Pro-arrhythmic Potential of GSK3039294 in Healthy Subjects
Pro-arrhythmic Potential of GSK3039294 in Healthy Subjects
GSK3039294 has been developed to offer an orally available alternative to parenteral
 GSK2315698 (miridesap) for plasma serum amyloid P component (SAP) depletion prior to and
 following use of anti-SAP Monoclonal Antibody (mAb) in the treatment of systemic amyloidosis.
 The primary objectives of the study are to assess the cardiac arrhythmic potential of
 GSK3039294 and evaluate safety and tolerability of repeat doses of GSK3039294, in healthy
 subjects relative to placebo for the same duration. This study will consist of two parts,
 Part A and a conditional Part B. Part A is designed as a randomized double-blinded, 3 period,
 placebo-controlled, repeat-dose, crossover study. The decision to initiate Part B will be
 based on an evaluation of data from Part A, which will include an overall assessment of
 safety, pharmacokinetics (PK) and pharmacodynamics (PD). In Part A, there will be three
 treatment periods with 7 days of dosing in each and minimum 7-day washout period between each
 treatment session. Each subject will receive two dose levels of GSK3039294 and placebo. In
 Part B, there will be two treatment periods with 7 days of dosing in each and minimum 7-day
 washout period. Each subject will receive one dose level of GSK3039294 and placebo. In Part
 A, approximately 48 subjects will be recruited for an estimated total of 36 completers. In
 Part B, approximately 32 subjects will be recruited for an estimated total of 24 completers.
 The study will last up to approximately 10 weeks from screening to follow-up.
Eligibility Criteria

 Inclusion Criteria:

 -  18 to 65 years of age inclusive at the time of signing the informed consent.

 -  Non-smokers only (defined as a non-smoker during the last 3 months prior to
 screening).

 -  Body weight > 50 kilograms and body mass index (BMI) and <=30 kilograms/meter square.

 -  Male subjects and women of non-child bearing potential only will be eligible.

 -  Male subjects with female partners of childbearing potential must comply with one of
 the following contraception requirements from the time of first dose of study
 medication until completion of the follow-up visit.

 -  Vasectomy with documentation of azoospermia.

 -  Male condom plus partner use of one of the contraceptive options: Contraceptive sub
 dermal implant that meets the effectiveness criteria of a <1% rate of failure per
 year, as stated in the product label; Intrauterine device or intrauterine system that
 meets the standard operating procedure (SOP) effectiveness criteria including a <1%
 rate of failure per year, as stated in the product label; Oral Contraceptive, either
 combined or progestogen alone; Contraceptive vaginal ring; Occlusive cap (female
 diaphragm or cervical/vault cap) with a vaginal spermicide (foam, gel, cream or
 suppository).

 -  Capable of giving signed informed.

 -  Healthy as determined by a responsible and experienced physician, based on a medical
 evaluation including medical history, physical examination, laboratory tests and
 cardiac monitoring.

 -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
 specifically listed in the inclusion or exclusion criteria, outside the reference
 range for the population being studied may be included only if the investigator in
 consultation with the Medical Monitor if required agree and document that the finding
 is unlikely to introduce additional risk factors and will not interfere with the study
 procedures.

 -  Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase and
 bilirubin <=1.5 ULN (Upper Limit of Normal) (isolated bilirubin >1.5 ULN is acceptable
 if bilirubin is fractionated and direct bilirubin <35%).

 Exclusion Criteria:

 -  History or presence of/significant history of or current cardiovascular, respiratory,
 hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders
 capable of significantly altering the absorption, metabolism, or elimination of drugs;
 constituting a risk when taking the study treatment; or interfering with the
 interpretation of data.

 -  Clinically significant blood pressure as determined by the investigator.

 -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
 (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 -  QT interval corrected for heart rate according to Fridericia's formula (QTcF)>450
 milliseconds.

 -  Screening 12-lead ECG with any of the following: second/third degree atrioventricular
 block (AVB); significant pathological Q-waves (defined as Q-wave > 40 milliseconds or
 depth greater than 0.4-0.5 millivolts); ventricular pre-excitation; complete left
 bundle branch block (LBBB); bradycardia as defined by sinus rate <= 35 beats per
 minute (BPM).

 -  Any clinically relevant abnormality on the screening medical assessment laboratory
 examination or ECG.

 -  A personal history of corrected QT interval (QTc) prolongation, symptomatic cardiac
 arrhythmias or cardiac arrest.

 -  Sinus bradycardia <= 35 BPM or junctional arrhythmia > 60 BPM for 10 seconds or longer
 on run-in Holter or pre-dose inpatient telemetry.

 -  Non-sustained supraventricular tachycardia (NSVT) or more than 30 Ventricular
 Premature Depolarization (VPD)/hour on run-in Holter or pre-dose inpatient telemetry.

 -  Atrial tachycardia > 100 BPM for 3 seconds or longer or more than 40 Atrial Premature
 Depolarization (APD)/hour on run-in Holter or pre-dose inpatient telemetry.

 -  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, unless in the opinion of the
 Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not
 interfere with the study procedures or compromise subject safety.

 -  Participation in the study would result in loss of blood or blood products in excess
 of 500 milliliters within 56-day period.

 -  Exposure to more than 4 new chemical entities within 12 months prior to the first
 dosing day.

 -  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).

 -  Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C
 antibody test result at screening.

 -  Positive Hepatitis C Ribonucleic acid (RNA) test result at screening or within 3
 months prior to first dose of study treatment.

 -  Positive pre-study drug/alcohol screen.

 -  Positive human immunodeficiency virus (HIV) antibody test.

 -  Regular use of known drugs of abuse.

 -  Regular alcohol consumption within six months prior to the study defined as: For
 United Kingdom (UK) sites an average weekly intake of >21 units for males or >14 units
 for females. One unit is equivalent to 8 grams of alcohol: a half-pint (equivalent to
 240 milliliters) of beer, one glass (125 milliliters) of wine or one (25 milliliters)
 measure of spirits.

 -  Urinary cotinine levels indicative of smoking/history/regular use of
 tobacco/nicotine-containing products within 3 months prior to screening.

 -  Sensitivity to heparin or heparin-induced thrombocytopenia.

 -  Sensitivity to any of the study treatments, or components thereof, or drug or other
 allergy that, in the opinion of the investigator or medical monitor, contraindicates
 participation in the study.