Clinical trial NCT01818011: A Three-part Study to Determine the Safety, Tolerability and Pharmacokinetics of GSK1322322 in Healthy Volunteers and Healthy Male Japanese Subjects
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Infections, Bacterial
Keywords: Japanese, GSK1322322, pharmacokinetics, relative bioavailability, single dose, repeat dose, healthy subjects, dose-escalation, antimicrobial, over granulation,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-03-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Composite of PK parameters for single oral dose of GSK1322322 in Part A
timeFrame: 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
measure: AUC(0-infinite) comparison for bioavailability assessment for three formulations of GSK1322322 in Part A
timeFrame: 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
measure: Composite of PK parameters to assess dose proportionality of the GSK1322322 Over-granulated formulation tablets of 1500 mg and 2000 mg
timeFrame: 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
measure: Composite of PK parameters for single oral dose of GSK1322322 in healthy Japanese subjects in Part B
timeFrame: 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
measure: Composite of PK parameters for single intravenous (IV) dose of GSK1322322 in healthy Japanese subjects in Part B
timeFrame: 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
measure: Composite of PK parameters for repeat IV dose of GSK1322322 in healthy Japanese subjects in Part C
timeFrame: 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 outcomes:
measure: Safety and tolerability of single oral dose of GSK1322322 in healthy subjects assessed by the collection of adverse events (AEs) in Part A
timeFrame: Up to 23 days
measure: Collection of AEs to assess safety and tolerability of single oral and IV GSK1322322 doses in healthy Japanese male subjects in Part B
timeFrame: Up to19 days
measure: Collection of AEs to assess safety and tolerability of repeat oral and IV GSK1322322 doses in healthy Japanese male Subjects in Part C
timeFrame: Up to18 days
measure: Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm in healthy subjects in Part A
timeFrame: Up to 23 days
measure: Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subjects in Part B
timeFrame: Up to 19 days
measure: Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, ECG intervals, ECG rhythm in healthy Japanese male Subject in Part C
timeFrame: Up to 18 days
measure: Dose proportionality of GSK1322322 following IV and oral single dose in Part B
timeFrame: 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
measure: GSK1322322 accumulation ratio following repeat IV administration in Part C
timeFrame: 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
measure: The potential relationship of CL/CLss following single IV dose versus body weight in Part B
timeFrame: 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
measure: The potential relationship of CL/CLss following repeat IV doses versus body weight in Part C
timeFrame: Up to 10 days. Collection will be done at pre-dose 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours post infusion
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.