for scientific merit and samples/data will be transferred only upon completion of a MTA or DUA, as appropriate. No PHI will be disclosed or shared.

Locations

US (1)