Effect of Alpelisib in Healthy Volunteers

Study Overview
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Brief Summary
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The goal of this clinical trial is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib versus placebo in healthy volunteers. The main questions it aims to answer are the impact of acute alpelisib-induced insulin resistance on parameters of glucose and lipid metabolism (how healthy people respond to temporary insulin resistance so that the investigators can see what happens to how the liver handles fat and sugar). Participants will: Consume their total calculated daily caloric needs in nutritional supplements, divided in three meals, and otherwise fast for 24 hours Take a dose of alpelisib 300 mg or placebo at bedtime Wear a continuous glucose monitor for 72 hours Participate in an oral glucose tolerance test (OGTT) Researchers will compare blood tests before and during OGTT in participants randomized (like the flip of a coin) to alpelisib versus placebo to see how the drug treatment affects plasma glucose, serum insulin, and serum lipid parameters (triglycerides, free fatty acids, and apolipoprotein B).

Detailed Description
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Non-alcoholic fatty liver disease (NAFLD) 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 NAFLD (IR-NAFLD) 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 ultimately plan to test whether the multifactorial IR in patients with NAFLD is selective by determining if inducing a discrete, pure form of IR, via pharmacologic inhibition of phosphoinositide-3-kinase (PI3K) with alpelisib, attenuates excessive DNL. However, because of the potential toxicities of alpelisib, the investigators first must test whether they can induce IR with a single dose. In order to ensure participants' safety, the investigators propose herein to perform a randomized, placebo-controlled, pilot & feasibility study of a single dose of alpelisib in healthy volunteers. Following a baseline blood draw on Day 1, participants will be fitted with a continuous glucose monitor. Once lab test results are confirmed as non-exclusionary, randomized participants will be instructed on Day 3 to consume their calculated total daily caloric needs in the form of a nutritional beverage, divided evenly over three meals, and otherwise will fast. On the evening of Day 3, participants will ingest a single dose either of placebo or alpelisib. The following morning (Day 4), about 10 hours later, blood will be drawn to check fasting levels of glucose, insulin, and certain lipid/lipoprotein parameters; the continuous glucose monitor will be removed at that point. Participants will then undergo an oral glucose tolerance test (OGTT) during which investigators will measure glucose, insulin, and lipid (triglycerides, free fatty acids) levels. If the investigators are able to determine reliable induction after a single dose of alpelisib, they will be able to move on to test its effect on volunteers with IR-NAFLD.

Official Title
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Insulin Resistance in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Alpelisib Pilot & Feasibility Study

Conditions
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Insulin Resistance, Hyperinsulinemia, Dyslipidemias

Intervention / Treatment
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* Drug: Alpelisib 150 mg [Piqray], 2 overencapsulated tablets (total: 300 mg)
* Drug: Placebo (microcrystalline cellulose), 2 capsules
* Device: FreeStyle Libre Pro
* Diagnostic Test: Oral glucose tolerance test (OGTT) with Trutol glucose beverage
* Dietary Supplement: BOOST Plus nutritional beverage


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 18-65 years, using highly effective contraception if of childbearing potential Able to understand written and spoken English and/or Spanish Body mass index of 18.0-26.9 kg/m2 Healthy, as determined by screening assessments and Principal Investigator's (PI's) clinical/scientific judgment. Healthy status is defined by the absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead EKG, and laboratory tests on blood and urine. Exclusion Criteria: Inability to provide informed consent in English or Spanish Concerns arising at screening visit (any of the following): i. Unwillingness to fast (except water) for up to 15 hours ii. Documented weight change of ≥ 3.0% of baseline within the previous 6 months iii. Abnormal blood pressure Systolic blood pressure < 90 mm Hg or > 160 mm Hg, and/or Diastolic blood pressure < 60 mm Hg or > 100 mm Hg iv. Abnormal resting heart rate ≤ 60 bpm or ≥ 100 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 v. 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 vi. Abnormal screening serum electrolytes and/or liver function tests vii. Laboratory evidence of prediabetic state or diabetes mellitus: Hemoglobin A1c ≥ 5.7%, and/or Fasting plasma glucose ≥ 100 mg/dL viii. Abnormal fasting lipids at screening (either of the following) Triglycerides ≥ 150 mg/dL LDL-cholesterol ≥ 160 mg/dL ix. Positive qualitative human chorionic gonadotropin beta subunit (β-hCG) (i.e., pregnancy test) in women of childbearing potential COVID-19 precautions i. Unwillingness to comply with masking requirements per hospital policy ii. Active, documented COVID-19 at any time after screening through study completion 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) Combined oral contraceptive pills taken daily, including during the study Intrauterine device (levonorgestrel-eluting or copper) active at the time of the study Medroxyprogesterone acetate (Depo-Provera®) injection active at the time of the study Etonogestrel implants (e.g., Implanon®, 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 iii. Women currently breastfeeding Any clinically relevant history or the presence of any active or chronic disease, including respiratory, renal, hepatic, gastrointestinal, hematological, lymphatic, neurological, cardiovascular, psychiatric, etc. disease or diseases except for: Osteoarthritis, not using chronic anti-inflammatory medications Non-melanoma skin cancer, localized and not receiving systemic therapy N.B. Minor chronic health problems that do not impair overall health/functional status and are judged unlikely to interfere with study conduct or data analysis may be permitted at the discretion of the PI Currently taking any prescription medications other than vitamins or other nutritional supplements, subject to review by the PI o Any participant using biotin (vitamin B7) at >1000 international units per day must not take it for 3 d prior to any study blood draw due to interference with laboratory assays Dermatologic concerns History of cutaneous and/or mucosal eruptive reactions to food or drugs, including, but not limited to, rash or urticaria Active skin conditions requiring ongoing care by a dermatologist except for localized non-melanoma skin cancer (not receiving systemic therapy) Clinical concern for alcohol overuse at screening and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females Current use of illicit drugs Tobacco smoking currently or within the previous 6 months 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 or cow dairy), 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 therapy or use of any biologicals within 6 months prior to screening or within 5 half-lives of an investigational agent or biologic, whichever is longer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alpelisib treatment<br>Participants will ingest a single dose of alpelisib 300 mg (two overencapsulated 150-mg tablets) | Drug: Alpelisib 150 mg [Piqray], 2 overencapsulated tablets (total: 300 mg)<br>* Participants will ingest two overencapsulated tablets of alpelisib at 23:00, along with a saltine cracker.<br>* Other names: Piqray;Device: FreeStyle Libre Pro<br>* Continuous glucose monitoring for 24 hours (double blinded)<br>Diagnostic Test: Oral glucose tolerance test (OGTT) with Trutol glucose beverage<br>* Participants will drink Trutol glucose beverage (D-glucose 75 g in 10 fl oz) and blood will be sampled at baseline and at 15, 30, 60, 90, 120, 150, and 180 minutes.<br>Dietary Supplement: BOOST Plus nutritional beverage<br>* Participants will consume a quantity of BOOST Plus calculated to match their daily caloric needs, divided over three liquid meals.<br>|
| Placebo Comparator: Placebo treatment<br>Participants will ingest a single dose of placebo (two capsules filled with microcrystalline cellulose) | Drug: Placebo (microcrystalline cellulose), 2 capsules<br>* Participants will ingest two capsules filled with microcrystalline cellulose at 23:00, along with a saltine cracker.<br>Device: FreeStyle Libre Pro<br>* Continuous glucose monitoring for 24 hours (double blinded)<br>Diagnostic Test: Oral glucose tolerance test (OGTT) with Trutol glucose beverage<br>* Participants will drink Trutol glucose beverage (D-glucose 75 g in 10 fl oz) and blood will be sampled at baseline and at 15, 30, 60, 90, 120, 150, and 180 minutes.<br>Dietary Supplement: BOOST Plus nutritional beverage<br>* Participants will consume a quantity of BOOST Plus calculated to match their daily caloric needs, divided over three liquid meals.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting plasma glucose | Fasting plasma glucose (units: mg/dL) after a single dose of alpelisib vs placebo. | Day 4 (10 hours after dose) | 
| Fasting serum insulin | Fasting serum insulin (units: micro-international units per milliliter, µIU/mL) levels after a single dose of alpelisib vs placebo. | Day 4 (10 hours after dose) | 
| Fasting serum C-peptide | Fasting serum C-peptide (units: ng/mL) after a single dose of alpelisib vs placebo. | Day 4 (10 hours after dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overnight glucose profile | Glucose levels (units: mg/dL) serially sampled in interstitial fluid by continuous glucose monitor | Days 3-4 (Approximately 24 hours) | 
| Plasma glucose levels during OGTT | Measurement of plasma glucose levels (units: mg/dL) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Plasma glucose area under the curve (AUC) during OGTT | Plasma glucose AUC (units: arbitrary units) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Serum insulin levels during OGTT | Measurement of serum insulin levels (units: µIU/mL) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Serum insulin area under the curve (AUC) during OGTT | Serum insulin AUC (units: arbitrary units) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Serum triglyceride levels during OGTT | Measurement of serum triglyceride levels (units: mg/dL) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Serum free fatty acid levels during OGTT | Measurement of serum free fatty acid levels (units: mmol/L) during OGTT in alpelisib vs placebo | Day 4 (Up to 180 minutes from the start of the procedure) | 
| Fasting serum or plasma apolipoprotein B levels | Measurement of serum or plasma apolipoprotein B (units: mg/dL) in alpelisib vs placebo | Day 4 (10 hours after dose) | 
| Fasting serum total cholesterol levels | Measurement of fasting serum total cholesterol (units: mg/dL) in alpelisib vs placebo | Day 4 (10 hours after dose) | 
| Fasting serum high-density lipoprotein (HDL) cholesterol levels | Measurement of fasting serum HDL cholesterol (units: mg/dL) in alpelisib vs placebo | Day 4 (10 hours after dose) | 
| Fasting serum low-density lipoprotein (LDL) cholesterol levels | Measurement of fasting serum LDL cholesterol (units: mg/dL) in alpelisib vs placebo | Day 4 (10 hours after dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin resistance, Hyperinsulinemia, Diabetes, Non-alcoholic fatty liver disease