NCT05733455

Effect of Alpelisib in Healthy Volunteers

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 23 (actual)
• Sponsor: Columbia University · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Accepted

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.

Conditions

• Insulin Resistance
• Hyperinsulinemia
• Dyslipidemias

Interventions

Type	Name	Description
DRUG	Alpelisib 150 mg [Piqray], 2 overencapsulated tablets (total: 300 mg)	Participants will ingest two overencapsulated tablets of alpelisib at 23:00, along with a saltine cracker.
DRUG	Placebo (microcrystalline cellulose), 2 capsules	Participants will ingest two capsules filled with microcrystalline cellulose at 23:00, along with a saltine cracker.
DEVICE	FreeStyle Libre Pro	Continuous glucose monitoring for 24 hours (double blinded)
DIAGNOSTIC_TEST	Oral glucose tolerance test (OGTT) with Trutol glucose beverage	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.
DIETARY_SUPPLEMENT	BOOST Plus nutritional beverage	Participants will consume a quantity of BOOST Plus calculated to match their daily caloric needs, divided over three liquid meals.

Timeline

• Start date: 2023-05-09
• Primary completion: 2023-12-01
• Completion: 2023-12-01
• First posted: 2023-02-17
• Last updated: 2023-12-21

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study