A Study in Healthy Subjects to Evaluate Pharmacokinetics and Food Effect After Dosing of GS-248

Conditions

Pharmacokinetic

Keywords

Pharmacokinetic

Brief summary

The study will collect information about pharmacokinetics (PK), safety and tolerability following a single dose of GS-248 in two different oral solid formulations in capsules to healthy subjects. It will also collect information about pharmacokinetics (PK), safety and tolerability following a single dose of one of the two formulations of GS-248 in fed condition.

Detailed description

The study is divided in two parts. Part I will evaluate PK, safety and tolerability of a single oral dose of two different formulations of GS-248 in fasting conditions. Part II will evaluate PK, safety and tolerability of one of the two different formulations of GS-248 in fed conditions. In Part I, a single oral dose of GS-248 in two different solid formulations will be administered to 14 healthy subjects. All subjects will first receive Formulation A and then Formulation B. A wash-out period of at least 4 days will be applied between the IMP administrations. Both doses contain 120 mg GS 248. For Part I, subjects will come to the clinic for single dose administration of Formulation A or Formulation B, respectively, and PK and safety assessments. Safety assessments include AE reporting, physical examination, ECG, vital signs, body temperature, and blood sampling for analysis of safety laboratory parameters. After evaluation of the PK profiles of Formulation A and B in Part I of the study, one formulation will be selected to be given following intake of a standardised breakfast in Part II of the study. Subjects will return to the clinic for a second dose of the selected formulation, yet now in fed conditions. The assessments during fed conditions will be the same as during fasting conditions except that the subjects will consume a high-fat high-calorie breakfast 30 minutes prior to IMP administration.

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Interventions

DRUGFormulation A GS-248

Formulation A of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.

DRUGFormulation B GS-248

Formulation B of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

The study is divided in two parts. Part I will evaluate PK, safety and tolerability of a single oral dose of two different formulations of GS-248 in fasting conditions. Part II will evaluate PK, safety and tolerability of one of the two different formulations of GS-248 in fed conditions. Subjects are expected to participate in both Part I and Part II.

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

Inclusion criteria

1. Willing and able to give written informed consent for participation in the study. 2. Healthy male or female subject aged ≥ 18 and ≤70 years. 3. Body Mass Index (BMI) ≥ 19.0 and ≤ 30.0 kg/m2. 4. Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. 5. Women of child bearing potential (WOCBP) must practice abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the subject) or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy (combined \[oestrogen and progestogen containing\] hormonal contraception \[oral, intravaginal, transdermal\], progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, implantable\], intrauterine device \[IUD\]or intrauterine hormone-releasing system \[IUS\]) from at least 4 weeks prior to dose to 4 weeks after last dose.

Exclusion criteria

1. Known allergy to GS-248. 2. Females who are breast feeding or who plan to become pregnant until 2 weeks after the end-of-study visit. 3. Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) at screening and within 24 h prior to the first administration of IMP. 4. Regular use of corticosteroids (inhaled and systemic), NSAIDs, aspirin or coxibs, antacids, PPIs, or any other medication that changes gastric pH within 14 days of study drug administration. 5. Regular use of any prescribed or non-prescribed medication including analgesics, herbal remedies, vitamins and minerals within 2 weeks prior to the (first) administration of IMP, except hormonal contraception and occasional intake of paracetamol (maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the Investigator. 6. Presence of inherited or acquired disorders of platelet function, bleeding or coagulation, as judged by the investigator. 7. History or presence of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. 8. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: * Systolic blood pressure \<90 or \>140 mmHg, or * Diastolic blood pressure \<50 or \>90 mmHg, or * Pulse \<40 or \>90 bpm 9. Positive test for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or HIV 1 and/or 2 antibodies at screening. 10. Presence or history of drug and/or alcohol abuse and/or excessive intake of alcohol and/or history, or current use, of anabolic steroids, as judged by the Investigator. 11. Positive test for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP. 12. Participation in other interventional studies within 3 months prior to administration of study drug. 13. Consumption of grapefruit, grapefruit juice, other grapefruit-containing products, or Seville oranges within 14 days of first IMP administration. 14. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. 15. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma. 16. Any planned major surgery within the duration of the study. 17. Prolonged QTcF (\>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG, as judged by the Investigator. 18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than three times per week is allowed before screening visit. 19. Regular excessive caffeine consumption defined by a daily intake of \>5 cups of caffeine-containing beverages. 20. Intake of xanthine- and/or taurine-containing energy drinks within 2 days prior to screening and prior to IMP administration. 21. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during three months prior to screening. 22. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements. 23. Estimated glomerular filtration rate (eGFR) \< 50 mL/min/1.73 m2 (determined by the revised Lund-Malmö GFR estimating equation). 24. Subjects with swallowing disorders, which may affect the subject´s capability to swallow the IMP. 25. Subjects who are vegetarian or for other reasons cannot eat the high-fat high-calorie breakfast.

Design outcomes

Primary

Measure	Time frame	Description
CL/F	CL/F was assessed for a single dose of GS-248 up to 48 hours.	The mean total clearance (CL/F) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean total clearance (CL/F) was calculated by non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
AUC0-inf	From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)	The Area Under the Curve (AUC) for the time interval 0-infinity of GS-248 after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean AUC of GS-248 was assessed by means of non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
AUC0-24h	From time 0 (time of dosing) to 24 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)	The Area Under the Curve (AUC) for the time interval 0-24h of GS-248 after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean AUC of GS-248 for the time interval 0-24 h was assessed by means of non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
Tmax	From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)	Time to Cmax (Tmax) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
T1/2(z)	T1/2 (z) was assessed for the terminal elimination phase up to 48 hours	Plasma half-life associated with the terminal elimination phase (T1/2(z)) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
Vz/F	Vz/F was assessed for the terminal elimination phase up to 48 hours.	The mean volume of distribution (Vz/F) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.
Cmax	From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)	The Maximal Plasma Concentration (Cmax) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Secondary

Measure	Time frame	Description
Number of Clinically Significant (CS) Changes in Physical Examination	Physical examination was performed at pre-defined timepoints from the Screening Visit until the End-of- Study Visit i.e. Visit 7, day 3, up to 30 days.	A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. A short version of physical examination included an assessment of selected body systems at the judgement of the Investigator but at least included cardiovascular, lung and abdomen. The results of the examinations were documented in the eCRF as normal, abnormal not clinically significant (NCS) or abnormal clinically significant (CS). Post-dose physical examination findings judged as abnormal CS were reported as AEs.
Number of Clinically Significant (CS) Changes in Vital Signs	Vital signs ware assessed at pre-defined timepoints from the Screening Visit until the End-of- Study Visit i.e. Visit 7, day 3, up to 30 days.	Systolic and diastolic blood pressure and pulse were measured in supine position after 10 minutes of rest. Vital signs were judged as normal, abnormal NCS or abnormal CS.
Number of Clinically Significant (CS) Changes in Resting 12-lead Electrocardiogram (ECG)	ECG evaluation was assessed at pre-defined timepoints from the Screening Visit until the End-of- Study Visit i.e. Visit 7, day 3, up to 30 days.	Single 12-lead ECG was recorded in supine position after 10 minutes of rest using an ECG machine. HR and PR, QRS, QT and QTcF intervals were recorded. Safety ECGs were reviewed and interpreted on-site by the Investigator. All ECGs were categorised as normal, abnormal, not clinically significant, or abnormal, clinically significant.
Number of Clinically Significant (CS) Changes in Safety Laboratory Parameters	Blood samples were collected at pre-defined timepoints from the Screening Visit until the End-of- Study Visit i.e. Visit 7, day 3, up to 30 days.	Blood samples for analysis of clinical chemistry and haematology parameters were collected through venepuncture or an indwelling venous catheter and sent to the certified clinical chemistry laboratory at Uppsala University Hospital and analysed by routine analytical methods. Urine analysis was performed at the research clinic using dip sticks. Safety laboratory parameters were judged as normal, abnormal NCS or abnormal CS.
Number of Treatment Related Adverse Events	AEs (including serious AEs [SAEs]) were collected from the start of IMP application in Part I until the end-of- study visit i.e. Visit 7, day 3, up to 30 days.	The grading of the severity/intensity (grade 1 to grade 5) of AEs followed the common terminology criteria for AEs (CTCAE) v5.0. AEs were assessed by the Investigator as unlikely, possibly or probably related to the IMP. An AE was considered causally related to the use of the IMP when the causality assessment was probable or possible.

Countries

Sweden

Participant flow

Recruitment details

The subjects were recruited from CTC's database of healthy volunteers and from advertising in media (including social media). Screening visits were performed at CTC research clinic. Recruitment period started 24MAR2020 (the day after approval received from IEC and CA) and lasted until 06APR2020 (date for last subject screened).

Pre-assignment details

Screening (Visit 1) took place from Day -28 to Day -1 and included an eligibility check and a general health assessment. A total of 29 subjects were screened for participation. Eleven subjects were screening failures and 4 subjects were reserves who were not used in the study. Fourteen subjects were included and dosed in the study.

Participants by arm

Arm	Count
Overall Trial All subjects who were included in the study i.e. randomized in Part I GS-248 Formulation A.	14
Total	14

Baseline characteristics

Characteristic	Overall Trial
Age, Continuous	44.3 years STANDARD_DEVIATION 17.1
BMI	25.1 kg/m^2 STANDARD_DEVIATION 3.7
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Height	171.6 cm STANDARD_DEVIATION 10.8
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	14 Participants
Region of Enrollment Sweden	14 participants
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	4 Participants
Weight	74.5 kg STANDARD_DEVIATION 17.14

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 14	0 / 13
other Total, other adverse events	6 / 14	5 / 14	2 / 13
serious Total, serious adverse events	0 / 14	0 / 14	0 / 13

Outcome results

Primary

AUC0-24h

The Area Under the Curve (AUC) for the time interval 0-24h of GS-248 after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean AUC of GS-248 for the time interval 0-24 h was assessed by means of non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: From time 0 (time of dosing) to 24 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	AUC0-24h	1420 h*nmol/L	Standard Deviation 459.4
Part I GS-248 Formulation B	AUC0-24h	1104 h*nmol/L	Standard Deviation 527.2
Part II GS-248 Formulation A in Fed Condition	AUC0-24h	1014 h*nmol/L	Standard Deviation 377.6
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	AUC0-24h	1419 h*nmol/L	Standard Deviation 478.2

Comparison: Relative bioavailability (A versus B)90% CI: [1.112, 1.6904]

Comparison: Relative bioavailability (A FED versus A FASTED)90% CI: [0.5728, 0.8759]

Primary

AUC0-inf

The Area Under the Curve (AUC) for the time interval 0-infinity of GS-248 after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean AUC of GS-248 was assessed by means of non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	AUC0-inf	1491 h*nmol/L	Standard Deviation 478.1
Part I GS-248 Formulation B	AUC0-inf	1182 h*nmol/L	Standard Deviation 567.4
Part II GS-248 Formulation A in Fed Condition	AUC0-inf	1119 h*nmol/L	Standard Deviation 463.9
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	AUC0-inf	1494 h*nmol/L	Standard Deviation 497.4

Comparison: Relative bioavailability (A versus B)90% CI: [1.0953, 1.6495]

Comparison: Relative bioavailability (A FED versus A FASTED)90% CI: [0.591, 0.9083]

Primary

CL/F

The mean total clearance (CL/F) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. The mean total clearance (CL/F) was calculated by non-compartmental analysis (NCA). Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: CL/F was assessed for a single dose of GS-248 up to 48 hours.

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	CL/F	132.9 L/h	Standard Deviation 50.59
Part I GS-248 Formulation B	CL/F	191.4 L/h	Standard Deviation 105
Part II GS-248 Formulation A in Fed Condition	CL/F	185.2 L/h	Standard Deviation 76.08
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	CL/F	133.7 L/h	Standard Deviation 52.56

Primary

Cmax

The Maximal Plasma Concentration (Cmax) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	Cmax	508.6 nmol/L	Standard Deviation 220.9
Part I GS-248 Formulation B	Cmax	384.5 nmol/L	Standard Deviation 219.1
Part II GS-248 Formulation A in Fed Condition	Cmax	289.5 nmol/L	Standard Deviation 184.4
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	Cmax	499.5 nmol/L	Standard Deviation 227.2

Comparison: Relative bioavailability (A versus B)90% CI: [1.111, 1.4514]

Comparison: Relative bioavailability (A FED versus A FASTED)90% CI: [0.3977, 0.7597]

Primary

T1/2(z)

Plasma half-life associated with the terminal elimination phase (T1/2(z)) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: T1/2 (z) was assessed for the terminal elimination phase up to 48 hours

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	T1/2(z)	10.69 hours	Standard Deviation 2.912
Part I GS-248 Formulation B	T1/2(z)	16.09 hours	Standard Deviation 15.26
Part II GS-248 Formulation A in Fed Condition	T1/2(z)	13.36 hours	Standard Deviation 9.914
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	T1/2(z)	10.91 hours	Standard Deviation 2.902

Primary

Tmax

Time to Cmax (Tmax) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: From time 0 (time of dosing) to 48 hours after dose (concentration measured at timepoints pre-dose and 0:15, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose)

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEDIAN)
Part I GS-248 Formulation A	Tmax	1.500 hours
Part I GS-248 Formulation B	Tmax	1.500 hours
Part II GS-248 Formulation A in Fed Condition	Tmax	3.000 hours
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	Tmax	1.500 hours

Primary

Vz/F

The mean volume of distribution (Vz/F) after a single dose of Formulation A and B of GS 248 respectively in fasting conditions and after a single dose of Formulation A of GS-248 in fed condition. Blood samples for bioanalysis of GS-248 and subsequent PK analysis were collected as venous blood samples.

Time frame: Vz/F was assessed for the terminal elimination phase up to 48 hours.

Population: Part I Formulation A: Data based on Formulation PK analysis set i.e. 14 subjects.~Part I Formulation B: Data based on Formulation PK analysis set i.e. 14 subjects.~Part II Formulation A fed: Data based on Formulation PK analysis set i.e. 13 subjects.~Part II Formulation A fasting (partial set): Data based on Formulation PK analysis set i.e. 13 subjects.

Arm	Measure	Value (MEAN)	Dispersion
Part I GS-248 Formulation A	Vz/F	2071 L	Standard Deviation 1035
Part I GS-248 Formulation B	Vz/F	3884 L	Standard Deviation 2940
Part II GS-248 Formulation A in Fed Condition	Vz/F	3110 L	Standard Deviation 1588
Part II GS-248 Formulation A in Fasting Condition (Partial Set)	Vz/F	2125 L	Standard Deviation 1057

Secondary

Number of Clinically Significant (CS) Changes in Physical Examination

A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. A short version of physical examination included an assessment of selected body systems at the judgement of the Investigator but at least included cardiovascular, lung and abdomen. The results of the examinations were documented in the eCRF as normal, abnormal not clinically significant (NCS) or abnormal clinically significant (CS). Post-dose physical examination findings judged as abnormal CS were reported as AEs.

Time frame: Physical examination was performed at pre-defined timepoints from the Screening Visit until the End-of- Study Visit i.e. Visit 7, day 3, up to 30 days.