Repeat Dose Safety Study for Compound to Treat Anaemia

The purpose of this study is to characterise the safety and tolerability of repeat doses of compound 1278863A in healthy subjects.

Official Title

A Phase I, Randomized, Single-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Repeat Oral Doses of 1278863A in Healthy Subjects

Conditions

• Healthy

Study Type

Interventional

Study Design

Basic Science, Randomised, Single Blind (Subject), Placebo Control, Parallel Assignment, Safety Study

Further Details

Primary outcome measures 

• Adverse events reporting
  [ Time Frame: throughout study ]
  [ Designated as safety issue: Yes ]
• Safety Labs (haematology)
  [ Time Frame: Screening, Days -1, 1-3, 5, 7, 9, 11, 14-18, 21, 25, 28 ]
  [ Designated as safety issue: Yes ]
• Vital signs (blood pressure and heart rate)
  [ Time Frame: Days 1-15, 28 ]
  [ Designated as safety issue: No ]
• 12-lead ECG
  [ Time Frame: Screening, Days 1-2, 4, 6, 8, 10, 12, 14, 28 ]
  [ Designated as safety issue: Yes ]
• Dual-lead cardiac monitoring (telemetry monitoring)
  [ Time Frame: Days -1 to 3, 14 ]
  [ Designated as safety issue: Yes ]
• Clinical monitoring/observation
  [ Time Frame: throughout ]
  [ Designated as safety issue: Yes ]
• Safety Labs (Chemistry)
  [ Time Frame: Screening, Days -1, 1-3, 7, 10, 14-15, 17, 21, 28 ]
  [ Designated as safety issue: Yes ]
• Safety Labs (Urinalysis)
  [ Time Frame: Screening, Days -1, 1-3, 7, 10, 14-15, 17, 21, 28 ]
  [ Designated as safety issue: Yes ]

Secondary outcome measures

• AUC(0-∞) on Day 1, AUC(0-τ), Cmax, tmax and t1/2, on Days 1 and 14
  [ Time Frame: Days 1-2, 4, 6, 8, 10, 12, 14-18 ]
  [ Designated as safety issue: No ]
• Trough plasma concentrations at the end of the dosing interval
  [ Time Frame: Days 2, 4, 6, 8, 10 and 12 ]
  [ Designated as safety issue: No ]
• Haemoglobin actual values, rate of rise, maximum change from baseline, and rate of decline following stopping of dosing
  [ Time Frame: Days 1, 7, 14, 21, 28 ]
  [ Designated as safety issue: No ]
• Foetal haemoglobin actual values, change from baseline, and percent of total haemoglobin
  [ Time Frame: Days 1, 7, 14, 21, 28 ]
  [ Designated as safety issue: No ]
• Actual values and change from baseline in erythropoietin
  [ Time Frame: Days 1-4, 7, 14-15, 18, 21 ]
  [ Designated as safety issue: No ]
• Actual values and change from baseline in absolute VEGF
  [ Time Frame: Days 1-2, 14-15, 18, 21 ]
  [ Designated as safety issue: No ]
• Actual values and change from baseline in hepcidin
  [ Time Frame: Days 1-2, 7, 14-15, 18, 21 ]
  [ Designated as safety issue: No ]
• Actual values and change from baseline in total iron binding capacity (TIBC)
  [ Time Frame: Screening, Days 1, 7, 14, 18, 21 ]
  [ Designated as safety issue: No ]
• Actual values and change from baseline in transferring saturation (%)
  [ Time Frame: Days 1, 7, 14, 18, 21 ]
  [ Designated as safety issue: No ] 

Study arms and assigned interventions

1. Experimental
   • Drug: 1278863 15mg, 25mg, 50mg, 150mg
2. Placebo Comparator
   • Drug: Placebo, matching placebo

Study Start

March 2009- August 2009

Eligibility & Criteria

• Ages eligible for study: 18 years to 55 years
• Genders eligible for study: Both
• Accepts healthy volunteers: Yes

Inclusion criteria

• Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Male or female between 18 and 55 years of age, inclusive.
• A female subject must be of non-childbearing potential.
• Male subjects must agree to use one of the acceptable contraception methods listed in the protocol
• Body weight greater than or equal to 50 kg and BMI within the range 19-31 kg/m² (inclusive).
• Capable of giving written informed consent
• QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.

Exclusion criteria

• The subject has a positive pre-study drug screen. 
• A hemoglobin value at screening is:
  • Male subjects or post-menopausal females: > 15.5 g/dL
  • Female subjects: > 14.5 g/dL
• The values of hematological parameters at screening are:
  MCV: outside the reference range and clinically significant deemed by the investigator and GSK Medical Monitor
• The values of the following tests at screening are:
  • TIBC: outside the reference range
  • Serum iron: outside the reference range
  • Serum ferritin: outside the reference range
• 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: < 60mL/min
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• 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
• Urinary cotinine levels indicative of smoking or 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 drug
• History of sensitivity to any of the study drugs, 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 patency)
• 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.
• History of peptic ulcer disease.
• History of malignancy tumor. Non-melanoma skin cancer that has been definitely removed is allowed.
• 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 red wine, seville oranges, grapefruit or grapefruit juice, exotic citrus fruits, grapefruit hybrids or fruit juices of the prohibited fruits from 7 days prior to the first dose of study medication
• 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.

Total Enrolment

24

Contact Details

Jeffery Wong, BASc 
61 3 9076 8947 
j.wong@nucleusnetwork.com.au

Annette Leahy, BHI 
61 3 9076 8900
a.leahy@nucleusnetwork.com.au