Pharmacokinetics of Gepotidacin Tablets in Adults and Ado... | NCT04079790

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Subjects receiving Gepotidacin in Part 1	Experimental	Healthy adult subjects will receive a single oral dose of gepotidacin 1500 mg (2 X 750 mg, treatment A), tablets, on Day 1 of Period 1; two oral doses of gepotidacin 3000 mg (4 x 750 mg, Treatment C), tablets, at 0 and 12 hours on Day 5 of Period 2; and two oral doses of gepotidacin 3000 mg (4 x 750 mg, treatment E), tablets, at 0 and 6 hours on Day 9 of Period 3.	Drug: Gepotidacin
Subjects receiving Placebo in Part 1	Placebo Comparator	Healthy adult subjects will receive a single oral dose of matching placebo (treatment B), tablets, on Day 1 of Period 1; two oral doses of matching placebo (treatment D), tablets, at 0 and 12 hours on Day 5 of Period 2; and two oral doses of matching placebo (treatment F), tablets, at 0 and 6 hours on Day 9 of Period 3.	Drug: Placebo
Subjects receiving Gepotidacin in Part 2	Experimental	Healthy adolescent subjects will receive a single oral dose of gepotidacin 1500 mg (2 x 750 mg, treatment A), tablets, on Day 1 of Period 1; and two oral doses of gepotidacin 3000 mg (4 x 750 mg, treatment G), tablets, at 0 and 6 hours on Day 1 of Period 2.	Drug: Gepotidacin
Subjects receiving Placebo in Part 2	Placebo Comparator	Healthy adolescent subjects will receive a single oral dose of matching placebo (treatment B), tablets on Day 1 of Period 1; and two oral doses of matching placebo (treatment H), tablets at 0 and 6 hours on Day 1 of Period 2.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Gepotidacin	Drug	Tablets containing gepotidacin mesylate with a unit dose of 750 mg will be administered orally with 240 milliliter (mL) of water.	Subjects receiving Gepotidacin in Part 1

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Time of the Last Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of Gepotidacin 1500 mg	Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC[0-infinity]) After Single Dose Administration of Gepotidacin 1500 mg	Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose (AUC[0-24]) After Single Dose Administration of Gepotidacin 1500 mg	Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours post-dose
Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 48 Hours Post-dose (AUC[0-48]) After Single Dose Administration of Gepotidacin 1500 mg	Blood samples were collected at indicated time points for pharmacokinetic analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Part 1- Period 1: Maximum Observed Concentration (Cmax) After Single Dose Administration of Gepotidacin 1500 mg

Secondary Outcomes

Measure	Description	Time Frame
Part 1- Period 1: Total Unchanged Drug (Ae Total) After Single Dose Administration of Gepotidacin 1500 mg	Urine samples were collected at indicated time points for PK analysis. PK parameters were calculated using standard non-compartmental analysis. Ae total was calculated by adding all the fractions of drug collected over all the allotted time intervals.	Pre-dose, 0-2, 2-4, 4-6, 6-8, 8-12, 12-24, 24-36 and 36-48 hours post-dose

Eligibility Module

Eligibility Criteria

Inclusion Criteria

Subjects in Part 1 must be >=18 to <=64 years of age inclusive, at the time of signing the informed consent.
Subjects in Part 2 must be >=12 to <18 years of age inclusive, at the time of signing the informed consent/assent.
Subjects who are healthy as determined by the investigator or medically qualified designee based on medical evaluation including medical history, physical examination, clinical laboratory tests, vital sign measurements, and 12-lead ECG results <450 millisecond (msec). A subject with clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the investigator feels and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Body weight >=40 kilogram (kg) and body mass index (BMI) within the range 18.5 - 32.0 kg per square meter (inclusive).
Male and/or female.
Female subjects: A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: a) Is not a woman of childbearing potential (WOCBP), or b) Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1% for at least 30 days prior to dosing until completion of the follow-up visit. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a highly sensitive negative pregnancy test before the first dose of study intervention.
Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the informed consent form/assent and protocol.

Exclusion Criteria

Clinically significant abnormality in the past medical history or at the screening physical examination that in the investigator's opinion may place the subject at risk or interfere with outcome variables of the study. This includes, but is not limited to, history or current cardiac, hepatic, renal, neurologic, gastrointestinal (GI), respiratory, hematologic, or immunologic disease.
Any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study intervention, or any other condition that may place the subject at risk, in the opinion of the investigator.
Female subject has a positive pregnancy test result or is lactating at screening or upon admission to the clinic.
Use of any systemic antibiotic within 30 days of screening.
Within 2 months before screening, either a confirmed history of Clostridium difficile diarrhea infection or a past positive of Clostridium difficile toxin test.
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
History of drug and/or alcohol abuse within 6 months before screening, as determined by the investigator, or has a positive drug screen at screening or upon admission to the clinic.
History of sensitivity to any of the study drug, components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline medical monitor contraindicates their participation.
History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic uses heparin to maintain intravenous cannula patency).
Subject must abstain from taking prescription or non-prescription drugs (except for hormonal contraceptives and/or acetaminophen), vitamins, and dietary or herbal supplements, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to study intervention until completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, the medication will not interfere with the study. Any exceptions will be discussed with the sponsor or medical monitor on a case-by-case basis and the reasons will be documented.
Previous exposure to gepotidacin within 12 months prior to starting study intervention.
Subject has participated in a clinical trial and has received an investigational product prior to gepotidacin administration within 30 days, 5 half-lives, or twice the duration of the biological effect of investigational product (whichever is longer).
Presence of hepatitis B surface antigen or positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention.
ALT >1.5 * upper limit of normal (ULN).
Bilirubin >1.5 * ULN (isolated bilirubin >1.5 * ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
History of any kidney disease or current or chronic history of impaired renal function as indicated by an estimated creatinine clearance <60 milliliter per minute (mL/min).
A positive test for human immunodeficiency virus antibody.
History of regular alcohol consumption within 6 months of screening defined as an average weekly intake of >21 units (or an average daily intake of >3 units) for males or an average weekly intake of >14 units (or an average daily intake >2 units) for females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of spirits, or 100 mL of wine.
Urinary cotinine level indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months before screening.
Clinically significant abnormal findings in serum chemistry, hematology, or urinalysis results obtained at screening or Day -1.
Baseline corrected QT interval using the Fridericia formula (QTcF) of >450 msec.
Subject has donated blood in excess of 500 mL within 12 weeks prior to dosing or participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
Subject is unable to comply with all study procedures, in the opinion of the investigator.
Subject should not participate in the study, in the opinion of the investigator or sponsor.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Las Vegas	Nevada	89113	United States

PubMed Identifier	Type	Citation	Retractions
34633853	Derived	Barth A, Hossain M, Brimhall DB, Perry CR, Tiffany CA, Xu S, Dumont EF. Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0126321. doi: 10.1128/AAC.01263-21. Epub 2021 Oct 11.

Arm/Group Information

ID	Title	Description
FG000	Gepotidacin (A/C/E)	Adult participants were randomized to receive a single dose of gepotidacin 1500 milligrams (mg) (Treatment A) on Day 1 of Period 1 followed by two doses of gepotidacin 3000 mg separated by 12 hours (Treatment C) on Day 5 of Period 2, and two doses of gepotidacin 3000 mg separated by 6 hours (Treatment E) on Day 9 of Period 3. All doses were administered orally with water after consumption of food.
FG001	Placebo (B/D/F)	Adult participants were randomized to receive a single dose of gepotidacin matching placebo (Treatment B) on Day 1 of Period 1 followed by two doses of gepotidacin matching placebo separated by 12 hours (Treatment D) on Day 5 of Period 2, and two doses of gepotidacin matching placebo separated by 6 hours (Treatment F) on Day 9 of Period 3. All doses were administered orally with water after consumption of food.
FG002	Gepotidacin (A/G)	Adolescent participants were randomized to receive a single dose of gepotidacin 1500 mg (Treatment A) on Day 1 of Period 1 followed by two doses of gepotidacin 3000 mg separated by 6 hours (Treatment G) on Day 1 of Period 2. All doses were administered orally with water after consumption of food.
FG003	Placebo (B/H)	Adolescent participants were randomized to receive a single dose of gepotidacin matching placebo (Treatment B) on Day 1 of Period 1 followed by two doses of gepotidacin matching placebo separated by 6 hours (Treatment H) on Day 1 of Period 2. All doses were administered orally with water after consumption of food.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Gepotidacin (A/C/E)	Adult participants were randomized to receive a single dose of gepotidacin 1500 milligrams (mg) (Treatment A) on Day 1 of Period 1 followed by two doses of gepotidacin 3000 mg separated by 12 hours (Treatment C) on Day 5 of Period 2, and two doses of gepotidacin 3000 mg separated by 6 hours (Treatment E) on Day 9 of Period 3. All doses were administered orally with water after consumption of food.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical	Baseline characteristics is presented for Safety Population which consisted of all participants who took at least 1 dose of study intervention. This population was used for demographic and safety summaries. One participant was randomized to Gepotidacin (A/G) arm but was unable to swallow the tablet and was not a part of Safety Population.

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Part 1- Period 1: Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Time of the Last Quantifiable Concentration (AUC[0-t]) After Single Dose Administration of Gepotidacin 1500 mg

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of gepotidacin. PK parameters were analyzed using standard non-compartmental analysis.

PK parameter Population consisted of all participants in the PK Population (participants who received at least 1 dose of gepotidacin and had evaluable post-dose plasma concentration data for gepotidacin), for whom valid and evaluable PK parameters were derived.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours*micrograms per milliliter

Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

ID	Title	Description
OG000	Part 1: Gepotidacin 1500 mg	Adult participants received a single oral dose of gepotidacin 1500 mg on Day 1 of Period 1

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 13, 2019	Jul 27, 2020	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Dec 10, 2019	Jul 27, 2020	SAP_001.pdf

ID	Term
D001423	Bacterial Infections and Mycoses
D007239	Infections