LAI115428 is a Phase I, randomized, repeat dose escalation study to determine the safety,
tolerability, and PK profile of intramuscular and subcutaneous injections of GSK1265744 in a
long acting parenteral (LAP) formulation in healthy subjects. Subjects will be randomized to
3 monthly dosing cohorts and 1 quarterly dosing cohort with either intramuscular or
subcutaneous dosing. In the monthly dosing cohorts subjects will receive GSK1265744 alone
for 2 months and then in combination with TMC278 long acting parenteral (LA) for 2 months.
For the quarterly dosing cohort, 2 quarterly intramuscular doses of GSK1265744 LAP will be
given alone. Three dose levels of GSK1265744 will be evaluated partly in combination with
TMC278 LA to adequately characterize the GSK1265744 LAP and TMC278 LA safety, tolerability,
and PK profile. A total enrolment of approximately 40 healthy subjects is planned for this
study.
GSK1265744 LAP safety and tolerability parameters including the collection of adverse eventsGSK1265744 LAP safety and tolerability parameters including change from baseline in clinical laboratory safety assessments
GSK1265744 LAP safety and tolerability parameters including change from baseline in electrocardiogram (ECG) measurements
GSK1265744 LAP safety and tolerability parameters including change from baseline in vital sign measurements
TMC278 LA safety and tolerability parameters including the collection of adverse events
TMC278 LA safety and tolerability parameters including change from baseline in clinical laboratory safety assessments
TMC278 LA safety and tolerability parameters including change from baseline in ECG measurements
TMC278 LA safety and tolerability parameters including change from baseline in vital sign measurements
Composite of PK parameters following single and repeat dose intramuscular or subcutaneous administration
Composite of GSK1265744 pharmacokinetic parameters following repeat dose oral administration
Composite of TMC278 LA pharmacokinetic parameters following single and repeat dose intramuscular administration
GSK1265744 LAP safety and tolerability parameters including change from baseline for clinical chemistry assessments (ALT, AST, ALP, Total and Direct Bilirubin).
Inclusion Criteria:
- AST, ALT, alkaline phosphatase and bilirubin greater than or equal to 1. 5xULN
(isolated bilirubin >1. 5xULN is acceptable if bilirubin is fractionated and direct
bilirubin <35%).
- 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 clinically significant abnormality or
laboratory parameters outside the reference range for the population being studied
may be included only if the Investigator and the GSK Medical Monitor agree that the
finding is unlikely to introduce additional risk factors and will not interfere with
the study procedures.
- Male or female between 18 and 64 years of age inclusive, at the time of signing the
informed consent.
- Females of childbearing potential with a negative pregnancy test (serum or urine) at
screen and at Day - 21, and agrees to use one of the contraception methods listed in
the protocol for an appropriate period of time (as determined by the product label or
investigator) prior to the start of dosing to sufficiently minimize the risk of
pregnancy at that point. Female subjects must agree to use contraception for six
months after the final dose of study drug.
- Body weight greater than or equal to 50 kg for men and greater than or equal to 45 kg
for women and body mass index (BMI) within the range 18. 5-31. 0 kg/m2 (inclusive).
- All Study subjects should be counseled on the practice of safer sexual practices
including the use of effective barrier methods (e. g. male condom/spermicide).
Exclusion Criteria:
- History of bleeding or clotting disorders including disseminated intravascular
coagulation, hemophilia Henoch-Schönlein purpura (allergic purpura), hereditary
hemorrhagic telangiectasia, thrombocytopenia, thrombophilia or Von Willebrand's
disease.
- High-risk behavior for HIV infection including one of the following risk factors
within six months before entering the study (day 1): Unprotected vaginal or anal sex
with a known HIV infected person or a casual partner, engaged in sex work for money
or drugs, acquired a sexually transmitted disease, high risk partner currently or in
the previous six months.
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- A positive pre-study (screening and Day -21) drug/alcohol screen.
- History of regular alcohol consumption within 6 months of the study as defined in the
protocol.
- 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.
- Refrain from use of prescription or non-prescription drugs, 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.
- 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. If heparin is used during PK
sampling, subjects with a history or sensitivity to heparin or heparin-induced
thrombocytopenia should not be enrolled.
- The subject has an underlying skin disease or disorder (i. e. infection, inflammation,
dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria.
Mild cases of localized acne or folliculitis are not exclusionary.)
- The subject has a tattoo or other dermatological condition overlying the gluteus
and/or abdominal region which may interfere with interpretation of injection site
reactions.
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- Pregnant females as determined by positive serum or urine hCG test at screening or
prior to dosing.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated.
- The subject's systolic blood pressure is outside the range of 90-140mmHg, or
diastolic blood pressure is outside the range of 45-90mmHg or heart rate is outside
the range of 50-100bpm for female subjects or 45-100 bpm for male subjects.
- History of clinically significant cardiovascular disease.
