Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1278863A in Healthy Subjects

A Phase I, Randomized, Single-Blind, Placebo-Controlled, Dose-Escalation (Part 1), Fixed Sequence and Open-Label (Part 2), Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1278863A in Healthy Subjects

GSK1278863A is a novel small molecule agent, which stimulates erythropoiesis through inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylases (EGLNs). This compound is being developed for the treatment of anemia. This study, PHI115385, will be the first administration of GSK1278863A to Japanese subjects to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses in healthy Japanese adult subjects. Healthy Caucasian adult subjects will be included in order to compare pharmacokinetics of GSK1278863A and its metabolite(s), and pharmacodynamics of GSK1278863A.

Study Overview

• Status: Completed
• Conditions: Anaemia
• Intervention / Treatment: Drug: GSK1278863A Placebo; Drug: GSK1278863A

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, Sydney, New South Wales, Australia, 2031
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AST, ALT, alkaline phosphatase and bilirubin >1.5xULN.
• Healthy Male or female between 20 and 65 years of age inclusive, at the time of signing the informed consent.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods.
• Body weight > 50 kg and BMI within the range 18.5 - 29.0 kg/m2 (inclusive).
• Capable of giving written informed consent.
• QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.
• Japanese defined 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 be also have lived outside Japan for less than 10 years.
• Caucasian, defined as an individual having four grandparents who are all descendents of the original peoples of Europe.

Exclusion Criteria:

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
• A positive pre-study drug screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines
• A hemoglobin value at Screening is of: Healthy male subjects or post-menopausal females: > 16.5 g/dL, Healthy female (non-childbearing potential) subjects: > 15.5 g/dL
• The values of hematological parameters at screening are: MCV: outside the reference range and deemed clinically significant by the investigator and GSK Medical Monitor.
• The values of the following tests at Screening, for healthy subjects are: TIBC: outside the reference range of the population being studied, Serum iron: outside the reference range of the population being studied, Serum ferritin: outside the reference range of the population being studied
• A value at screening is greater than the upper limit of reference range for the following clinical laboratory parameters: AST, ALT, direct bilirubin.
• Clinically significant abnormal CPK determined by the Investigator and GSK Medical Monitor.
• Calculated creatinine clearance: < 80 mL/min
• A positive test for HIV antibody
• History of drug abuse or dependence within 6 months of the study.
• History of regular alcohol consumption within 6 months of the study
• History or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• 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, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. By exception, subject may take acetaminophen (<2 grams/day) up to 48 hours prior to the first dose of study drug.
• 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 heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula).
• 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 the study drugs. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include cholecystectomy, gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue. Examples of conditions that could interfere with hepatic function include Gilberts syndrome.
• History of peptic ulcer disease or chronic rectal bleeding.
• History of malignancy. Non-melanoma skin cancer that has been definitely removed is allowed.
• Subjects with a baseline medical history of proliferative diabetic retinopathy, preproliferative diabetic retinopathy, or wet age-related macular degeneration (AMD).
• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
• Lactating females.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
• Consumption of >3 servings per day of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, broccoli, green beans, or apples from 7 days prior to the first dose of investigational product, unless in the opinion of the Investigator and GSK Medical Monitor this will not interfere with the study procedures and compromise subject safety.
• 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.
• Subject is mentally or legally incapacitated.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: GSK1278863A Placebo; 5, 25 and 100 mg matched	Drug: GSK1278863A Placebo; Matching size, shape and color; Drug: GSK1278863A; A round, biconvex, white film coated tablet
Experimental: GSK1278863A 10mg; A round, biconvex, white film coated tablet	Drug: GSK1278863A Placebo; Matching size, shape and color; Drug: GSK1278863A; A round, biconvex, white film coated tablet
Experimental: GSK1278863A 25mg; A round, biconvex, white film coated tablet	Drug: GSK1278863A; A round, biconvex, white film coated tablet
Experimental: GSK1278863A 50mg; A round, biconvex, white film coated tablet	Drug: GSK1278863A; A round, biconvex, white film coated tablet
Experimental: GSK1278863A 100mg; A round, biconvex, white film coated tablet	Drug: GSK1278863A; A round, biconvex, white film coated tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability		up to 96 hr
AUC(0-t), AUC(0-∞), Cmax, tmax and t½ of GSK1278863A		up to 96 hr
Changes from Baseline of Clinical laboratory tests	Platelet Count , RBC Indices, WBC Differential, RBC Count, WBC Count, Lymphocytes, Reticulocyte Count, Hemoglobin, Hematocritm, BUN, Ptassium, AST, Total and direct bilirubin, Creatinine, Chloride, ALT, Uric Acid, Glucose, Total CO2, GGT, Albumin, Sodium, Calcium, Alkaline phosphatase, Total Protein, CPK, Iron Ferritin, TIBC	0,2448 and 96 hr
Changes from Baseline of Vital signs	systolic and diastolic blood pressure and pulse rate	0, 1,2,3,4,8 and 24hr
Change from Baseline of 12-lead ECG		0,4 and 8 hr

Secondary Outcome Measures

Outcome Measure	Time Frame
Hemoglobin endpoints: Hemoglobin actual values, change from baseline, rate of rise/decline, maximum change from baseline, and maximum % change from baseline	up to 96 hr

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2011
• Primary Completion (Actual): June 3, 2011
• Study Completion (Actual): June 3, 2011

Study Registration Dates

• First Submitted: April 5, 2012
• First Submitted That Met QC Criteria: January 22, 2015
• First Posted (Estimate): January 28, 2015

Study Record Updates

• Last Update Posted (Actual): June 22, 2017
• Last Update Submitted That Met QC Criteria: June 21, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Glycine Agents; Glycine
• Other Study ID Numbers: 115385

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Clinical Study Report
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Individual Participant Data Set
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Annotated Case Report Form
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 115385
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register