Alpelisib Challenge Test (ACT)

Alpelisib Challenge Test (ACT) for Assessment of Pancreatic β-Cell Reserve, Pilot & Feasibility Study

The goal of this study is to test a potentially easier method for measuring how much insulin a person is capable of producing than the current gold-standard method, the "hyperglycemic clamp." Participants will come in for a two-day (overnight) visit in which they will first undergo a "hyperglycemic clamp," in which they receive an intravenous (into the vein) infusion of glucose (sugar) in order to measure the maximum amount of insulin their body produces in response. They will then consume a series of three standardized meals throughout the rest of the day. At 23:00, they will take a single dose of alpelisib, a drug that interferes within insulin's actions in the body. Then, the following morning, they will undergo a "Mixed Meal Tolerance Test" in which they consume a standardized liquid nutritional beverage and have blood drawn periodically before and during the test.

Inclusion Criteria:

• Adults aged 18-70 years

• Able to understand wrifen and spoken English and/or Spanish

• Body mass index of 18-45 kg/m2 (or 18-42 kg/m2 for those of Asian ancestry)

  • For Lean group: BMI 18.0-24.9 kg/m2 (or 18.0-22.9 kg/m2 for those of Asian ancestry)
  • For Overweight group: BMI 25.0-29.9 kg/m2 (or 23.0-27.4 kg/m2 for those of Asian ancestry)
  • For Obesity group: BMI 30.0-45.0 kg/m2 (or 27.5-42 kg/m2 for those of Asian ancestry)

Exclusion Criteria:

• Inability to provide informed consent in English or Spanish

• Unwillingness to fast (except water) for up to 18 hours

• Unwillingness not to get out of bed and to use bedpan/urinal to void for up to 15 hours

• Documented weight change of ≥ 5.0% of baseline within the previous 3 months

• Abnormal blood pressure

  • Systolic blood pressure < 90 mm Hg or > 160 mm Hg, and/or
  • Diastolic blood pressure < 55 mm Hg or > 100 mm Hg

• Abnormal resting heart rate < 55 bpm or ≥ 110 bpm

  • Sinus tachycardia that has been extensively worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion
  • Sinus bradycardia between heart rates of 45 and 54 bpm may be permitted at the PI's discretion if in a clinically appropriate setting (e.g., toned athlete, taking beta blockers)

• Abnormal (i.e., non-regular) heart rhythm detected on physical exam

• Abnormal screening serum electrolytes judged by the PI to be potentially clinically significant

• Liver function abnormalities (either of the following)

  • Transaminases (AST or ALT) > 3.0 x the upper limit of normal
  • Total bilirubin > 1.25 x the upper limit of normal

• Laboratory evidence of diabetes mellitus:

  • Hemoglobin A1c ≥ 6.5%, and/or
  • Fasting plasma glucose ≥ 126 mg dL-1

• Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential

• Women currently pregnant

• Women currently breastfeeding

• History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes):

  • Hemoglobin A1c ≥ 6.5%, or rapid rise in documented HbA1c values causing clinical concern for evolving insulin deficiency
  • Plasma glucose ≥ 126 mg/dL after 8-h fast
  • Plasma glucose of ≥ 200 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

• History of gestational diabetes mellitus within the previous 5 years

• Use of most antidiabetic medications within the 90 days prior to screening

  • Exceptions: thiazolidinediones, sulfonylureas, meglitinides, DPP4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, amylin mimetics, acarbose, insulin
  • Metformin is acceptable provided that recruits meet all of the inclusion criteria at screening

• Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease)

• 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)
  • History of percutaneous coronary intervention
  • Congestive heart failure (NYHA Class ≥ 2)
  • Severe valvular heart disease (e.g., aortic stenosis)
  • Pulmonary hypertension

• 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)

• 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)

• 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
  • Differentiated thyroid cancer (AJCC 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 certain medications currently or within 30 days prior to screening:

  • Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 30 d prior to screening, except allowances for:

    • Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., ACEi/ARB used for uncomplicated hypertension rather than for congestive heart failure, etc.)
    • Note, as above, that antidiabetic drugs except metformin within 30 d of screening are excluded

  • 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 tobacco use (smoking more than 1 cigarette per week) or regular nicotine vaping (daily)

• 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 14 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.

• Concurrent enrollment in another clinical study of any investigational drug/biologic therapy within 5 half-lives of an investigational agent or biologic.