Effect of Alpelisib in Healthy Volunteers
Condition: Insulin Resistance; Hyperinsulinemia; Dyslipidemias
MeSH terms: Non-alcoholic Fatty Liver Disease; Insulin Resistance; Dyslipidemias; Hyperinsulinism
Study type: Interventional
Phase: Phase 1

Summary: 
      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: 
      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.
    

Intervention name(s): Alpelisib 150 mg [Piqray], 2 overencapsulated tablets (total: 300 mg); Placebo (microcrystalline cellulose), 2 capsules; FreeStyle Libre Pro; Oral glucose tolerance test (OGTT) with Trutol glucose beverage; BOOST Plus nutritional beverage
Intervention type(s): Drug; Drug; Device; Diagnostic Test; Dietary Supplement
Intervention description(s): Participants will ingest two overencapsulated tablets of alpelisib at 23:00, along with a saltine cracker.; Participants will ingest two capsules filled with microcrystalline cellulose at 23:00, along with a saltine cracker.; Continuous glucose monitoring for 24 hours (double blinded); 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.; Participants will consume a quantity of BOOST Plus calculated to match their daily caloric needs, divided over three liquid meals.
Other intervention name(s): Piqray
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Insulin resistance; Hyperinsulinemia; Diabetes; Non-alcoholic fatty liver disease