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

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open, One-sequence, Three-period Study in Healthy Subjects to Evaluate Pharmacokinetics and Food Effect After Oral Single Dosing of Two Different Solid Formulations of GS-248

Conditions
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Pharmacokinetic

Intervention / Treatment
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* Drug: Formulation A GS-248
* Drug: Formulation B GS-248


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study. Healthy male or female subject aged ≥ 18 and ≤70 years. Body Mass Index (BMI) ≥ 19.0 and ≤ 30.0 kg/m2. Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. 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: Known allergy to GS-248. Females who are breast feeding or who plan to become pregnant until 2 weeks after the end-of-study visit. 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. 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. 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. Presence of inherited or acquired disorders of platelet function, bleeding or coagulation, as judged by the investigator. 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. 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 Positive test for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or HIV 1 and/or 2 antibodies at screening. 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. Positive test for drugs of abuse or alcohol at screening or on admission to the unit prior to administration of the IMP. Participation in other interventional studies within 3 months prior to administration of study drug. Consumption of grapefruit, grapefruit juice, other grapefruit-containing products, or Seville oranges within 14 days of first IMP administration. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma. Any planned major surgery within the duration of the study. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG, as judged by the Investigator. 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. Regular excessive caffeine consumption defined by a daily intake of >5 cups of caffeine-containing beverages. Intake of xanthine- and/or taurine-containing energy drinks within 2 days prior to screening and prior to IMP administration. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during three months prior to screening. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 (determined by the revised Lund-Malmö GFR estimating equation). Subjects with swallowing disorders, which may affect the subject´s capability to swallow the IMP. Subjects who are vegetarian or for other reasons cannot eat the high-fat high-calorie breakfast.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I GS-248 Formulation A<br>Formulation A given in fasting state. | Drug: Formulation A GS-248<br>* Formulation A of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.<br>|
| Active Comparator: Part I GS-248 Formulation B<br>Formulation B given in fasting state. | Drug: Formulation B GS-248<br>* Formulation B of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.<br>|
| Other: Part II GS-248 Formulation A or B<br>Formulation A or B given in fed condition | Drug: Formulation A GS-248<br>* Formulation A of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.<br>Drug: Formulation B GS-248<br>* Formulation B of GS-248 in a capsule, dose 120 mg given as a single-dose of 3 capsules a´40 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | 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) | 
| 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. | T1/2 (z) was assessed for the terminal elimination phase up to 48 hours | 
| 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. | Vz/F was assessed for the terminal elimination phase up to 48 hours. | 
| 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. | CL/F was assessed for a single dose of GS-248 up to 48 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Related Adverse Events | 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. | 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. | 
| 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. | 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. | 
| Number of Clinically Significant (CS) Changes in Vital Signs | 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. | 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. | 
| Number of Clinically Significant (CS) Changes in Resting 12-lead Electrocardiogram (ECG) | 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. | 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. | 
| Number of Clinically Significant (CS) Changes in Safety Laboratory Parameters | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetic