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Insulin ResistancePhase 1NCT06354088

Human Models of Selective Insulin Resistance: Alpelisib, Part I

A Phase 1 study testing Alpelisib 300 mg, [1-13C] sodium acetate and [6,6-2H2] D-glucose in people with Insulin Resistance and Prediabetic State, run by Columbia University at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 70 yearsHealthy volunteers can take part
What is being tested?
Alpelisib 300 mg, [1-13C] sodium acetate and [6,6-2H2] D-glucose
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
32 participants
Where
1 siteUnited States
Study dates
24 Apr 2024to 31 Dec 2026
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 35Show fewer
  • 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:
  • Significant cardiovascular diseases (N.B. uncomplicated hypertension is not exclusionary)
  • Severe liver disease, including advanced fibrosis (e.g., fibrosis score F3-F4 by vibration-controlled transient elastography) and cirrhosis
  • Psychiatric diseases causing functional impairment that: (1) Are or have been decompensated within 1 year of screening, and/or (2) Require use of anti-dopaminergic antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine)
  • Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation
  • Bleeding disorders, including due to anticoagulation, or significant anemia (see above)
  • Active malignancy, or hormonally active benign neoplasm, except allowances for non-melanoma skin cancer and differentiated thyroid cancer (Stage I only)
  • Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above
  • Use of oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 30 days; topical and inhaled formulations are permitted
  • History of certain weight-loss (bariatric) surgery, including:
  • Roux-en-Y gastric bypass
  • Biliopancreatic diversion
  • Restrictive procedures (lap band, sleeve gastrectomy) performed within the past 6 months
  • Clinical concern for alcohol overuse based on chart review and/or by recruit's report of more than 14 standard drinks per week for males or more than 7 standard drinks per week for females
  • Regular use of tobacco, either daily or an average of at least 1 cigarette per day, and/or nicotine vaping more than 1 day per week
  • Clinical concern for use of illicit drugs other than marijuana or lawfully prescribed medications based on recruit's report, chart review, and point-of-care urine drug test at screening
  • History of or ongoing febrile illness within 30 days of screening
  • 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.
  • Known allergy/hypersensitivity to any component of the medicinal product formulations (including soy, cow dairy, or gluten), other biologics, venipuncture materials, plastics, adhesive or silicone, or ongoing clinically important allergy/hypersensitivity as judged by the investigator.
  • Dietary restrictions (e.g., vegan, kosher, halal) on gelatin present in overencapsulation
  • Concurrent enrollment in another clinical study of any investigational drug/biologic therapy within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.
  • Prior participation in other studies led by Dr. Cook (PI) is excluded from this prohibition according to his medical/scientific judgment.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Joshua R Cook, MD, PhD contact

2123056289

jrc2175@cumc.columbia.edu

Ishwari Nagnur contact

2123059336

imn2113@cumc.columbia.edu

United States1 site, 1 recruiting

  • Columbia University Irving Medical Center

    New York, New York, 10032

    Joshua R Cook, MD, PhD, 2123056289, jrc2175@cumc.columbia.edu

    Ishwari Nagnur, 2123059336, zds2120@cumc.columbia.edu

    Recruiting

Other trials in United States

About this study

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 while participants are fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages.

The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.

Read the detailed description

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the mechanisms linking IR to unhealthy fat accumulation in liver remains unclear. "Pure" IR would be expected to disinhibit hepatic glucose production while dampening hepatic triglyceride (TG) biosynthesis, but the excessive hepatic de novo lipogenesis (DNL) of IR-associated MASLD suggests that hepatic IR is "selective." However, the concept of IR selectivity is controversial, and because of clinical heterogeneity, lead-time discrepancies, co-morbidities, and medication effects, parsing out this pathophysiologic conundrum in humans is challenging. The investigators plan to test whether the multifactorial IR in patients at risk of T2DM/MASLD is selective by determining if inducing a discrete, "pure" form of IR, via pharmacologic inhibition of phosphoinositide-3-kinase (PI3K) with alpelisib, versus placebo, attenuates excessive DNL. Investigators will also study this question in healthy, insulin-sensitive (IS) volunteers.

Participants in this randomized crossover trial will be admitted twice to the inpatient clinical research unit. During each admission, they will take a dose of either alpelisib or placebo (in randomized order) in the evening and receive infusions of [13C] sodium acetate and [2H] D-glucose to measure DNL and endogenous glucose production (EGP), respectively, during an overnight fast. DNL measurement will then continue during the following day during 8 hours of standardized mixed-meal feedings. Blood will be drawn at defined intervals for determining levels of glucose, insulin, lipids including triglycerides and free fatty acids, and tracer/tracee enrichments for the stable-isotope tracers. There will be a 2-8-week hiatus for drug washout between the two inpatient study admissions.

Being tested
Alpelisib 300 mg, Placebo, [1-13C] sodium acetate, [6,6-2H2] D-glucose, Mixed Meal Tolerance Test
Keywords
Insulin resistance, Hyperinsulinemia, Non-Alcoholic Fatty Liver Disease, Hepatic steatosis, De novo lipogenesis, Glucose production
Medical subject headings
Insulin Resistance, Prediabetic State, Overweight, Obesity, Non-alcoholic Fatty Liver Disease, Hyperinsulinism, Fatty Liver

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Alpelisib 300 mgDrug

    Also called Piqray

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

  • PlaceboDrug

    Also called Placebo capsules

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

  • [1-13C] sodium acetateDrug

    Also called C13A

    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)

  • [6,6-2H2] D-glucoseDrug

    Also called D2-glucose, D2G

    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)

  • Mixed Meal Tolerance TestDiagnostic test

    Also called Boost drink

    All participants will undergo two serial standardized meals of Nestlé BOOST Plus on Study Day 2 over 8 hours. (Non-experimental.)

  • Nestlé BOOST PlusDietary supplement

    Participants will consume standardized portions of Nestlé BOOST Plus as meal replacements on Study Day 1 and as two serial mixed meal tolerance tests on Study Day 2. (Non-experimental.)

Study groups in NCT06354088
Study groupRoleWhat they receive
Placebo then alpelisib (Insulin Sensitive group)ExperimentalOn 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.
Receives: Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Diagnostic Test: Mixed Meal Tolerance Test; Dietary Supplement: Nestlé BOOST Plus
Alpelisib then placebo (Insulin Sensitive group)ExperimentalOn 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.
Receives: Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Diagnostic Test: Mixed Meal Tolerance Test; Dietary Supplement: Nestlé BOOST Plus
Placebo then alpelisib (Insulin Resistant group)ExperimentalOn 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.
Receives: Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Diagnostic Test: Mixed Meal Tolerance Test; Dietary Supplement: Nestlé BOOST Plus
Alpelisib then placebo (Insulin Resistant group)ExperimentalOn 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.
Receives: Drug: Alpelisib 300 mg; Drug: Placebo; Drug: [1-13C] sodium acetate; Drug: [6,6-2H2] D-glucose; Diagnostic Test: Mixed Meal Tolerance Test; Dietary Supplement: Nestlé BOOST Plus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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: %

    Measured: Up to 24 hours after dosing

  2. 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

    Measured: Up to 24 hours after dosing

  3. 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

    Measured: Up to 15 hours after dosing

  4. 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

    Measured: Up to 15 hours after dosing

Secondary outcomes (8)

  1. Serum insulin level

    Serum insulin levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding.

    During Study Day 2 of both study visits, starting after investigational agent dose.

    units: µIU/mL

    Measured: Approximately 11-19 hours after dosing

  2. Plasma glucose level

    Plasma glucose levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding.

    During Study Day 2 of both study visits, starting after investigational agent dose.

    units: mg/dL

    Measured: Approximately 11-19 hours after dosing

  3. Triglycerides level

    (Serum or plasma) triglyceride levels in response to placebo vs alpelisib following an overnight fast and then hourly during refeeding.

    During Study Day 2 of both study visits, starting after investigational agent dose.

    units: mg/dL

    Measured: Approximately 11-19 hours after dosing

  4. Free fatty acids level

    (Serum or plasma) triglyceride levels in response to placebo vs alpelisib following an overnight fast and then periodically during refeeding.

    During Study Day 2 of both study visits, starting after investigational agent dose.

    units: mmol/L

    Measured: Approximately 11-19 hours after dosing

  5. Glucose kinetics: rate of appearance (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

    Measured: Up to 15 hours after dosing

  6. Glucose kinetics: rate of appearance (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

    Measured: Up to 15 hours after dosing

  7. Glucose kinetics: rate of disappearance (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

    Measured: Up to 15 hours after dosing

  8. Glucose kinetics: rate of disappearance (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

    Measured: Up to 15 hours after dosing

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Apr 2024
  2. Study start24 Apr 2024
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
32 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06354088
Sponsor's protocol ID
AAAU9636
Other IDs
K12DK133995, K23DK140614
Status last verified
Aug 2026
First submitted
3 Apr 2024
Last updated
24 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Alpelisib 300 mg, [1-13C] sodium acetate and [6,6-2H2] D-glucose in people with Insulin Resistance and Prediabetic State, run by Columbia University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 24 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Joshua R Cook, MD, PhD (2123056289, jrc2175@cumc.columbia.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hepatic de novo lipogenesis (DNL) (absolute value) (time frame: Up to 24 hours after dosing). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06354088.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Aug 2026.

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