A Study to Evaluate Safety, Tolerability and Pharmacokine... | NCT02751424

Description Module

Brief Summary

A phase I, first-time-in-human (FTIH), randomized, double-blind, placebo controlled, dose-escalation study is conducted to determine the safety, tolerability, and pharmacokinetic (PK) profile of GSK3342830 after administration of single intravenous (IV) infusion in Part 1 and repeat IV infusion in Part 2 in healthy subjects. Part 1 will investigate escalating single IV doses of GSK3342830. Part 2, will investigate escalating repeat IV doses of GSK3342830 with repeat dosing for 15 days as follows: a single IV infusion on Day 1, TID (three times a day) IV infusions on Days 2 through 14 (approximately every 8 hours), and a single IV infusion on Day 15. The planned starting GSK3342830 dose in Part 1 is 250 milligram (mg) administered as a single IV infusion. The dose is planned to increase in subsequent cohorts to 500, 1000, 2000, 4000, and less than or equal to (≤) 6000 mg. Part 1 will be divided into 6 cohorts (A-F) and each cohort will enroll 10 subjects (6 in active and 2 in placebo). Dose escalation will be conducted only if it is supported by the preliminary safety, tolerability, and PK results from the preceding dose levels in the study. The repeat dose escalation component (Part 2) of this study will be planned to be initiated after completion and evaluation of the all single dose cohorts up to and including 4000 mg.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
GSK3342830 single dose in Part 1	Experimental	Enrolled subject will receive single escalation dose of GSK3342830. The escalating doses will be evaluated in six cohorts as A- 250 mg, B-500 mg, C-1000 mg, D-2000 mg, E-4000 mg, and F-=<6000 mg. In each cohort 6 subjects will receive GSK3342830 in form of infusion for 1 h, therefore approximately 36 subjects will receive GSK3342830. Dose escalation will be based on evaluation of the preceding dose levels in the study.	Drug: GSK3342830
Placebo single dose in Part 1	Placebo Comparator	Enrolled subject will receive single escalation dose of placebo. In each cohort, 2 subjects will receive placebo in form of infusion for 1 h, therefore approximately 12 subjects will receive placebo.	Drug: Placebo
GSK3342830 repeat Dose in Part 2	Experimental	Enrolled subject will receive repeat escalating dose of GSK3342830. GSK3342830 as a single IV infusion will be administered on Day 1, TID (8 hours apart) IV infusions on Days 2 through 14, and a single IV infusion on Day 15. The escalating doses will be evaluated in three cohorts as G-1000 mg, H-2000 and I-4000 mg. In each cohort 8 subjects will receive GSK3342830 in form of infusion for 1 h, therefore approximately 24 subjects will receive GSK3342830. The starting dose and maximum dose may change based on clinical safety and PK findings in Part 1 or earlier doses in Part 2 respectively.	Drug: GSK3342830
Placebo repeat Dose in Part 2	Placebo Comparator	Enrolled subject will receive repeat escalation dose of placebo. Placebo as a single IV infusion will be administered on Day 1, TID (8 hours apart) IV infusions on Days 2 through 14, and a single IV infusion on Day 15. In each cohort, 2 subjects will receive placebo in form of infusion for 1 h, therefore approximately 6 subjects will receive placebo.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
GSK3342830	Drug	A pyrogen free lyophilized formulation, white to yellowish brown powder containing 1000 mg of GSK3342830A (as free base) per vial. The reconstituted solution looks like a clear, colorless to yellow or brownish yellow liquid, free from visible particulate matter will be administered as IV infusion over 1 hour.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part 1: Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE)	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, Requires hospitalization or prolongation of existing hospitalization, Results in disability/incapacity, Is a congenital anomaly/birth defect, medical judgement and is associated with liver injury or liver impartment. The number of participants with AEs and SAEs assessed in Part 1 (Single dose) of the study were reported.	Up to Day 43
Part 2: Number of Participants With AE and SAE	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, Requires hospitalization or prolongation of existing hospitalization, Results in disability/incapacity, Is a congenital anomaly/birth defect, medical judgement and is associated with liver injury or liver impartment. The number of participants with AEs and SAEs assessed in Part 2 (Repeat dose) of the study were reported.	Up to Day 56
Part 1: Number of Participants With Abnormal Hematology Parameters as a Measure of Safety-Grade 3 or Higher	Blood samples were collected and processed to measure the number of participants with abnormal platelet counts, red blood cells (RBC) count, white blood cells (WBC) count (absolute), hemoglobin, hematocrit, reticulocytes, total iron, total iron binding capacity (TIBC), ferritin, RBC indices (mean corpuscle volume [MCV], mean corpuscle hemoglobin [MCH] and mean corpuscle hemoglobin concentration [MCHC]) and differential WBC count (neutrophils, lymphocytes, monocytes, eosinophil's, and basophils). Participants with abnormalities of Grade 3 or higher have been reported.	Up to Day 2

Secondary Outcomes

Measure	Description	Time Frame
Part 1-Area Under the Plasma Concentration (AUC) From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Across All Treatments AUC(0-t) for GSK3342830	AUC (0-t) is defined as AUC from time zero to the last quantifiable concentration after dosing. Blood samples were collected on Day 1 at indicated timepoints (pre-dose, 0.5 hr, 1hr, 1.25 hr, 1.5 hr, 2 hr, 3 hr,3.5 hr, 4 hr, 4.5 hr, 5 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr 24 hr, 36 hr and 48 hr post-dose. The Part 1 phase of the study comprised of single dosing of participants. Log untransformed values for AUC (0-t) have been presented.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Between 18 and 55 years of age, inclusive, at the time of signing the informed consent.
Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter 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 >50 kilogram (kg) (110 pounds [lb]) for men and >40 kg (99 lb) for women and body mass index within the range of 18.5 to 30 kg per square meter (m^2), inclusive.
Male or Female subjects. Males: Male subjects with female partners of child-bearing potential must agree to use one of the highly effective contraception from the time of first dose of study drug until completion of the Follow-up visit, and Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin [hCG] test), not lactating, and considered to be of non-reproductive potential (non-reproductive potential is defined as: Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented bilateral oophorectomy).
Postmenopausal defined as 12 months of spontaneous amenorrhea and in questionable cases a blood sample with simultaneous follicle-stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post menopausal status before study enrolment.
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions.

Exclusion Criteria:

Alanine aminotransferase (ALT) not within normal limits; bilirubin >1.5× upper limit of normal (ULN; isolated bilirubin >1.5× ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Corrected QT (QTc) >450 milliseconds (msec).
Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic, or gastrointestinal condition or history of such a condition that, in the opinion of the investigator, may place the subject at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism, or excretion of drugs.
Use of a systemic antibiotic within 30 days of screening.
Ongoing febrile illness.
Confirmed history of Clostridium difficile diarrhea
Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose of study treatment, unless in the opinion of the Investigator, the medication will not interfere with the study procedures or compromise subject safety.
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 milliliter (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.
History of hypersensitivity attributed to beta-lactam antibiotics (including cephalosporin, carbapenem, or penicillin antibiotics) or other drugs, a history of multiple antibiotic intolerances, or a history of serious adverse drug reactions.
Sensitivity to poison ivy or other catechol-related hypersensitivity (e.g., mango allergy).
History of sensitivity to heparin or heparin-induced thrombocytopenia.
History of latex allergy.
History of sensitivity to any of the study treatments or components thereof, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
Presence of hepatitis B surface antigen or positive hepatitis C antibody test result at screening or within 3 months before the first dosing day in this study.
Serum creatinine >ULN.
Glomerular filtration rate <90 millilter per minute per 1.73 square meter (mL/min/1.73m^2) as calculated by the Chronic Kidney Disease Epidemiology Collaboration formula
Albumin to creatinine ratio (ACR) >0.03 mg/mg. In the event of an ACR above this threshold, eligibility may be confirmed by a second measurement.
Urinalysis positive for blood without other cause identified.
A positive pre-study drug or alcohol screen.
A positive test for human immunodeficiency virus antibody at or before screening.
Participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
The subject has participated in a clinical trial and has received an investigational product within the following time period before the first dosing day in this study: 30 days, 5 half lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than 4 new chemical entities within 12 months before the first dosing day in this study.
Exclusion criteria for screening and baseline 12-lead ECG: Heart rate <40 and >100 beats per minute for males and <50 and >100 beats per minute (for females), pulse rate is <120 and >220 msec, QRS is <70 and >120 msec, and corrected QT interval using Bazett's formula (QTcB ) and corrected QT interval using Fridericia's formula (QTcF ) >450 msec.. Also apart from this, subject having evidence of previous myocardial infarction, bundle branch block and Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], Wolf-Parkinson-White syndrome), sinus pauses more than 3 seconds, non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats), or any significant arrhythmia that, in the opinion of the investigator will interfere with the safety of the individual subject.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Adelaide	South Australia	5000	Australia

PubMed Identifier	Type	Citation	Retractions
30536589	Derived	Tenero D, Farinola N, Berkowitz EM, Tiffany CA, Qian Y, Xue Z, Raychaudhuri A, Gardiner DF. Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Aug;8(6):754-764. doi: 10.1002/cpdd.637. Epub 2018 Dec 10.

Arm/Group Information

ID	Title	Description
FG000	GSK3342830 250 mg	Healthy adult participants in this cohort, were administered GSK3342830 dose in Part 1 as 250 milligram (mg),for 1 hour (hr) as a single intravenous (IV) infusion, on Day 1.
FG001	GSK3342830 500 mg	Healthy adult participants in this cohort received an escalated dose GSK3342830 at 500 mg, for 1 hr, as a single IV infusion on Day 1.
FG002	GSK3342830 1000 mg	The healthy adult participants in this cohort received an escalated dose GSK3342830 at 1000 mg, for 1 hr, as a single IV infusion on Day 1.
FG003	GSK3342830 2000 mg	The healthy adult participants in this cohort received an escalated dose of GSK3342830 at 2000 mg, for 1 hr, as a single IV infusion on Day 1.
FG004	GSK3342830 4000 mg	The healthy adult participants in this cohort received an escalated dose of GSK3342830 at 4000 mg, for 1 hr, as a single IV infusion on Day 1.
FG005	GSK3342830 6000 mg	The healthy adult participants in this cohort received an escalated dose of GSK3342830 at 6000 mg, for 1 hr, as a single IV infusion on Day 1.
FG006	Placebo, Part 1	Healthy adult participants from each cohort received placebo in form of infusion for 1 hr, on Day 1.
FG007	GSK3342830 1000 mg TID	Healthy adult participants in this repeat dose escalation cohort were administered GSK3342830 dose, in Part 2 as 1000 mg, as a single IV infusion on Day 1, three times a day (TID) IV infusions (approximately every 8 hrs) on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and a single IV infusion on Day 15.
FG008	Placebo, Part 2	Healthy adult participants in this repeat dose escalation cohort were administered with matching placebo to GSK3342830 1000 mg TID, Single IV infusion on Day 1, TID IV infusions (approximately every 8 hrs) on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and a single IV infusion on Day 15.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 1, 2016	Jan 8, 2018	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Aug 17, 2017	Jan 8, 2018	SAP_001.pdf

ID	Term
D001424	Bacterial Infections
D016905	Gram-Negative Bacterial Infections

ID	Term
D001423	Bacterial Infections and Mycoses
D007239	Infections

ID	Title	Description
BG000	GSK3342830 250 mg	Healthy adult participants in this cohort, were administered GSK3342830 dose in Part 1 as 250 mg, for 1 hr as a single IV infusion, on Day 1.
BG001	GSK3342830 500 mg