Clinical trial NCT02751424: A Study to Evaluate Safety, Tolerability and Pharmacokinetics of Ascending Intravenous Single Dose and Repeat Dose of GSK3342830
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Infections, Bacterial
Keywords: Multidrug-resistant
Gram negative bacterial infection
Safety
Pharmacokinetic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-04-26
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Part 1: Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE)
timeFrame: Up to Day 43
measure: Part 2: Number of Participants With AE and SAE
timeFrame: Up to Day 56
measure: Part 1: Number of Participants With Abnormal Hematology Parameters as a Measure of Safety-Grade 3 or Higher
timeFrame: Up to Day 2
measure: Part 2: Number of Participants With Abnormal Hematology Parameters as a Measure of Safety-Grade 3 or Higher
timeFrame: Up to Day 15
measure: Part 1: Number of Participants With Abnormal Clinical Chemistry Parameters as a Measure of Safety-Grade 3 or Higher
timeFrame: Day 2
measure: Part 2: Number of Participants With Abnormal Clinical Chemistry Parameters as a Measure of Safety-Grade 3 or Higher
timeFrame: Up to Day 15
measure: Part 1: Number of Participants Having Abnormal Urine Parameters (Using Dipstick Test) as a Measure of Safety
timeFrame: Up to Day 2
measure: Part 2: Number of Participants Having Abnormal Urine Parameters (Using Dipstick Test) as a Measure of Safety
timeFrame: Day 2, 5, 10 and Day 15
measure: Part 1: Number of Participants With Electrocardiogram (ECG) Parameters of Potential Clinical Importance (PCI)
timeFrame: Up to Day 3
measure: Part 2: Number of Participants With ECG Parameters of PCI
timeFrame: Up to Day 16
measure: Part 1: Number of Participants With Vital Signs of Potential Clinical Importance (PCI)
timeFrame: Up to Day 3
measure: Part 2: Number of Participants With Vital Signs of PCI
timeFrame: Up to Day 16
Secondary outcomes:
measure: 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
timeFrame: 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
measure: Part 1-AUC Pre Dose to Infinite (Inf) Time (AUC [0-inf]) of GSK3342830
timeFrame: 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
measure: Part 1-Maximum Plasma Concentration (Cmax) of GSK3342830
timeFrame: 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
measure: Part 1-Time to Maximum Plasma Concentration (Tmax) of GSK3342830
timeFrame: 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
measure: Part 1-Terminal Elimination Half-life (t1/2) of GSK3342830 in Plasma
timeFrame: 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
measure: Part 1-Total Systemic Clearance (CL) of GSK3342830 in Plasma
timeFrame: 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
measure: Part 1-Steady-state Volume (Vss) of Distribution of GSK3342830 in Plasma
timeFrame: 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
measure: Part 1-Urinary Excretion Ratio Relative to Dose (Feu [t1-t2]) of GSK3342830
timeFrame: 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
measure: Part 1-Renal Clearance (CLr) of GSK3342830 in Urine
timeFrame: 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
measure: Part 1-Amount Excreted in Urine (Ae) of GSK3342830 in Urine
timeFrame: 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
measure: Part 1:Dose Proportionality: AUC (0-t)
timeFrame: 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
measure: Part 1:Dose Proportionality: AUC (0-inf)
timeFrame: 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
measure: Part 1:Dose Proportionality: Cmax
timeFrame: 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
measure: Part 2-AUC (0-inf) of GSK3342830
timeFrame: 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
measure: Part 2-Cmax of GSK3342830
timeFrame: 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
measure: Part 2-Tmax of GSK3342830
timeFrame: 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
measure: Part 2-Terminal t1/2 of GSK3342830 in Plasma
timeFrame: 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
measure: Part 2-Total CL of GSK3342830 in Plasma
timeFrame: 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
measure: Part 2- Vss of Distribution of GSK3342830 in Plasma
timeFrame: 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
measure: Part 2-Urinary Excretion Ratio Relative to Dose Feu (t1-t2) of GSK3342830
timeFrame: 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
measure: Part 2- Trough Concentration (Ctau)
timeFrame: 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
measure: Part 2-CLr of GSK3342830 in Urine
timeFrame: 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
measure: Part 2- Ae of GSK3342830 in Urine
timeFrame: Day 1 and Day 15 at (Pre-dose, 0 to 8 and 8 to 24 hrs post-dose)
measure: Part 2: AUC From Time Zero to Last Measurable Concentration AUC (0- Tau)
timeFrame: 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
measure: Part 2: Dose Proportionality: AUC (0-tau)
timeFrame: 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
measure: Part 2: Observed Accumulation Ratio (Ro) Based on AUC and Cmax of GSK3342830 After Administration of Repeat IV Doses, as Data Permit
timeFrame: 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
measure: Part 2: Steady-state Ratio (Rss) of GSK3342830 to Assess Time Invariance, as Data Permit
timeFrame: 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
measure: 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
timeFrame: 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
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.