Infection, Human Immunodeficiency Virus
Conditions
Keywords
Single Dose Escalation, Repeat Dose Escalation, GSK2838232, Ritonavir
Brief summary
The proposed study, 200207 is a double blind, placebo controlled, single and repeat dose escalation study to investigate the safety, tolerability and PK of GSK2838232 alone and when co-administered with RTV 100 milligram (mg) Once daily (QD). This study will enable future clinical development of GSK2838232 in healthy subjects and in a Phase IIa proof of concept study in Human Immunodeficiency Virus (HIV) infected patients. This study is a single and repeat dose escalation study and will be conducted as two Parts. Part A will evaluate GSK2838232 20 mg and 50 mg administered QD for 8 days and Part B will evaluate GSK2838232 10 mg, 20 mg, and 50 mg, co-administered with RTV 100 mg, QD for 11 days. The extended period of dosing is to account for the longer terminal phase half-life of GSK2838232 when given with RTV. Dose cohorts will be enrolled sequentially; enrollment into a cohort will commence following review of interim PK and safety data from at least 4 subjects in the preceding cohort. Subjects in both parts will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose. Maximum duration of study participation will be approximately 7 weeks. Approximately 40 healthy subjects will be enrolled, 8 subjects/cohort. Subjects will be randomized 3:1 to receive GSK2838232 or placebo.
Interventions
DRUGGSK2838232
GSK2838232 will be available as oral suspension dispersion in hydromellulose acetate succinate bulk powder/10, 20 and 50 mg which is to be administered orally QD for 8 days (Part A) or 11 days (Part B), morning dose, following an overnight fast of at least 10 hours
DRUGPlacebo
Matching placebo of Suspension to active dose, administered orally QD for 8 days (Part A) or 11 days (Part B), morning dose, following an overnight fast of at least 10 hours
DRUGRitonavir
Ritonavir will be available as white film-coated ovaloid tablets of 100 mg tablet/100mg to be administer orally, QD
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 55 years of age inclusive, at the time of signing the informed consent * 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. * 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. * A Creatinine clearance (CLcr) \>80 millilitre per minute (mL/min) as determined by Cockcroft-Gault equation where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in units of milligram / decilitre (mg/dL); CLcr (mL/min) = (140 - age) \* Wt / (72 \* Scr) (times 0.85 if female). * Body weight \>= 50 kilogram (kg \[110 pounds {lbs}\]) for men and \>= 45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kilogram per meter square kg/m\^2 (inclusive) * Male or Female; Female subject of non-reproductive potential : is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: 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; Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until one week after the last dose of study medication. a) Vasectomy with documentation of azoospermia, b) Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant that meets the standard operating procedure (SOP) effectiveness criteria including a \<1% rate of failure per year, as stated in the product label, Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1% rate of failure per year, as stated in the product label, Oral Contraceptive, either combined or progestogen alone Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. * Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite pharmacokinetic profile of GSK2838232, , with and without RTV for Part A and Part B | Up to 144 hours post dose of Day 11 | PK assessments will include: On Day 1: Area under the concentration-time curve over the dosing interval (AUC\[0 tau\], Maximum observed concentration (Cmax), Pre-dose (trough) concentration at the end of the dosing interval (Ctau), time of occurrence of Cmax (tmax), lag time before observation of drug concentrations in sampled matrix (tlag), on Day 8 (Part A) or Day 11 (Part B): AUC(0-tau), Cmax, Ctau, tmax, tlag, terminal phase half-life (t1/2), last observed quantifiable concentration (Clast), time of last quantifiable concentration (tlast), Apparent clearance following oral dosing (CL/F). |
| Adverse events (AEs) assessments | Up to approximately 7 weeks | Safety was assessed by monitoring AE and serious AEs (SAE). AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact |
| Safety assessed by laboratory evaluations | Up to approximately 7 weeks | Laboratory evaluations will include hematology, clinical chemistry, urinalysis assessments |
| Vital signs assessments | Up to approximately 7 weeks | Vital signs will be measured in semi-supine position after 10 minutes rest and will include systolic and diastolic blood pressure and pulse rate. |
| Electrocardiogram (ECG) parameters assessments | Up to approximately 7 weeks | Triplicate OR Single 12-lead ECGs will be obtained at each timepoint during the study after a 10 minute rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite pharmacokinetic profile to assess accumulation of GSK2838232 with and without RTV | Up to Day 17 | Accumulation will also be evaluated for each treatment by determining the ratio of Day 8 (Part A) or Day 11 (Part B) to Day 1 AUC(0 tau) (ratio of \[AUC{0-tau}\]), Cmax (R\[Cmax\]), and Ctau (R\[Ctau\]) |
| Pharmacokinetic profile to assess time to steady-state of GSK2838232 with and without RTV | Up to Day 17 | Pre-dose concentrations on Day 2-8 (Part A) and Day 2-11 (Part B) |
| Pharmacokinetic profile to compare the pharmacokinetics of GSK2383232 with and without RTV | Up to Day 17 | GSK2838232 AUC(0-tau), Cmax, and Ctau |
| Composite pharmacokinetic profile of GSK2838232 to dose proportionality with and without RTV | Up to Day 17 | GSK2838232 AUC(0-tau), Cmax, Ctau |
Countries
United States
Outcome results
None listed