CompletedPhase 1ACTRN12619000655145

A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment

Sponsor

Gilead Sciences Inc

Enrollment

20 participants

Start Date

Jul 24, 2019

Study Type

Interventional

Conditions

Nonalcoholic Steatohepatitis (NASH)

Summary

Renal impairment has been associated with changes in drug absorption, plasma protein binding, transport, and tissue distribution. The goal of this study is to understand the effect of renal impairment on the PK of GS-9674 and GS-0976 and their metabolites to provide GS-9674 and GS-0976 dosing recommendations in patients with renal impairment. In accordance with regulatory guidance, this study will determine whether the PK of GS-9674, GS-0976 and their respective metabolites is altered in patients with severe renal impairment (not on dialysis), as compared to a control group. The control group will be comprised of subjects with normal renal function and matched with respect to age, BMI, and gender. As renal excretion of GS-9674 or GS-0976 is a minor pathway for their elimination in humans as shown in previous studies, renal impairment should not substantially affect the exposures of GS-9674, GS-0976 and their respective metabolites; thus, a study design that evaluates PK of the agent at the “extremes” of renal function is appropriate. A single-dose study is deemed satisfactory and is expected to accurately predict PK under steady-state conditions in the studied population since both GS-9674 and GS-0976 do not exhibit time-dependent PK. GS-0976 and GS-9674 will be dosed sequentially separated by an adequate washout period of 7 days. Moreover, no drug-drug interactions occur between GS-0976, GS-9674 and their respective metabolites, as demonstrated by lack of PK changes in previous Gilead sponsored study, following coadministration of GS-0976 and GS-9674 for 7 days. The data generated from this study will support the development of GS-0976 and GS-9674 for the treatment of Nonalcoholic Steatohepatitis (NASH). Study subjects’ participation may contribute to understanding the safety, tolerability, and PK of GS-9674, and GS-0976 in individuals with severe renal impairment. Eligible subjects will be enrolled and will receive a single dose of 20 mg GS-0976 administered orally on Day 1, single dose of GS-9674 PTM administered orally on Day 6 and single dose of 100 mg GS-9674 administered orally on Day 7. Plasma and urine PK samples, blood PD sampled will be collected as described in section 4. Safety assessments will be evaluated throughout the study.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 70 Yearss

Inclusion Criteria29

A) All Subjects
Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures
Male or female aged 18 through 70 years of age, inclusive at screening
Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 6 months prior to the first dose of study drug
Have a calculated BMI of greater than or equal to 18.0 and less than or equal to 38.0 kg/m^2 at screening
Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 (unless permanently sterile or in postmenopausal state)
Female subjects must refrain from egg donation and in vitro fertilization during treatment and until at least 30 days after the last dose of study drug
Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
Male subjects must refrain from sperm donation from clinic admission, throughout the study period, and continuing for at least 90 days following the last dose of study drug
Subjects have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug
Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator
Must be willing and able to comply with all study requirements
B) Subjects with Severe Renal Impairment
Must have a diagnosis of chronic (> 6 months), stable renal impairment with no clinically significant change in renal function status within 90 days prior to study drug administration (Day 1).
Estimated glomerular filtration rate (eGFR) using the MDRD equation must be less than 30 mL/min/1.73m^2, based on serum creatinine as measured at the screening evaluation eGFR (mL/min/1.73 m^2) = 175 × (*Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
Scr – serum creatinine
Must have the following laboratory parameters at screening:
a. Total bilirubin < 2.0 mg/dL
b. Serum albumin greater than or equal to 2.5 g/dL
c. INR < 1.5, unless on a prescribed medication known to alter this test
d. Platelets > 90,000 mm^3
e. Hemoglobin > 8.5 g/dL
f. AST less than or equal to 2x ULN
g. ALT less than or equal to 2x ULN
C) Healthy Matched Control Subjects
Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
eGFR using the MDRD equation must be greater than 90 mL/min/1.73m^2, based on serum creatinine as measured during screening evaluation eGFR (mL/min/1.73 m^2) = 175 × (*Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
Screening laboratory evaluations (hematology, chemistry, and urinalysis) must fall within the normal range of the local laboratory’s reference ranges unless the results had been determined by the investigator to have no clinical significance.
Match in age (+\- 10 years), gender, and BMI (+\- 15%, greater than or equal to 18 to less than or equal to 38 kg/m ) with the respective subject in the renal impairment group

Exclusion Criteria27

A) All subjects
Be pregnant or lactating
Have received any study drug within 30 days prior to study dosing
Have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody
Have poor venous access that limits phlebotomy
Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
Have a history of any of the following:
a. Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticarial
b. Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
c. Known hypersensitivity to the study drugs their metabolites or to formulation excipients
d. Significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40%), a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years
e. Syncope, palpitations, or unexplained dizziness
f. Implanted defibrillator or pacemaker
g. Liver disease, including Gilbert disease
h. Severe peptic ulcer disease, gastroesophageal reflux disease, or other gastric acid hypersecretory conditions requiring prolonged (> 6 months) medical treatment
i. Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary
Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol
B) Subjects with Severe Renal Impairment
Require or anticipated to require dialysis within 90 days of study entry
History of clinically significant medical condition other than renal impairment, which in the opinion of the investigator may interfere with the conduct of the study
Received treatment with trimethoprim or cimetidine (affects the elimination of creatinine) or with competitors of renal tubular excretion (e.g. probenecid, chronic high dose non-steroidal anti-inflammatory drugs) within 28 days of Day -1
Received known nephrotoxic drugs (e.g. aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamindine, cyclosporine, tacrolimus, herbal remedies) within 28 days of Day -1
Aside from renal insufficiency expected laboratory values, abnormal laboratory values, that in the opinion of the Investigator, would interfere with subject treatment, assessment or compliance with the protocol
C) Healthy Matched Controlled Subjects
Positive test for drugs of abuse, including alcohol at Screening or on Day -1
Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications

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Interventions

Group A- Eligible subjects (Non-smoking males and non-pregnant/non-lactating female subjects with body mass index (BMI) from 18 to 38 kg/m^2; ages 18-70 years inclusive with severe renal impairment (based on estimated glomerular filtration rate by Modification of Diet in Renal Disease [eGFR_{MDRD}] < 30 mL/min/1.73 m^2) at screening without clinical and/or laboratory evidence for worsening renal impairment within the screening period ) will be enrolled and will receive the following treatments: *Single dose of GS-0976 20 mg (1 x 20 mg tablet) administered orally in the morning on Day 1 in fasted state *Single dose of GS-9674 placebo-to-match (PTM) administered orally in the morning on Day 6 in fasted state *Single dose of GS-9674 100 mg (1 x 100 mg tablet) administered orally in the morning on Day 7 in fasted state During each treatment the corresponding drug (or PTM) will be administered at approximately the same time in the morning on Day 1 (GS-0976), Day 6 (GS-9674 PTM), and Day 7 (GS-9674) with 240 mL of water following an overnight fast (no food or drinks except water) for at least 10 hours. Following dosing, subjects will be restricted from food intake until after collection of the 4-hour blood draw. Other than the water provided with dosing, water and other fluids will be withheld for 1 hour before and until 2 hours after dose administration. Water may be freely consumed by all subjects following the 2-hour blood draw for the remainder of the collection period. A meal will be provided to subjects after the 4 hour post dose blood draw. All meals and/or snacks given to subjects during their stay in the clinical study facility will be standardized for all subjects and should be similar in calorie and fat content per site practice and taken at approximately the same time each day. Subjects will be confined to the study clinic starting at on Day -1 until completion of assessments on Day 11 or Day 20 per Investigator’s discretion to ensure compliance and for safety observation. The investigator will maintain an accurate inventory of all study drug(s). Each dose of the study drug(s) administered at the study center will be administered by qualified study center staff. The dose of study drug(s) administered to subjects in the clinic under the supervision of staff, which indicates the date and quantity of each dosage formulation dispensed to individual subjects. Where possible, IMP should be destroyed at the site. If the site has an appropriate standard operating procedure for drug destruction as determined by Gilead Sciences, the site may destroy used (empty or partially empty) and/or unused IMP supplies. If the site does not have acceptable procedures in place for drug destruction,study drug supplies can be returned to the designated depot following drug accountability and drug inventory reconciliation.