Infection, Human Immunodeficiency Virus
Conditions
Keywords
Ritonavir, Safety, Continuation Single Dose Escalation, GSK2838232
Brief summary
This study investigates the safety, tolerability and PKs of GSK2838232 with and without Ritonavir, and to evaluate different formulations of GSK2838232 in healthy subjects. This study will evaluate higher single and RTV boosted doses to support continued clinical development of GSK2838232 at clinically relevant doses, and subsequently in those infected with HIV in a dose ranging phase 2 study. The study is conducted in 2 parts: Part A and Part B, study Part A and Part B may be conducted in parallel. Approximately 20 healthy subjects will be enrolled into the study, 8 in Part A and 12 in Part B. Part A is a double-blind, randomized, placebo-controlled, 4-period, single dose escalation design. Subjects will be randomized 3:1 to receive GSK2838232 or placebo. Subjects randomized to placebo will receive placebo in all four periods. Following completion of Period 2 PK assessments at 96hr post-dose, subjects will begin daily dosing of RTV 100mg for a total of 26 days. Part B is a randomized, open-label, unbalanced, 3-period, cross-over design; subjects will be randomized 1:1 to each sequence. The relative bioavailability of single 100mg doses of powder in a bottle (PIB) active pharmaceutical ingredient (API) of GSK2838232 versus PIB spray-dried dispersion (SDD) will be assessed. A single dose of GSK2838232 will co-administered on the 10th day of RTV dosing; RTV dosing will continue for an additional 4 days (total of 14 days). Subjects will have a screening visit within 30 days prior to first dose and a follow-up visit 7-14 days after the last dose.
Interventions
DRUGGSK2838232 PIB (SDD)
GSK2838232 will be available as oral suspension dispersion in hydromellulose acetate succinate bulk powder/10, 20, 50, 200 and 500 mg in part A, while 100 mg in Part B. GSK2838232 will be administered orally once daily (QD) as single doses in the morning following an overnight fast of at least 10 hours.
DRUGGSK2838232 PIB (API)
GSK2838232 will be available as oral suspension bulk powder/100 mg in Part B. GSK2838232 will be administered orally QD as single doses in the Morning following an overnight fast of at least 10 hours.
DRUGPlacebo
Matching placebo of Suspension to active dose, administered orally QD as single doses in the morning 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. Ritonavir will be administered orally, once daily in Part A, Period 3 Days 1-14 and Period 4 from Days 1-12 and will be administer orally once daily in Part B for 9 days prior to dosing in Period 3 and on Days 10-14 of Period 3.
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 |
|---|---|---|
| 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. |
| 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. |
| Composite PK profile of GSK2838232, , with and without RTV for Part A and Part B | During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 - Day 13 (Period 4). During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3) | PK assessments will include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC 0-infinity), area under the concentration-time curve over the dosing interval (AUC 0-t), concentration at 24 hours post dose (C24), oral clearance (CL/F), maximum observed concentration (Cmax), last quantifiable concentration (Clast), time of occurrence of Cmax (tmax), time of last observed concentration (tlast), terminal phase half-life (t1/2), and time of first quantifiable concentration (tlag). |
| Composite PK profile of GSK2838232 to assess the relative bioavailability of the PIB API suspension versus PIB SDD suspension (Part B) | During Part B: Day 1 to Day 4 (Period 1 & 2), Day 10-Day 14 (Period 3) | PK assessments will include: GSK2838232 AUC(0-infinity), Cmax |
| Composite PK profile of GSK2838232 to assess single dose proportionality of GSK2838232 with and without steady-state RTV (Part A) | During Part A: Day 1 to Day 5 (Period 1 & 2), Day 10-Day 15 (Period 3), Day 8 - Day 13 (Period 4). | PK assessments will include: GSK2838232 AUC(0 - infinity), AUC(0-t) and Cmax |
Countries
United States
Outcome results
None listed