A Study to Investigate the Safety, Tolerability and Pharmacokinetics of Oral and Intravenous GSK1322322 in Healthy Subjects

NCT ID: NCT01610388

Last Updated: 2017-06-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 61 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-13
• Study Completion Date: 2012-01-26

Brief Summary

This first time in human (FTIH) study will be the first administration of GSK1322322 as an intravenous formulation and will investigate safety, tolerability, and pharmacokinetics in healthy subjects. One cohort of subjects will undergo bronchoalveolar lavage (BAL) for determination of GSK1322322 concentrations in lung with simultaneous comparison to plasma concentrations to evaluate drug penetration in the lung. The study will evaluate the absolute bioavailability of an oral tablet formulation as compared to the IV formulation.In addition, Amendment 01 will enable the investigation of an improved IV formulation (GSK1322322J mesylate salt) in an additional repeat dosing cohort and the supra-therapeutic cohort.

Conditions

Infections, Bacterial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Cohort A1

Single dose 60 minute infusion of 500mg IV GSK1322322/placebo followed by BID for 4 days

Group Type: EXPERIMENTAL

500mg IV GSK1322322/placebo

Intervention Type: DRUG

500mg IV

Cohort A2

Single dose 30 minute infusion of 500mg IV GSK1322322/placebo followed by BID for 4 days

Group Type: EXPERIMENTAL

500mg IV GSK1322322/placebo

Intervention Type: DRUG

500mg IV

Cohort B

Initial single 1000mg oral GSK1322322/placebo dose, initial single dose 1000mg IV GSK1322322/placebo followed by BID for 4 days

Group Type: EXPERIMENTAL

1000mg oral GSK1322322/placebo

Intervention Type: DRUG

1000mg oral

1000mg IV GSK1322322/placebo

Intervention Type: DRUG

1000mg IV

Cohort C

Initial single 1500mg oral GSK1322322/placebo dose, initial single dose 1500mg IV GSK1322322/placebo followed by BID for 4 days

Group Type: EXPERIMENTAL

1500mg oral GSK1322322/placebo dose

Intervention Type: DRUG

1500mg oral

1500mg IV GSK1322322/placebo

Intervention Type: DRUG

1500mg IV

Cohort D

Single dose 2000mg IV GSK1322322J/placebo

Group Type: EXPERIMENTAL

2000mg IV GSK1322322J/placebo

Intervention Type: DRUG

2000mg IV

Cohort E

Single dose 3000mg IV GSK1322322J/placebo

Group Type: EXPERIMENTAL

3000mg IV GSK1322322J/placebo

Intervention Type: DRUG

3000mg IV

Cohort F

1000mg IV GSK1322322J/placebo followed by BID for 4 days

Group Type: EXPERIMENTAL

1000mg IV GSK1322322J/placebo

Intervention Type: DRUG

1000mg IV

Interventions

500mg IV GSK1322322/placebo

500mg IV

Intervention Type: DRUG

1000mg oral GSK1322322/placebo

1000mg oral

Intervention Type: DRUG

1000mg IV GSK1322322/placebo

1000mg IV

Intervention Type: DRUG

1500mg oral GSK1322322/placebo dose

1500mg oral

Intervention Type: DRUG

1500mg IV GSK1322322/placebo

1500mg IV

Intervention Type: DRUG

2000mg IV GSK1322322J/placebo

2000mg IV

Intervention Type: DRUG

3000mg IV GSK1322322J/placebo

3000mg IV

Intervention Type: DRUG

1000mg IV GSK1322322J/placebo

1000mg IV

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including [medical history, physical examination, laboratory tests and ECGs. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included at the discretion of the Investigator only if the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the final follow up visit.
• Body weight greater than or equal to 50 kilograms and body mass index (BMI) between 18.5-29.9 (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• QTcB less than 450 millisecond (msec); or QTcB less than 480 msec in subjects with Bundle Branch Block on Screening ECG

Exclusion Criteria

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Contraindications to bronchoalveolar lavage including hypercapnia greater than 50 mm Hg, refractory hypoxemia, reactive airway disease or asthma, unstable angina or acute myocardial infarction in the last 6 months, heart failure, and severe hemostatic alterations (Cohort C only).
• A positive pre-study drug/alcohol screen.
• A positive test for HIV antibody.
• History of regular alcohol consumption within 6 months of the study
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current 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 four new chemical entities within 12 months prior to the first dosing day.
• 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) prior to the first dose of study medication, and within 5 days following discontinuation of GSK1322322 (for sensitive and narrow therapeutic index CYP3A4 substrates), unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• Use of antacids, H2 blockers, proton pump inhibitors, vitamins, and iron supplements within 7 days prior to the first dose of study medication and for the duration of the trial, including follow-up.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• History of sensitivity to medications used in study, ie Atropine, Midazolam, Fentanyl, Lidocaine, Codeine (Cohort C only) that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Where participation in the study would result in donation of blood or blood products in excess of 500 milliliters within a 56 day period.
• Pregnant females as determined by positive [serum or urine] test at screening or prior to dosing.

Lactating females.

• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• Consumption of red wine, seville oranges, grapefruit or grapefruit juice [and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices] from 7 days prior to the first dose of study medication.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 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

Minneapolis, Minnesota, United States

Countries

United States

References

Naderer OJ, Rodvold KA, Jones LS, Zhu JZ, Bowen CL, Chen L, Dumont E. Penetration of GSK1322322 into epithelial lining fluid and alveolar macrophages as determined by bronchoalveolar lavage. Antimicrob Agents Chemother. 2014;58(1):419-23. doi: 10.1128/AAC.01836-13. Epub 2013 Nov 4.

Reference Type: DERIVED

PMID: 24189245 (View on PubMed)

Study Documents

Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Annotated Case Report Form

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

View Document

Related Links

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Other Identifiers

113376

Identifier Type: -

Identifier Source: org_study_id