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A Study to Evaluate Safety, Tolerability and Pharmacokinetics of Ascending Intravenous Single Dose and Repeat Dose of GSK3342830

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ClinicalTrials.gov Identifier: NCT02751424
Recruitment Status : Terminated (Study data is currently under review.)
First Posted : April 26, 2016
Results First Posted : September 12, 2018
Last Update Posted : September 12, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Infections, Bacterial Drug: GSK3342830 Drug: Placebo Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase I, Randomized, Double-Blind (Sponsor Unblinded), Single-Center, Placebo-Controlled, Two-Part Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Ascending Single and Repeat Intravenous Doses of GSK3342830 in Healthy Adult Subjects
Actual Study Start Date : June 13, 2016
Actual Primary Completion Date : February 2, 2017
Actual Study Completion Date : February 2, 2017

Arm Intervention/treatment
Experimental: GSK3342830 single dose in Part 1
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
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.

Placebo Comparator: Placebo single dose in Part 1
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
A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.

Experimental: GSK3342830 repeat Dose in Part 2
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
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.

Placebo Comparator: Placebo repeat Dose in Part 2
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.
Drug: Placebo
A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.




Primary Outcome Measures :
  1. Part 1: Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE) [ Time Frame: Up to Day 43 ]
    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.

  2. Part 2: Number of Participants With AE and SAE [ Time Frame: Up to Day 56 ]
    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.

  3. Part 1: Number of Participants With Abnormal Hematology Parameters as a Measure of Safety-Grade 3 or Higher [ Time Frame: Up to Day 2 ]
    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.

  4. Part 2: Number of Participants With Abnormal Hematology Parameters as a Measure of Safety-Grade 3 or Higher [ Time Frame: Up to Day 15 ]
    Blood samples were collected and processed to measure the number of participants with abnormal platelet counts, RBC count, WBC count (absolute), hemoglobin, hematocrit, reticulocytes, total iron, TIBC, ferritin, RBC indices MCV, MCH and MCHC and differential WBC count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils). These were collected on Day 2, 5, 10 and Day 15, during Part 2 of the study. Part 2 is repeat dose escalation. Participants with abnormalities of Grade 3 or higher have been reported.

  5. Part 1: Number of Participants With Abnormal Clinical Chemistry Parameters as a Measure of Safety-Grade 3 or Higher [ Time Frame: Day 2 ]
    Blood samples were collected and processed to measure the number of participants with abnormal blood urea nitrogen (BUN), creatinine, glucose, bicarbonate, sodium, potassium, chloride, calcium, aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP) levels, uric acid, total and direct bilirubin, total protein and albumin. These were collected on Day 1, during Part 1(single dose escalation) of the study. Participants with abnormalities Grade 3 or higher were reported.

  6. Part 2: Number of Participants With Abnormal Clinical Chemistry Parameters as a Measure of Safety-Grade 3 or Higher [ Time Frame: Up to Day 15 ]
    Blood samples were collected and processed to measure the number of participants with abnormal BUN, creat, glucose, bicarbonate, sodium, potassium, chloride, calcium, AST/SGOT, ALT/SGPT, ALP levels, uric acid, total and direct bilirubin, total protein and albumin. These were collected on Day 2, 5, 10 and Day 15 during Part 2 (repeat dose escalation), of the study. Participants with abnormalities Grade 3 or higher were reported.

  7. Part 1: Number of Participants Having Abnormal Urine Parameters (Using Dipstick Test) as a Measure of Safety [ Time Frame: Up to Day 2 ]
    An aliquot of the urine samples from first morning void urine samples was collected to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal), albumin to creatinine ration (ACR), neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Urine samples were analyzed after the end of the study to verify if a clinical signal is detected. Urine samples were collected on Day 1 of Part 1 (Single-dose escalation) of the study.

  8. Part 2: Number of Participants Having Abnormal Urine Parameters (Using Dipstick Test) as a Measure of Safety [ Time Frame: Day 2, 5, 10 and Day 15 ]
    An aliquot of the urine samples from first morning void urine samples was collected to analyze specific gravity, pH, glucose, protein, blood and ketone bodies by dipstick method, microscopic examination (if blood or protein is abnormal), ACR, NGAL and KIM-1. These urine samples were analyzed after the end of the study to verify if a clinical signal is detected. The samples were collected on Day 2, 5, 10, and Day 15 of Part 2 (Repeat dose escalation) of the study.

  9. Part 1: Number of Participants With Electrocardiogram (ECG) Parameters of Potential Clinical Importance (PCI) [ Time Frame: Up to Day 3 ]
    Triplicate 12-lead ECGs were obtained at least 5 minutes apart within 1 hr before dosing. Single ECGs were obtained at all other time points on Day 1 at 0.5 hr, 1 hr, 1.5 hr, 2, 3, 4, 6, 12 and 24 hr, Day 2 (36 hr) and Day 3 (48 hr) during Part 1 (single dose escalation phase) of the study. All the 12-lead ECGs were measured using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  10. Part 2: Number of Participants With ECG Parameters of PCI [ Time Frame: Up to Day 16 ]
    Triplicate 12-lead ECGs were obtained at least 5 minutes apart within 1 hr before the start of infusion (pre-dose) on Day 1. Single ECGs were obtained at 0.5, 1, 1.5, 2, 3, 4, 6, and 12 hrs after the start of infusion on Day 1 and Day 15, within 1 hr before the start of the morning infusion on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and in the morning on Day 16. All the 12-lead ECGs were measured using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  11. Part 1: Number of Participants With Vital Signs of Potential Clinical Importance (PCI) [ Time Frame: Up to Day 3 ]
    The vital sign includes systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate and temperature which were measured in a semi-supine position, where the participant had rested in the same position for at least 5 minutes. The number of participants with vital values, of PCI were reported. These were collected on Day 1 at pre-dose, 0.5 hr, 1 hr, 1.5 hr, 2, 3, 4, 6, 12 and 24 hr, Day 2 (36 hr) and Day 3 (48 hr) during Part 1 (single dose escalation phase) of the study.

  12. Part 2: Number of Participants With Vital Signs of PCI [ Time Frame: Up to Day 16 ]
    The vitals for systolic, diastolic blood pressure, heart rate, respiratory rate and temperature were taken in a semi-supine position, where the participant had rested in the same position for atleast 5 minutes. The number of participants with vital values, of PCI were reported. These were collected from Day 1 to Day 16. Assessments were done within 1 hr before the start of infusion (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, and 12 hrs after the start of infusion on Days 1 and 15, within 1 hr before the start of the morning infusion and on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, and in the morning on Day 16.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    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.

  2. Part 1-AUC Pre Dose to Infinite (Inf) Time (AUC [0-inf]) of GSK3342830 [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    AUC (0-inf) is defined as AUC extrapolated from time zero to infinity. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for AUC (0-inf) have been presented.

  3. Part 1-Maximum Plasma Concentration (Cmax) of GSK3342830 [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    Cmax was defined as the maximum concentration of drug GSK3342830, in plasma. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for Cmax have been presented.

  4. Part 1-Time to Maximum Plasma Concentration (Tmax) of GSK3342830 [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    Tmax was defined as time required to achieve Cmax for drug GSK3342830, in plasma. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for tmax have been presented.

  5. Part 1-Terminal Elimination Half-life (t1/2) of GSK3342830 in Plasma [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    t ½ is defined as the time required by the drug to reduce to half its quantity. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for t1/2 have been presented.

  6. Part 1-Total Systemic Clearance (CL) of GSK3342830 in Plasma [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    The systemic CL is a PK measure of volume of plasma from which the drug is removed per unit time. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for CL have been presented.

  7. Part 1-Steady-state Volume (Vss) of Distribution of GSK3342830 in Plasma [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    Vss reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces. 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. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for Vss have been presented.

  8. Part 1-Urinary Excretion Ratio Relative to Dose (Feu [t1-t2]) of GSK3342830 [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose ]
    Urine samples were collected at indicated timepoints pre-dose and post dose. The Feu has been reported from 0 to 4, 4 to 8, 8 to 12, 12 to 24 and 24 to 48 hrs. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data is not available. The standard deviation could not be calculated as only single participant was present. Log untransformed values for Feu (t1-t2) have been presented.

  9. Part 1-Renal Clearance (CLr) of GSK3342830 in Urine [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    The renal clearance (CLr) is a PK measure of volume of drug is removed per unit time. Urine samples were collected at indicated timepoints pre-dose and post dose. This part 1 phase of the study comprised of single dosing of the participants. Log untransformed values for CLr have been presented.

  10. Part 1-Amount Excreted in Urine (Ae) of GSK3342830 in Urine [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    Ae is defined as amount of drug GSK3342830, excreted in urine. Urine samples were collected pre-dose (within a 24-hr period before dosing, may begin on Day -1) and 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hrs post-dose. Log untransformed values for Ae have been presented.

  11. Part 1:Dose Proportionality: AUC (0-t) [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    Blood samples were collected at Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose. Dose proportionality was assessed for AUC(0-inf) and Cmax after single dose administration. AUC(0-inf) was selected as the AUC exposure measure as it is the default AUC parameter for single dose administration and the observed data permitted its calculation.

  12. Part 1:Dose Proportionality: AUC (0-inf) [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    Blood samples were collected at Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48 hr post-dose. The data for estimate slope for log dose, has been reported.

  13. Part 1:Dose Proportionality: Cmax [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    Blood samples were collected at Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose. The data for estimate slope for log dose, has been reported.

  14. Part 2-AUC (0-inf) of GSK3342830 [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15 ]
    AUC (0-inf), was defined as AUC extrapolated from time zero to infinity Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion. The untransformed values for AUC(0-inf) have been presented.

  15. Part 2-Cmax of GSK3342830 [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr, post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15 ]
    Cmax was defined as the maximum concentration of drug GSK3342830, in plasma. It was collected at Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion.

  16. Part 2-Tmax of GSK3342830 [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    Tmax was defined as time required to achieve Cmax for drug GSK3342830, in plasma. It was collected at Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion.

  17. Part 2-Terminal t1/2 of GSK3342830 in Plasma [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    t ½ is defined as the time required by the drug to reduce to half its quantity. Blood samples were collected at Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion.

  18. Part 2-Total CL of GSK3342830 in Plasma [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15 ]
    The systemic CL is a PK measure of volume of plasma from which the drug is removed per unit time. The blood samples of 3 mL were collected at Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion.

  19. Part 2- Vss of Distribution of GSK3342830 in Plasma [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    Vss reflects the actual blood and tissue volume into which a drug is distributed and the relative binding of drug to protein in these spaces. The blood samples of 3 mL were collected at Day 1 at pre-dose (15 minutes) and 0.5 hr, 1 hr (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hrs after start of infusion. Single pre-dose samples on mornings of Days 3, 6, 9, 12, and 13. Serial samples (Day 15) time points: pre-dose (15 minutes) and 0.5 hr, 1 (end of infusion), 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hrs after start of infusion.

  20. Part 2-Urinary Excretion Ratio Relative to Dose Feu (t1-t2) of GSK3342830 [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15 ]
    The Feu has been reported from 0 to 4, 4 to 8, 8 to 12, 12 to 24 and 24 to 48 hrs. These were collected in opaque bottles at pre-dose (within a 24-hr period before dosing, may begin on Day -1) and 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hrs post-dose.

  21. Part 2- Trough Concentration (Ctau) [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    Blood samples were collected on Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15. The untransformed values for Ctau have been presented.

  22. Part 2-CLr of GSK3342830 in Urine [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    The renal CLr is a PK measure of volume of plasma from which the drug is removed per unit time.These were collected in opaque bottles on Day 1 and Day 15 at (Pre-dose, 0 to 8 and 8 to 24 hrs post-dose). The untransformed values for CLr have been presented.

  23. Part 2- Ae of GSK3342830 in Urine [ Time Frame: Day 1 and Day 15 at (Pre-dose, 0 to 8 and 8 to 24 hrs post-dose) ]
    Ae defines as the amount of drug GSK3342830, excreted in urine. These were collected in opaque bottles on Day 1 and Day 15 at (Pre-dose, 0 to 8 and 8 to 24 hrs post-dose). The untransformed values for Ae have been presented.

  24. Part 2: AUC From Time Zero to Last Measurable Concentration AUC (0- Tau) [ Time Frame: Day 1 (pre-dose, 0.5 hr, 1 hr, 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, 48hr post-dose ]
    It was defined as Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the time of the last measureable concentration. 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. Log untransformed values for AUC (0 to tau) have been presented.

  25. Part 2: Dose Proportionality: AUC (0-tau) [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr, post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15 ]
    Blood samples were collected at Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 hr post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 hr post-dose at Day 15. Data cannot be summarized because only 1 dose level studied so dose proportionality analysis cannot be performed as no comparison can be conducted.

  26. Part 2: Observed Accumulation Ratio (Ro) Based on AUC and Cmax of GSK3342830 After Administration of Repeat IV Doses, as Data Permit [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    The accumulation ratio has been reported. Sampling was done at Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15. Data cannot be summarized because only 1 dose level studied so dose proportionality analysis cannot be performed as no comparison can be conducted.

  27. Part 2: Steady-state Ratio (Rss) of GSK3342830 to Assess Time Invariance, as Data Permit [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    Sampling was done at Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15. Since the study was terminated early, data is only available for one dose level for Part 2. Some subjects have only partial data and were not dosed on Day 15.

  28. Part 2: Trough Plasma Concentrations at the End of the Dosing Interval (Ctau) to Assess the Achievement of Steady-state of GSK3342830 After Administration of Repeat IV Doses, as Data Permit [ Time Frame: Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15 ]
    Sampling was done at Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, and 24 h post-dose at Day 1. Pre-dose on Day 3, 6, 9, 12, and 13. Pre-dose, and 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, and 8 h post-dose at Day 15. The untransformed values for Ctau have been presented.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02751424


Locations
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Australia, South Australia
GSK Investigational Site
Adelaide, South Australia, Australia, 5000
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] November 1, 2016
Statistical Analysis Plan  [PDF] August 17, 2017


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02751424     History of Changes
Other Study ID Numbers: 204847
First Posted: April 26, 2016    Key Record Dates
Results First Posted: September 12, 2018
Last Update Posted: September 12, 2018
Last Verified: June 2018
Keywords provided by GlaxoSmithKline:
Multidrug-resistant
Gram negative bacterial infection
Safety
Pharmacokinetic
Additional relevant MeSH terms:
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Bacterial Infections