Single Dose, Pharmacokinetic, Safety, Tolerability and QTc Study of GSK1278863 in Healthy Volunteers

NCT02293148 | Completed Phase 1

• 1 other identifier: 113635
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being performed to comply with regulatory requirements that all new non-antiarrhythmic drugs must be assessed for potential effects on cardiac repolarization through electrocardiographic evaluation in a 'Thorough QT/ Corrected QT interval (TQT)' study. This will be a two part study, Part A will be an open-label, single oral dose study design in order to evaluate the pharmacokinetics, safety and tolerability of a 500 milligram (mg) dose of GSK1278863 and Part B will be a single-blind, randomized, placebo-controlled, single, oral dose, four-way crossover study design. Parts A and B will be conducted in healthy adult subjects with 12-lead electrocardiograms (ECGs), clinical laboratory safety tests, vital sign measurements, physical examinations, adverse event reports, and pharmacokinetic samples collected throughout the study.

Conditions

Anaemia

Keywords

Prolyl hydroxylase inhibitor; GSK1278863; Anemia; QTc; erythropoiesis stimulating agent

Outcome Measures

Primary Outcomes (6)

• Composite of pharmacokinetic (PK) parameters for GSK1278863 and its metabolites for Part A

  Plasma concentrations of GSK1278863 and its metabolites (GSK2391220 \[M2\], GSK2506104 \[M3\], GSK2487818 \[M4\], GSK2506102 \[M5\], GSK2531398 \[M6\], and GSK2531401 \[M13\]) and derived pharmacokinetic parameters including maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax), Area under the concentration-time curve (AUC)

  Pre Dose, 0.25hour (h), 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 18h, and 24h post dose in each treatment period

• Change from baseline in QT duration corrected for heart rate by Fridericia's formula (QTcF) interval for Part B

  Change from baseline in QTcF interval at each time-point (average of at least three 12-lead Holter ECG replicates per time-point (Pre-dose, Day 1 \[0.25h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 18h\] and 24h) for 75 and 500 mg dose of GSK1278863 as compared with time-matched placebo

  At each treatment period (there are 4 periods) up to 24 hours

• Assessment of 12-lead ECG for Part A

  12-lead ECGs will be obtained at each time-point

  Up to Week 3

• Assessment of Vital Signs for Part A

  Vital Signs includes. temperature, systolic and diastolic blood pressure (BP) and pulse

  Up to Week 3

• Number of participants with Adverse Events (AE) for Part A

  An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  Up to Week 3

• Assessment of Clinical Laboratory Tests for Part A

  Clinical Laboratory Tests includes Hematology, Clinical Chemistry and Urinalysis

  Up to Week 3

Secondary Outcomes (10)

• Change from baseline in QT duration corrected for heart rate by Bazett's formula (QTcB), heart rate (HR), PR, QRS, and QT interval corrected for heart rate (QTci/QTciL interval) for GSK1278863 for Part B

  Up to Week 9

• Change from baseline in QTcB, HR, PR, QRS, and QTci/QTciL interval for moxifloxacin for Part B

  Up to Week 9

• Composite of PK parameters for GSK1278863, its metabolites and moxifloxacin for Part B

  Pre-dose, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 18h, and 24h in each treatment period of part B

• Maximal change from baseline in ECG parameters for Part B

  Up to Week 9

• Change from baseline for other ECG parameters for Part B

  Up to Week 9

Study Arms (2)

GSK1278863 (Part A)

EXPERIMENTAL

All subjects will receive a single, oral 500 mg dose of GSK1278863 on Day 1 administered as 5 x 100 mg tablets of GSK1278863. Additional doses/cohorts may be added depending upon the emerging safety, tolerability, pharmacokinetic and/or pharmacodynamics findings at the 500 mg dose level in Part A

Drug: GSK1278863 500 mg

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B)

EXPERIMENTAL

Subjects will be assigned to one of four treatment sequences (A-1 x Moxifloxacin placebo tablet, 3 x 25 mg tablets of GSK1278863, 2 x GSK1278863 matched placebo; B-1 x Moxifloxacin placebo tablet, 5 x 100 mg tablets of GSK1278863; C-1 x Moxifloxacin placebo tablet, 5 x GSK1278863 matched placebo tablets; D-1 x 400 mg Moxifloxacin tablet, 5 x GSK1278863 matched placebo tablets) (ABDC, BCAD, CDBA, DACB) in accordance with the randomization schedule

Drug: GSK1278863 75 mg; Drug: GSK1278863 500 mg; Drug: Moxifloxacin 400 mg; Drug: Placebo matching GSK1278863; Drug: Placebo matching Moxifloxacin

Interventions

GSK1278863 75 mg DRUG

A round, biconvex, white film coated tablet available in two doses (25 and 100 mg)

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B)

GSK1278863 500 mg DRUG

A round, biconvex, white film coated tablet available in two doses (25 and 100 mg)

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B); GSK1278863 (Part A)

Moxifloxacin 400 mg DRUG

Oblong, dull red, film-coated, convex tablets with M400 on one side

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B)

Placebo matching GSK1278863 DRUG

A round, biconvex, white film coated tablet as matching placebo for GSK1278863

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B)

Placebo matching Moxifloxacin DRUG

Capsule shaped white film coated tablet as matching placebo for Moxifloxacin

GSK1278863 (75 mg/500 mg)/Moxifloxacin 400 mg/Placebo (Part B)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects who are between 18 and 45 years and of age, inclusive at the time of signing the informed consent form
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring obtained at the Screening visit.
• The determination of clinical significance will be made by the Investigator and the GlaxoSmithKline (GSK) Medical Monitor and will require that the finding is unlikely to introduce additional risk factors or interfere with the study procedures, or the integrity of the study
• Hemoglobin values at screening greater than the lower limit of the laboratory reference range and less than or equal to 16.0 gram (g)/decilitre (dL) for males and less than or equal to 14.0 g/dL for females
• No significant abnormality on 12-lead ECG at screening, including the following specific requirements:
• Ventricular rate \>= 40 beats per minute; PR interval \<= 210milliseconds (msec); Q waves \< 30msec (up to 50msec permitted in lead III only); QRS interval to be \>= 60msec and \< 120msec; The waveforms must enable the QT interval to be clearly defined; QTcF interval must be \< 450msec.
• Body weight \>= 50 kilograms (kg) and body mass index (BMI) within the range 19-29.9 kg/meter square (m\^2) (inclusive).
• Female and Male:
• Female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as:
• Pre-menopausal females with one of the following:
• Documented tubal ligation
• Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
• Hysterectomy
• Documented Bilateral Oophorectomy

You may not qualify if:

• Hypertensive (diastolic BP \>90 millimetres of mercury \[mmHg\] or systolic BP \>140 mmHg) at screening
• A supine mean heart rate outside the range 50-100 beats per minute (bpm) at screening
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \>1.5x Upper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
• History or presence of any medically significant disease, or any disorder that would introduce additional risk or interfere with the study procedures or outcome. In particular, a family history of QT prolongation, of early or sudden cardiac death or of early cardiovascular disease
• NOTES:
• The QTc is the QTcF interval
• The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial
• Serum calcium, magnesium or potassium levels outside the normal reference range
• History of deep vein thrombosis, stroke, transient ischemic attack, pulmonary embolism or other thrombosis related condition within the last five years
• History of myocardial infarction or acute coronary syndrome
• Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of GSK1278863. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue
• Evidence of active peptic, duodenal or esophageal ulcer disease at Screening OR history of clinically significant gastrointestinal bleeding
• Subjects with chronic inflammatory joint disease (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis)
• Subjects with a history of pulmonary artery hypertension

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Links

• Results for study 113635 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Anemia

Interventions

GSK1278863; Moxifloxacin

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2014
• First Posted: November 18, 2014
• Study Start: November 17, 2014
• Primary Completion: March 10, 2015
• Study Completion: March 10, 2015
• Last Updated: July 24, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (1)