Human Models of Selective Insulin Resistance: Alpelisib, Part I

NCT06354088 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: AAAU9636K12DK133995K23DK140614
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to understand how the blood sugar-lowering hormone insulin works in healthy adults versus those who are at risk for type 2 diabetes. The study will use a drug called alpelisib, which interferes with insulin's actions in the body, to answer the study's main question: does the liver continue to respond to insulin's stimulation of fat production even when it loses the ability to stop making glucose (sugar) in response to insulin. Researchers will compare the impact of single doses of both alpelisib and placebo (inert non-drug) in random order (like flipping a coin) in study participants. Participants will be asked to stay twice overnight in the hospital, take single doses of alpelisib and placebo (one or the other on each of the two hospital stays), and receive intravenous (into the vein) infusions of non-radioactive "tracer" molecules that allow researchers to measure the production of glucose (sugar) and fats by the liver. Measurements will be done both overnight, while participants are asleep and fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages during the following day. The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.

Conditions

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

Keywords

Insulin resistance; Hyperinsulinemia; Non-Alcoholic Fatty Liver Disease; Hepatic steatosis; De novo lipogenesis; Glucose production

Outcome Measures

Primary Outcomes (4)

• Hepatic de novo lipogenesis (DNL) (absolute value)

  Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG. During both inpatient (overnight) study visits, starting after investigational agent dose. units: %

  Up to 24 hours after dosing

• Hepatic de novo lipogenesis (DNL) (relative value)

  Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG. During both inpatient (overnight) study visits, starting after investigational agent dose. unit: fold difference and/or ∆% versus other group

  Up to 24 hours after dosing

• Endogenous glucose production (EGP) (absolute value)

  Calculated from D2G tracer enrichment by the Steele equations. During both inpatient (overnight) study visits, starting after investigational agent dose. units: mg/kg/min

  Up to 15 hours after dosing

• Endogenous glucose production (EGP) (relative value)

  Calculated from D2G tracer enrichment by the Steele equations. During both inpatient (overnight) study visits, starting after investigational agent dose. units: fold difference and/or ∆% versus other group

  Up to 15 hours after dosing

Secondary Outcomes (8)

• Serum insulin level

  Approximately 11-19 hours after dosing

• Plasma glucose level

  Approximately 11-19 hours after dosing

• Triglycerides level

  Approximately 11-19 hours after dosing

• Free fatty acids level

  Approximately 11-19 hours after dosing

• Glucose kinetics: rate of appearance (absolute value)

  Up to 15 hours after dosing

Study Arms (4)

Placebo then alpelisib (Insulin Sensitive group)

EXPERIMENTAL

On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.

Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Dietary Supplement: Nestlé BOOST Plus

Alpelisib then placebo (Insulin Sensitive group)

EXPERIMENTAL

On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.

Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Dietary Supplement: Nestlé BOOST Plus

Placebo then alpelisib (Insulin Resistant group)

EXPERIMENTAL

On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.

Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Dietary Supplement: Nestlé BOOST Plus

Alpelisib then placebo (Insulin Resistant group)

EXPERIMENTAL

On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.

Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Dietary Supplement: Nestlé BOOST Plus

Interventions

Alpelisib 300 mg DRUG

All participants will ingest one dose of alpelisib 300 mg (2 x 150-mg overencapsulated tablets) on one of two study admissions.

Also known as: Piqray

Alpelisib then placebo (Insulin Resistant group); Alpelisib then placebo (Insulin Sensitive group); Placebo then alpelisib (Insulin Resistant group); Placebo then alpelisib (Insulin Sensitive group)

Placebo DRUG

All participants will ingest one dose of placebo (2 overencapuslated doses of microcrystalline cellulose) on one of two study admissions.

Also known as: Placebo capsules

Alpelisib then placebo (Insulin Resistant group); Alpelisib then placebo (Insulin Sensitive group); Placebo then alpelisib (Insulin Resistant group); Placebo then alpelisib (Insulin Sensitive group)

[1-13C] sodium acetate DRUG

All participants will receive continuous infusions of \[1-13C\] sodium acetate for up to 23 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)

Also known as: C13A

Alpelisib then placebo (Insulin Resistant group); Alpelisib then placebo (Insulin Sensitive group); Placebo then alpelisib (Insulin Resistant group); Placebo then alpelisib (Insulin Sensitive group)

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

All participants will receive continuous infusions of \[6,6-2H2\] D-glucose for up to 15 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)

Also known as: D2-glucose, D2G

Alpelisib then placebo (Insulin Resistant group); Alpelisib then placebo (Insulin Sensitive group); Placebo then alpelisib (Insulin Resistant group); Placebo then alpelisib (Insulin Sensitive group)

Nestlé BOOST Plus DIETARY_SUPPLEMENT

All participants will ingest standardized mixed meals of Nestlé BOOST Plus on Study Day 1 and then smaller portions hourly x 8 hours on Study Day 2 of each study visit. (non-experimental)

Also known as: Boost drink

Alpelisib then placebo (Insulin Resistant group); Alpelisib then placebo (Insulin Sensitive group); Placebo then alpelisib (Insulin Resistant group); Placebo then alpelisib (Insulin Sensitive group)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 18-70 years
• Able to understand written and spoken English and/or Spanish
• Body mass index of:
• For Group IS: BMI 18-25 kg/m2
• For Group IR: BMI 30-45 kg/m2
• Evidence of insulin sensitivity or insulin resistance:
• Insulin sensitive (for Group IS) defined as all of the following: (1) Fasting serum insulin ≤ 10 µIU/mL, (2) Absence of dysglycemia (fasting plasma glucose \< 100 mg/dL and hemoglobin A1c \< 5.7%), (3) Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score \< 2.5, and (4) Fibrosis-4 (FIB-4) score \< 1.3
• Insulin resistant (for Group IR) defined as fasting serum insulin ≥ 13 µIU/mL plus at least one of the following: (1) Presence of prediabetic state (fasting plasma glucose 100-125 mg/dL and/or hemoglobin A1c 5.7-6.4%), and/or HOMA-IR ≥ 2.5

You may not qualify if:

• Inability to provide informed consent in English or Spanish
• Concerns arising at screening visit:
• Abnormal vital signs: (1) Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg and/or (2) Diastolic blood pressure \< 55 mm Hg or \> 100 mm Hg and/or (3) Abnormal resting heart rate \< 55 bpm (except at PI's discretion) or ≥ 110 bpm
• Abnormal screening serum electrolytes judged by the PI to be potentially clinically significant, including liver function abnormalities (either of the following): (1) Transaminases (AST or ALT) \> 3.0 x the upper limit of normal and/or (2) Total bilirubin \> 1.25 x the upper limit of normal
• Laboratory evidence of diabetes mellitus: (1) Hemoglobin A1c ≥ 6.5%, and/or (2) Fasting plasma glucose ≥ 126 mg/dL
• Reproductive concerns i. Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential ii. Women currently pregnant iii. Women currently breastfeeding
• Concerns related to glucose metabolism
• History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes)
• History of gestational diabetes mellitus within the previous 5 years
• Use of most antidiabetic medications (other than metformin) within the 90 days prior to screening: 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)
• Concerns related to lipid metabolism
• Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative
• Use of certain lipid-lowering drugs within 14 d prior to screening visit: fibrates (e.g., fenofibrate, gemfibrozil), prescription-strength omega-3 fatty acids (e.g., icosapent ethyl), high-dose niacin (\>100 mg daily)
• Known, documented history, at the time of screening, of any of the following medical conditions:
• Severe liver disease, including advanced fibrosis (e.g., fibrosis score F3-F4 by vibration-controlled transient elastography) and cirrhosis

Sponsors & Collaborators

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

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

MeSH Terms

Conditions

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

Interventions

Alpelisib; Sodium Acetate; Glucose; delta inulin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Acetic Acid; Acetates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hexoses; Monosaccharides; Sugars; Carbohydrates

Study Officials

• Joshua R Cook, MD, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joshua R Cook, MD, PhD

CONTACT

2123056289; jrc2175@cumc.columbia.edu

Ishwari Nagnur

CONTACT

2123059336; imn2113@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: April 3, 2024
• First Posted: April 9, 2024
• Study Start: April 24, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 9, 2026

Record last verified: 2026-04

Locations

US (1)