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

NCT ID: NCT02751424

Last Updated: 2018-09-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-13
• Study Completion Date: 2017-02-02

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.

Conditions

Infections, Bacterial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

GSK3342830

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.

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.

Group Type: EXPERIMENTAL

GSK3342830

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.

Interventions

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.

Intervention Type: DRUG

Placebo

A clear and colorless solution containing 0.9% sodium chloride. It will administered as IV infusion over 1 hour.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Adelaide, South Australia, Australia

Countries

Australia

References

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.

Reference Type: DERIVED

PMID: 30536589 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

204847

Identifier Type: -

Identifier Source: org_study_id