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Effect of Alpelisib in Healthy Volunteers

Primary Purpose

Insulin Resistance, Hyperinsulinemia, Dyslipidemias

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
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
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Insulin Resistance focused on measuring Insulin resistance, Hyperinsulinemia, Diabetes, Non-alcoholic fatty liver disease

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Columbia University Irving Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Alpelisib treatment

Placebo treatment

Arm Description

Participants will ingest a single dose of alpelisib 300 mg (two overencapsulated 150-mg tablets)

Participants will ingest a single dose of placebo (two capsules filled with microcrystalline cellulose)

Outcomes

Primary Outcome Measures

Fasting plasma glucose
Fasting plasma glucose (units: mg/dL) after a single dose of alpelisib vs placebo.
Fasting serum insulin
Fasting serum insulin (units: micro-international units per milliliter, µIU/mL) levels after a single dose of alpelisib vs placebo.
Fasting serum C-peptide
Fasting serum C-peptide (units: ng/mL) after a single dose of alpelisib vs placebo.

Secondary Outcome Measures

Overnight glucose profile
Glucose levels (units: mg/dL) serially sampled in interstitial fluid by continuous glucose monitor
Plasma glucose levels during OGTT
Measurement of plasma glucose levels (units: mg/dL) during OGTT in alpelisib vs placebo
Plasma glucose area under the curve (AUC) during OGTT
Plasma glucose AUC (units: arbitrary units) during OGTT in alpelisib vs placebo
Serum insulin levels during OGTT
Measurement of serum insulin levels (units: µIU/mL) during OGTT in alpelisib vs placebo
Serum insulin area under the curve (AUC) during OGTT
Serum insulin AUC (units: arbitrary units) during OGTT in alpelisib vs placebo
Serum triglyceride levels during OGTT
Measurement of serum triglyceride levels (units: mg/dL) during OGTT in alpelisib vs placebo
Serum free fatty acid levels during OGTT
Measurement of serum free fatty acid levels (units: mmol/L) during OGTT in alpelisib vs placebo
Fasting serum apolipoprotein B levels
Measurement of serum apolipoprotein B (units: mg/dL) in alpelisib vs placebo
Fasting serum total cholesterol levels
Measurement of fasting serum total cholesterol (units: mg/dL) in alpelisib vs placebo
Fasting serum high-density lipoprotein (HDL) cholesterol levels
Measurement of fasting serum HDL cholesterol (units: mg/dL) in alpelisib vs placebo
Fasting serum low-density lipoprotein (LDL) cholesterol levels
Measurement of fasting serum LDL cholesterol (units: mg/dL) in alpelisib vs placebo
Fasting triglyceride levels in very low-density lipoprotein (VLDL)
Measurement of fasting serum VLDL-triglycerides (units: mg/dL) in alpelisib vs placebo
Fasting apolipoprotein B (ApoB) levels in very low-density lipoprotein (VLDL)
Measurement of fasting serum VLDL-ApoB (units: mg/dL) in alpelisib vs placebo

Full Information

First Posted
February 3, 2023
Last Updated
May 12, 2023
Sponsor
Columbia University
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1. Study Identification

Unique Protocol Identification Number
NCT05733455
Brief Title
Effect of Alpelisib in Healthy Volunteers
Official Title
Insulin Resistance in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Alpelisib Pilot & Feasibility Study
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 9, 2023 (Actual)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Columbia University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Resistance, Hyperinsulinemia, Dyslipidemias
Keywords
Insulin resistance, Hyperinsulinemia, Diabetes, Non-alcoholic fatty liver disease

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Alpelisib treatment
Arm Type
Experimental
Arm Description
Participants will ingest a single dose of alpelisib 300 mg (two overencapsulated 150-mg tablets)
Arm Title
Placebo treatment
Arm Type
Placebo Comparator
Arm Description
Participants will ingest a single dose of placebo (two capsules filled with microcrystalline cellulose)
Intervention Type
Drug
Intervention Name(s)
Alpelisib 150 mg [Piqray], 2 overencapsulated tablets (total: 300 mg)
Other Intervention Name(s)
Piqray
Intervention Description
Participants will ingest two overencapsulated tablets of alpelisib at 23:00, along with a saltine cracker.
Intervention Type
Drug
Intervention Name(s)
Placebo (microcrystalline cellulose), 2 capsules
Intervention Description
Participants will ingest two capsules filled with microcrystalline cellulose at 23:00, along with a saltine cracker.
Intervention Type
Device
Intervention Name(s)
FreeStyle Libre Pro
Intervention Description
Continuous glucose monitoring for 24 hours (double blinded)
Intervention Type
Diagnostic Test
Intervention Name(s)
Oral glucose tolerance test (OGTT) with Trutol glucose beverage
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
BOOST Plus nutritional beverage
Intervention Description
Participants will consume a quantity of BOOST Plus calculated to match their daily caloric needs, divided over three liquid meals.
Primary Outcome Measure Information:
Title
Fasting plasma glucose
Description
Fasting plasma glucose (units: mg/dL) after a single dose of alpelisib vs placebo.
Time Frame
Day 4 (10 hours after dose)
Title
Fasting serum insulin
Description
Fasting serum insulin (units: micro-international units per milliliter, µIU/mL) levels after a single dose of alpelisib vs placebo.
Time Frame
Day 4 (10 hours after dose)
Title
Fasting serum C-peptide
Description
Fasting serum C-peptide (units: ng/mL) after a single dose of alpelisib vs placebo.
Time Frame
Day 4 (10 hours after dose)
Secondary Outcome Measure Information:
Title
Overnight glucose profile
Description
Glucose levels (units: mg/dL) serially sampled in interstitial fluid by continuous glucose monitor
Time Frame
Days 3-4 (Approximately 24 hours)
Title
Plasma glucose levels during OGTT
Description
Measurement of plasma glucose levels (units: mg/dL) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Plasma glucose area under the curve (AUC) during OGTT
Description
Plasma glucose AUC (units: arbitrary units) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Serum insulin levels during OGTT
Description
Measurement of serum insulin levels (units: µIU/mL) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Serum insulin area under the curve (AUC) during OGTT
Description
Serum insulin AUC (units: arbitrary units) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Serum triglyceride levels during OGTT
Description
Measurement of serum triglyceride levels (units: mg/dL) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Serum free fatty acid levels during OGTT
Description
Measurement of serum free fatty acid levels (units: mmol/L) during OGTT in alpelisib vs placebo
Time Frame
Day 4 (Up to 180 minutes from the start of the procedure)
Title
Fasting serum apolipoprotein B levels
Description
Measurement of serum apolipoprotein B (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)
Title
Fasting serum total cholesterol levels
Description
Measurement of fasting serum total cholesterol (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)
Title
Fasting serum high-density lipoprotein (HDL) cholesterol levels
Description
Measurement of fasting serum HDL cholesterol (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)
Title
Fasting serum low-density lipoprotein (LDL) cholesterol levels
Description
Measurement of fasting serum LDL cholesterol (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)
Title
Fasting triglyceride levels in very low-density lipoprotein (VLDL)
Description
Measurement of fasting serum VLDL-triglycerides (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)
Title
Fasting apolipoprotein B (ApoB) levels in very low-density lipoprotein (VLDL)
Description
Measurement of fasting serum VLDL-ApoB (units: mg/dL) in alpelisib vs placebo
Time Frame
Day 4 (10 hours after dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zachary Sone
Phone
212-305-9336
Email
zds2120@cumc.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joshua R Cook, MD, PhD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joshua R Cook, MD, PhD
Phone
212-305-6289
Email
jrc2175@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Joshua R Cook, MD, PhD
First Name & Middle Initial & Last Name & Degree
Julia J Wattacheril, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Blood samples will be banked in our Insulin Resistance Biobank and will be made available to other researchers for legitimate research purposes upon request. Associated data will be shared along with specimens in the smallest possible quantity and on a need-to-know basis. No Protected Health Information (PHI) will ever be disclosed to other researchers. All requests will be reviewed by the PI for scientific merit and samples/data will be transferred only upon completion of an Institutional Review Board-approved Material Transfer Agreement (MTA) and/or Data Use Agreement (DUA), as appropriate.
IPD Sharing Time Frame
Indefinitely following study completion.

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Effect of Alpelisib in Healthy Volunteers

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