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

Study Overview
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Brief Summary
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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.

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

Conditions
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PD Effects of GS-0976 (NDI-010976) on Fractional DNL

Intervention / Treatment
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* Drug: GS-0976
* Drug: Placebo
* Other: 1-13C acetate
* Other: Fructose solution


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg GS-0976 (Cohort 1)<br>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<br>* Capsule(s) administered orally<br>* Other names: NDI-010976;Drug: Placebo<br>* Capsule(s) administered orally<br>Other: 1-13C acetate<br>* 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours<br>Other: Fructose solution<br>* Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses<br>|
| Experimental: 200 mg GS-0976 (Cohort 2)<br>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<br>* Capsule(s) administered orally<br>* Other names: NDI-010976;Drug: Placebo<br>* Capsule(s) administered orally<br>Other: 1-13C acetate<br>* 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours<br>Other: Fructose solution<br>* Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses<br>|
| Experimental: 20 mg GS-0976 (Cohort 3)<br>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<br>* Capsule(s) administered orally<br>* Other names: NDI-010976;Drug: Placebo<br>* Capsule(s) administered orally<br>Other: 1-13C acetate<br>* 10 g ± 0.25 g in 1000 mL 0.45% saline solution administered intravenously for 19 hours<br>Other: Fructose solution<br>* Fructose solution administered orally under fasted conditions immediately after study drug and every 30 minutes for a total of 20 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fractional de novo lipogenesis, DNL, pharmacodynamic, pharmacokinetic