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This is Phase I, 4-period, randomized, active-and placebo-controlled, double-blind crossover, single-dose study to evaluate the effects of a therapeutic (1000 milligram [mg]) and supratherapeutic (1800 mg) dose of GSK2140944 with a positive control (moxifloxacin 400 mg) and placebo on the corrected QT interval (QTc) as assessed by continuous 12-lead Holter electrocardiograms (ECGs) in approximately 55 healthy volunteers.
All subjects will receive single doses of GSK2140944 1000 mg, GSK2140944 1800 mg, moxifloxacin 400 mg, and placebo in a randomized sequence. A double-dummy approach will be used to maintain blinding. Thus, on each dosing day, moxifloxacin or moxifloxacin placebo and GSK2140944 or placebo will be administered.
Subjects will be screened within 30 days prior to entry to the clinic. Subjects will report to the clinical unit on Day -2 of Period 1 and on Day -1 in subsequent periods. Subjects will remain confined until check out procedures have been completed on Day 3 (5 days confinement in Period 1 and 4 days in the following 3 periods). There will be a washout of at least 7 days between doses. The follow-up visit will occur 7-10 days after the final dose. Total duration of the study (from screening to the follow-up visit) will be approximately 60 days.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sequence ABDC | Experimental | Subjects will be administered treatments in Sequence ABDC where, A= GSK2140944 1000 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; B= GSK2140944 1800 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; C= GSK2140944 placebo IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning and D= Moxifloxacin 400 mg administered orally in morning and GSK2140944 placebo administered as IV infusion over 120 minutes |
|
| Sequence BCAD | Experimental | Subjects will be administered treatments in Sequence BCAD where, A= GSK2140944 1000 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; B= GSK2140944 1800 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; C= GSK2140944 placebo IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning and D= Moxifloxacin 400 mg administered orally in morning and GSK2140944 placebo administered as IV infusion over 120 minutes |
|
| Sequence CDBA | Experimental | Subjects will be administered treatments in Sequence CDBA where, A= GSK2140944 1000 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; B= GSK2140944 1800 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; C= GSK2140944 placebo IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning and D= Moxifloxacin 400 mg administered orally in morning and GSK2140944 placebo administered as IV infusion over 120 minutes |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GSK2140944 | Drug | GSK2140944 is available in dose strength 1000 mg and 1800 mg for single IV dose over 2 hours administration as a pale yellow to greyish yellow cake for reconstitution |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline in corrected QT interval, using the Fridericia formula (QTcF) for GSK2140944 (1000 mg and 1800 mg) | ECGs will be measured using a 24-hour continuous 12-lead Holter monitor. ECGs will be extracted up to 10 replicates at the following time points: at 3 time points pre-dose (45, 30, and 15 minutes prior to starting the infusion) and 0.25, 0.5, 1.0, 1.5, 2.0 (end of infusion), 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24 and 48 hours after dosing, for a total of 16 time points per treatment period | Up to 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline in ECG parameters for GSK2140944 (1000 mg and 1800 mg) | ECGs will be measured using a 24-hour continuous 12-lead Holter monitor at predefined timepoints. ECG parameters includes QT (QT interval), QT corrected according to the Bazett formula (QTcB), QT/RR pairs from the defined time points at which subjects are supinely resting (QTci), Individually corrected QT interval (QTcI), heart rate (HR), PR interval, and the complex of 3 of the graphical deflections seen on a typical ECG (QRS) interval |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Austin | Texas | 78744 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28223381 | Derived | Hossain M, Zhou M, Tiffany C, Dumont E, Darpo B. A Phase I, Randomized, Double-Blinded, Placebo- and Moxifloxacin-Controlled, Four-Period Crossover Study To Evaluate the Effect of Gepotidacin on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram in Healthy Volunteers. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02385-16. doi: 10.1128/AAC.02385-16. Print 2017 May. |
| Label | URL |
|---|---|
| Results for study 115775 can be found on the GSK Clinical Study Register. | View source |
| ID | Type | URL | Comment |
|---|---|---|---|
| 115775 | Statistical Analysis Plan | View IPD |
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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| ID | Term |
|---|---|
| D012141 | Respiratory Tract Infections |
| ID | Term |
|---|---|
| D007239 | Infections |
| D012140 | Respiratory Tract Diseases |
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Not provided
| ID | Term |
|---|---|
| C000612856 | gepotidacin |
| D000077266 | Moxifloxacin |
| ID | Term |
|---|---|
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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| Sequence DACB | Experimental | Subjects will be administered treatments in Sequence DACB where, A= GSK2140944 1000 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; B= GSK2140944 1800 mg IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning; C= GSK2140944 placebo IV infusion over 120 minutes and single dose of moxifloxacin placebo administered orally in morning and D= Moxifloxacin 400 mg administered orally in morning and GSK2140944 placebo administered as IV infusion over 120 minutes |
|
| GSK2140944 placebo | Drug | GSK2140944 placebo is 0.9% sodium chloride available for single IV dose over 2 hours administration. |
|
| Moxifloxacin | Drug | Moxifloxacin is available as pinkish red tablet with dose strength 400 mg for single oral dose to be administered in the morning in the fasted state with approximately 240 mL of water. |
|
| Moxifloxacin placebo | Drug | Moxifloxacin placebo is available as white, film-coated tablet. containing nonactive material for single oral dose to be administered in the morning in the fasted state with approximately 240 mL of water. |
|
| Up to 48 hours |
| Categorical outliers in ECG parameters for GSK2140944 (1000 mg and 1800 mg) | ECGs will be measured using a 24-hour continuous 12-lead Holter monitor at predefined time points. Categorical outliers ECG parameters includes QTc, HR, PR, and QRS interval | Up to 48 hours |
| Change from baseline in ECG parameters for moxifloxacin | ECGs will be measured using a 24-hour continuous 12-lead Holter monitor at predefined time points. ECG parameters includes QTcF, QTcB, QTci, QTcI, QT, HR, PR, and QRS interval | Up to 48 hours |
| Composite of pharmacokinetic (PK) parameters for GSK2140944 (1000 mg and 1800 mg) | PK parameters including area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-infinity]), area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration (AUC[0-t]), systemic clearance of parent drug (CL), maximum observed concentration (Cmax) | Up to 48 hours |
| Composite of PK parameters for moxifloxacin | PK parameters including AUC(0-infinity), AUC(0-t), CL, apparent clearance of parent drug after oral dosing (CL/F), Cmax, λz, t1/2, tmax, Vss, Vz, apparent volume of distribution after oral dosing (Vz/F). | Up to 48 hours |
| Plasma concentrations and change in QTcF for GSK2140944 and moxifloxacin | The relationship between GSK2140944 plasma concentration following single IV administration and the baseline adjusted QTcF interval corrected for placebo will be explored | Up to 48 hours |
| Amount excreted (Ae) in urine of unchanged GSK2140944 (1000 mg and 1800 mg) | Urinary recovery of unchanged drug that is total amount of drug excreted in urine (Ae), calculated by adding all the fractions of drug collected over all the allotted time intervals | Up to 48 hours |
| Fraction of the dose (fe) excreted in urine | Fraction of the dose (fe) will be calculated as, percentage fe= (Ae/Dose) × 100 | Up to 48 hours |
| Renal clearance | Renal clearance of drug will be calculated as: Ae/ AUC(0-t) | Up to 48 hours |
| Assessment of ECG | Single 12-lead safety ECGs will be obtained at predefined time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals | Up to Day 48 |
| Change from baseline in vital sign measurements | Vital signs includes temperature, systolic and diastolic blood pressure and pulse rate and respiratory rate | Up to Day 48 |
| Number of subjects with adverse events (AEs) | An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product | Up to Day 48 |
| Toxicity grading of clinical laboratory test results | Clinical laboratory parameters includes hematology, clinical chemistry, and urinalysis | Up to Day 48 |
For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Informed Consent Form | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Individual Participant Data Set | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Clinical Study Report | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Annotated Case Report Form | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Dataset Specification | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 115775 | Study Protocol | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |