Study to Evaluate the Pharmacodynamic Effects of a Single Oral Dose of GS-0976 (NDI-010976) in Healthy Adult Subjects

A Randomized, Double-Blind, Placebo-Controlled Study To Evaluate the Pharmacodynamic Effects of A Single Oral Dose of NDI-010976 in Healthy Adult Subjects

The primary objective of this study is to assess the pharmacodynamic (PD) effects of GS-0976 (NDI-010976) on fractional de novo lipogenesis (DNL) following a single oral dose administration in overweight and/or obese, but otherwise healthy, male adults.

Study Overview

• Status: Completed
• Conditions: PD Effects of GS-0976 (NDI-010976) on Fractional DNL
• Intervention / Treatment: Drug: GS-0976; Drug: Placebo; Other: 1-13C acetate; Other: Fructose solution

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Overweight and/or obese, but otherwise healthy males
• Weight ≥ 50.0 kg
• Body Mass Index (BMI): 25.0 - 32.0 kg/m^2, inclusive

Exclusion Criteria:

• Intolerance to or malabsorption of fructose
• A history of clinically significant gastrointestinal disease and/or surgery, which would result in the subject's inability to absorb or metabolize the study drug (e.g., gastrectomy, gastric bypass, cholecystectomy).
• In the opinion of the Investigator, a history of clinically significant hematologic, renal, hepatic, bronchopulmonary, neurological, psychiatric, metabolic , endocrine disorder (e.g., diabetes, thyroid disease), or cardiovascular disease.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50 mg GS-0976 (Cohort 1); Sequence 1: Period 1 (2 days): 50 mg (1 x 50 mg capsule) + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): placebo + IV infusion 1-13C acetate and fructose solution Sequence 2: Period 1 (2 days): placebo + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): 50 mg (1 x 50 mg capsule) + IV infusion 1-13C acetate and fructose solution	Drug: GS-0976; Capsule(s) administered orally; Other Names: NDI-010976; Drug: Placebo; Capsule(s) administered orally; Other: 1-13C acetate; 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours; Other: Fructose solution; Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses
Experimental: 200 mg GS-0976 (Cohort 2); Sequence 3: Period 1 (2 days): 200 mg (1 x 200 mg capsule) + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): placebo + IV infusion 1-13C acetate and fructose solution Sequence 4: Period 1 (2 days): placebo + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): 200 mg (1 x 200 mg capsule) + IV infusion 1-13C acetate and fructose solution	Drug: GS-0976; Capsule(s) administered orally; Other Names: NDI-010976; Drug: Placebo; Capsule(s) administered orally; Other: 1-13C acetate; 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours; Other: Fructose solution; Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses
Experimental: 20 mg GS-0976 (Cohort 3); Sequence 5: Period 1 (2 days): 20 mg (2 X 10 mg capsule) + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): placebo + IV infusion 1-13C acetate and fructose solution Sequence 6: Period 1 (2 days): placebo + IV infusion 1-13C acetate and fructose solution; Washout Period (minimum of 5 days); Period 2 (2 days): 20 mg (2 X 10 mg capsule) + IV infusion 1-13C acetate and fructose solution	Drug: GS-0976; Capsule(s) administered orally; Other Names: NDI-010976; Drug: Placebo; Capsule(s) administered orally; Other: 1-13C acetate; 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours; Other: Fructose solution; Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in fractional DNL (% new palmitate)	Predose and up to 10 hours postdose
Change in DNL over time following administration of GS-0976 and placebo	Predose and up to 10 hours postdose
Change from baseline over time in adiponectin	Baseline and up to 10 hours postdose
Percent change from baseline over time in adiponectin	Baseline and up to 10 hours postdose
Change from baseline over time in leptin	Baseline and up to 10 hours postdose
Percent change from baseline over time in leptin	Baseline and up to 10 hours postdose
Change from baseline over time in blood ketones	Baseline and up to 10 hours postdose
Percent change from baseline over time in blood ketones	Baseline and up to 10 hours postdose
Change from baseline over time in lipid profile	Baseline and up to 10 hours postdose
Percent change from baseline over time in lipid profile	Baseline and up to 10 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and severity of treatment-emergent adverse events (TEAEs) following single oral doses of GS-0976 and placebo		Up to 42 days
Percentage of participants experiencing abnormal clinical laboratory tests		Up to 42 days
Pharmacokinetics (PK) of GS-0976 and its metabolite: tmax	Tmax is defined as the time (observed time point) of Cmax.	Baseline and up to 10 hours postdose
PK of GS-0976 and its metabolite: Cmax	Cmax is defined as the maximum concentration of drug.	Baseline and up to 10 hours postdose
PK of GS-0976 and its metabolite: AUC_0-t	AUC_0-t is defined as the concentration of drug over time from time zero to time "t".	Baseline and up to 10 hours postdose

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Collaborators: Nimbus Apollo
• Investigators: Study Director: Rob Myers, MD, Gilead Sciences

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: August 19, 2016
• First Submitted That Met QC Criteria: August 19, 2016
• First Posted (Estimate): August 24, 2016

Study Record Updates

• Last Update Posted (Estimate): August 24, 2016
• Last Update Submitted That Met QC Criteria: August 19, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetic; pharmacodynamic; fractional de novo lipogenesis; DNL
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Firsocostat
• Other Study ID Numbers: 0976-103