A Three-part Study to Determine the Safety, Tolerability and Pharmacokinetics of GSK1322322 in Healthy Volunteers and Healthy Male Japanese Subjects

Infections, Bacterial Clinical Trial

Official title:

A Three-Part Phase I, Open-Label, Single Ascending Dose, and A Single-Blind, Placebo-Controlled, Repeat Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Relative Bioavailability of Intravenous and Oral GSK1322322 in Healthy Volunteers and Healthy Male Japanese Subjects

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01818011
• Other study ID #: 116266
• Status: Terminated
• Phase: Phase 1
• Start date: August 7, 2013
• Est. completion date: October 18, 2013

Study information

• Verified date: January 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objectives of this study are to assess the safety, tolerability and pharmacokinetics of GSK1322322 following intravenous (IV) and oral administration. GSK1322322 shows broad spectrum antibacterial activity against pathogens involved in respiratory tract infections as well as methicillin-resistant S. Aureus (MRSA).

This study consists of three parts (Part A, Part B and Part C). The results from Part A of this study will enable use of large-scale, commercial tablets produced for administration to patients in pivotal clinical trials of GSK1322322. The results from Parts B and C will support enrolment of Japanese subjects in future clinical studies. Additionally, the results will support the dose selection for further clinical development of GSK1322322 in hospitalized patients with severe bacterial infections in Japan and other Asian populations.

In Part A, subjects will undergo screening, 4 treatment periods receiving single dose of each of: 1500 mg Initial, fit-for-purpose tablet (product code AP), 1500 mg Over granulated tablet (product code AR), and the 1500 mg and 2000 mg of intended commercial tablets (product code AU).

In Part B of the study subjects will undergo screening, and be randomized to receive 3 doses of GSK1322322 oral cohort (100 mg, 1500 mg and 2000 mg) or IV cohort (600 mg, 900 mg and 1200 mg) each in 3 treatment periods.

Part C will be a single-blind, placebo-controlled, repeat dose study of GSK1322322 in healthy Japanese male subjects. GSK1322322 will be administered (fasted) via IV for 4 days BID, followed by administration of GSK1322322 orally (fed) for 6 days BID. A follow-up evaluation will be conducted 7-10 days following last dose of for each subjects in each Part of the study.

Approximately 12 subjects will be enrolled in each part of the study such that approximately 8, 6, and 9 subjects complete dosing and critical assessments in part A,B, and C respectively.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 12
• Est. completion date: October 18, 2013
• Est. primary completion date: October 18, 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria

• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening and check in.

• 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.

• Part A: Male or female (of non childbearing potential) between 18 and 65 years of age inclusive, at the time of signing the informed consent.

• Part A: 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 [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international unit (MlU)/milliliter (mL) and estradiol <40 picogram [pg]/mL (<147 picomoles [pmol]/litre [L]) is confirmatory].

• Part B and C: Japanese defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese. Japanese subjects should also have lived outside Japan for less than 10 years. Subjects should consume a typical Japanese diet on a regular basis.

• Parts B and C: Males between 20 and 65 years of age inclusive, at the time of signing the informed consent.

• Subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the final follow up visit.

• Body weight >=45.0 kilograms and body mass index (BMI) within the range 18.5 to 29.9 kg/meter^2 (inclusive).

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

• QT duration corrected for heart rate by Bazett's formula (QTcB) <=450 millisecond (msec); or QTcB < 480 msec in subjects with Bundle Branch Block on Screening ECG.

Exclusion Criteria

• A positive pre-study Hepatitis B surface antigen, positive Hepatitis C antibody, a positive test for human immune virus (HIV) 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).

• A positive pre-study drug/alcohol screen.

• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males. One unit is equivalent to 10 gram (g) of alcohol: 270 mL of full strength beer (4.8%), 375mL of mid strength beer (3.5%), 470mL of light beer (2.7%), 250mL pre-mix full strength spirit (5%), 100mL of wine (13.5%) and 30mL of spirit (40%).

• 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.

• 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) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety due to potential drug interaction. 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.

• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.

• Parts B and C: Female subjects.

• Part A: Pregnant females as determined by positive [serum or urine] human chorionic gonadotropin (hCG) test at screening or prior to dosing.

• Part A: Lactating females.

• Part A: Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 3 months prior to screening.

• Part B and C: Subjects with a smoking history of >10 cigarettes per day in the last 3 months.

• 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.

• Unable to refrain from 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.

• Screening Holter monitoring shows one or more of the following: Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization) and/or Any conduction abnormality on Holter monitoring (including but not specific to left or right complete bundle branch block, AV block [second degree or higher in an awake state; similar findings in sleeping subjects would not represent holter based exclusion, provided that they represent physiologic rhythm variants], Wolf Parkinson White [WPW] syndrome), sinus pauses>3 seconds, non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats) or any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety of the individual subject.

• Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Male subjects with Heart rate <40 and >100 beats per minute (bpm), PR interval <120 and >220 msec, QRS duration <70 and >120 msec, QT interval corrected for heart rate (Bazett) >450 msec.

Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [second degree or higher], WPW syndrome, sinus pauses >3 seconds, non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats) or any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety of the individual subject.

Related Conditions & MeSH terms

• Bacterial Infections
• Infections, Bacterial

Intervention

Drug:
• GSK1322322 Initial fit for purpose tablets
Beige, capsule shaped, film-coated tablet with unit dose strength of 500 mg/tablet and dose level of 1500 mg (3 x 500 mg) for single dose oral administration in Part A
• GSK1322322 over granulated tablets
Light beige, oval shaped, film-coated tablet with unit dose strength of 500 mg/tablet and dose level of 1500 mg (3 x 500 mg) for single dose oral administration in Part A
• GSK1322322 intended commercial tablets
Light beige, oval shaped, film-coated tablet with unit dose strength of 500 mg/tablet and dose level of 1000 mg (2 x 500),1500 mg (3 x 500 mg) and 2000 mg (4 x 500mg) for single dose oral administration in Part A and B and repeat dose administration twice daily in Part C
• Placebo tablets
Light beige, oval-shaped, film-coated tablet for repeat dose oral administration (BID for 6 days) in Part C
• 13C-GSK1322322 stable isotope powder
White to slightly colored non-sterile crystalline powder for oral suspension with dose level of 50 mg as a single dose with GSK1322322 tablets in Part A
• GSK1322322 for injection
White to slightly colored lyophilized powder cake in clear glass vials with unit dose strength of 400 mg/vial and dose levels of 600 mg (1.5 x 400 mg/vial), 900 mg (2.25x400mg/vial), 1200 mg (3x400mg/vial and 1200 mg (3 x 400 mg) for IV administration either as single dose in Part B or as a repeat dose (BID for 4 days) in Part C
• Placebo injection
A clear and colorless 0.9% Sodium Chloride solution for intravenous administration twice daily for 4 days in Part C

Locations

Country	Name	City	State
United States	GSK Investigational Site	Overland Park	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (1)

Parr A, Badman G, Bowen CL, Coffin M, Gupta M, Jones L, Kurtinecz M, Naderer O, Travis E, Zhu J, Patel P. Application of a Stable Isotope Approach to Evaluate Impact of Changes in Manufacturing Parameters for an Immediate-Release Tablet. J Clin Pharmacol. 2016 Jul;56(7):801-5. doi: 10.1002/jcph.664. Epub 2016 Jan 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of PK parameters for single oral dose of GSK1322322 in Part A	PK parameters include: area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC[0-t]), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinite]), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2)	Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
Primary	AUC(0-infinite) comparison for bioavailability assessment for three formulations of GSK1322322 in Part A	To evaluate the relative oral bioavailability, the AUC (0-infinite) of the three formulations (Initial fit-for-purpose tablets, Over-granulated tablets, and Intended commercial tablets) will be compared. Bioavailability is defined as the amount of drug available at the site of action after administration	Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
Primary	Composite of PK parameters to assess dose proportionality of the GSK1322322 Over-granulated formulation tablets of 1500 mg and 2000 mg	PK parameters include: AUC (0-infinite) and Cmax. to demonstrate similar or different bioavailability across the two dose levels in Part A	Up to 16 days in Part A. Collection will be done for each period at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72 hours post dose
Primary	Composite of PK parameters for single oral dose of GSK1322322 in healthy Japanese subjects in Part B	PK parameters include: AUC(0-t), AUC (0-infinite), Cmax, tmax, and t1/2	Up to 12 days in Part B. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post dose
Primary	Composite of PK parameters for single intravenous (IV) dose of GSK1322322 in healthy Japanese subjects in Part B	PK parameters include: AUC(0-t), AUC (0-infinite), Cmax, volume of distribution at steady state (Vss), mean residence time intravenous (MRTiv), t1/2, and systemic clearance of parent drug (CL)	Up to 12 days in Part B. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post infusion start
Primary	Composite of PK parameters for repeat IV dose of GSK1322322 in healthy Japanese subjects in Part C	In Part C, on Day 1 after the morning IV dose, area under the concentration-time curve from time zero (pre-dose) to 12 hours after dosing [AUC(0-12)] and Cmax will be computed; on Day 4 after the morning IV dose, area under the concentration-time curve over the dosing interval [AUC(0-tau)], Cmax, and systemic clearance at steady state (CLss) will be computed; on Day 10, after the oral morning dose, AUC(0-tau), Cmax, tmax, will be computed	Up to 10 days in Part C. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post dose on Day 1, Day 4 and Day 10
Secondary	Safety and tolerability of single oral dose of GSK1322322 in healthy subjects assessed by the collection of adverse events (AEs) in Part A	AEs will be collected from the start of study treatment and until the follow-up contact	Up to 23 days
Secondary	Collection of AEs to assess safety and tolerability of single oral and IV GSK1322322 doses in healthy Japanese male subjects in Part B	AEs will be collected from the start of study treatment and until the follow-up contact	Up to19 days
Secondary	Collection of AEs to assess safety and tolerability of repeat oral and IV GSK1322322 doses in healthy Japanese male Subjects in Part C	AEs will be collected from the start of study treatment and until the follow-up contact	Up to18 days
Secondary	Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm in healthy subjects in Part A	Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (blood pressure [BP], and heart rate), ECG intervals, and ECG rhythm will be measured	Up to 23 days
Secondary	Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subjects in Part B	Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (BP and heart rate), ECG intervals, and ECG rhythm will be measured	Up to 19 days
Secondary	Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subject in Part C	Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (BP and heart rate), ECG intervals, and ECG rhythm will be measured	Up to 18 days
Secondary	Dose proportionality of GSK1322322 following IV and oral single dose in Part B	To evaluate doe proportionality AUC(0-infinity) following oral and IV administration at different doses	Up to 12 days. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post dose
Secondary	GSK1322322 accumulation ratio following repeat IV administration in Part C	To evaluate the accumulation ratio following repeat IV administration of GSK1322322, Day 4 GSK1322322 AUC(0-tau) from the morning dose will be compared to AUC(0-12) on Day 1 from the morning dose	Day 1 and Day 4. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post infusion start
Secondary	The potential relationship of CL/CLss following single IV dose versus body weight in Part B	To estimate the effect of body weight on PK parameter of GSK1322322, the potential relationship of CL/CLss following single IV dose versus body weight will be explored	Up to 12 days. Collection will be done at pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48 and 72 hours post infusion start
Secondary	The potential relationship of CL/CLss following repeat IV doses versus body weight in Part C	To estimate the effect of body weight on PK parameter of GSK1322322, the potential relationship of CL/CLss following repeat IV doses versus body weight will be explored	Up to 10 days. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post infusion

External Links

•   Results for study 116266 can be found on the GSK Clinical Study Register.