Infection, Human Immunodeficiency Virus
Conditions
Keywords
GSK2838232, HIV, repeated dose escalation, immediate release tablet, single dose escalation
Brief summary
GSK2838232 is a Human Immunodeficiency Virus (HIV) maturation inhibitor being developed for the treatment of HIV in combination with other antiretroviral therapy (ART). The primary objectives of this study are to investigate the safety, tolerability, and pharmacokinetics (PK) of single and repeat doses of GSK2838232. This study will be a double-blind, placebo-controlled, single and repeat dose escalation study. This study will be conducted in two Parts: single escalating doses (Part 1A and 1B), and repeated escalating once daily (QD) doses for 11 days (Part 2) of GSK2838232 co-dosed with RTV. During Part 1A, single doses of GSK2838232 (as of active pharmaceutical ingredient-powder in bottle \[API PiB\]) 50 milligrams (mg), 100mg and 200mg will be administered with RTV. Part 1B will evaluate the relative bioavailability of single doses of crystalline active pharmaceutical ingredient (API) Immediate Release Tablet (IR) tablets versus API PiB as reference, administered with RTV. In Part 2, multiple doses of GSK2838232 will be co-administered with RTV 100mg QD for 11 days as sequential dose cohorts. Maximum duration of study participation will be approximately 10 weeks.
Interventions
DRUGGSK2838232 PIB
GSK2838232 will be available as oral suspension for reconstitution, will be administered as 50, 100 and 200 mg in Part A and as 20, 50, 100 or 200 mg in Part B.
DRUGGSK2838232 IR1
GSK2838232 will be available as film-coated tablet for oral use
DRUGGSK2838232 IR2
GSK2838232 will be available as film-coated tablet for oral use
DRUGPlacebo PIB
Oral suspension of hydromellulose acetate succinate will be supplied as powder-in-bottle for reconstitution.
DRUGRitonavir
It is to be purchased by site. It will be white film-coated ovaloid tablets for oral administration.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Age: 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
, and 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) \>80milliliter/minute (mL/min) as determined by Cockcroft-Gault equation CLcr (mL/min) = (140 - age) \* weight (Wt) / (72 \* serum creatinine \[Scr\]) (times 0.85 if female) where age is in years, Wt is in kilogram (kg), and Scr is in units of milligram / decilitre (mg/dL);. * Body weight \>= 50.0 kg (110 pounds \[lbs.\]) for men and \>= 45.0kg (99lbs) for women and body mass index (BMI) * Male or females of non-reproductive potential: A female subject is eligible to participate if she is not pregnant \[as confirmed by a negative serum human chorionic gonadotrophin (hCG) test\], not lactating, and of non-reproductive potential which is defined as: 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 Post menopausal 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) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they 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. Vasectomy with documentation of azoospermia, or Male condom plus partner use of one of the contraceptive options following: 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 as described in Study protocol which includes compliance with the requirements and restrictions listed in the consent form and in protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration-time curve over the dosing interval (Ctau) of GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose.On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose | — |
| Maximum observed concentration (Cmax) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Concentration at 24 hours post dose (C24) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Last measurable concentration (Clast) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Time of occurence of Cmac (tmax) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Lag time before observation of drug concentrations in sampled matrix (tlag) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Terminal phase half life (t1/2) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Time of last observed quantifiable concentration (t-last) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Cmax of GSK2826232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose.On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose | — |
| Clast of GSK2826232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose.On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose | — |
| Number of participants with adverse events (AEs) | Approximately 10 weeks | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Safety as assessed by absolute values and change from Baseline in hematology parameters -Part 1 | Baseline (Day -1) and up to 10 weeks | Hematology parameters includes platelet count, red blood cells (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cells (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, reticulocyte count, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. Hematology parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit. |
| Safety as assessed by absolute values and change from Baseline in hematology parameters - Part 2 | Baseline (Day-1) and up to Day 31 for each cohort. | Hematology parameters includes platelet count, RBC count, MCV, neutrophils, WBC count (absolute), MCH, lymphocytes, reticulocyte count, MCHC, monocytes, hemoglobin, eosinophils, hematocrit and basophils. Hematology parameters will be evaluated at Day -1, Day 2, Day 4, day 8, Day 11, Day 14, Day 17, Day 31 for each cohort |
| Safety as assessed by absolute values and change from Baseline in clinical chemistry parameters -Part 1 | Baseline (Day -1) and up to 10 weeks | Clinical chemistry parameters includes blood urine nitrogen (BUN), potassium, aspartate aminotransferase (AST), Lipase, Creatinine, Sodium, alanine aminotransferase (ALT), total protein, glucose, chloride, alkaline phosphatase, albumin, magnesium, total carbon dioxide (CO2), total and direct bilirubin, uric acid, calcium, phosphorus and gamma-glutamyl transferase (GGT). Clinical chemistry parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit. |
| Safety as assessed by absolute values and change from Baseline in clinical chemistry parameters- Part 2 | Baseline (Day-1) and up to Day 31 for each cohort. | Clinical chemistry parameters includes BUN, potassium, AST, lipase, creatinine, sodium, ALT, total protein, glucose, chloride, alkaline phosphatase, albumin, magnesium, total CO2, total and direct bilirubin, uric acid, calcium, phosphorus and GGT. Clinical chemistry parameters will be evaluated at Day -1, Day 2, Day 4, day 8, Day 11, Day 14, Day 17, Day 31 for each cohort |
| Safety as assessed by absolute values and change from Baseline in urinalysis parameters-Part 1 | Baseline (Day -1) and up to 10 weeks | Urinalysis parameters includes specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination. Urinalysis parameters will be evaluated at Day -2, Day -1, Day 2, Day 4, Day 14 of each visit. |
| Safety as assessed by absolute values and change from Baseline in urinalysis parameters-Part 2 | Baseline (Day-1) and up to Day 31 for each cohort. | Urinalysis parameters includes specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination. Urinalysis parameters will be evaluated at Day -1, Day 2, Day 4, Day 11, Day 14, Day 17, Day 31 for each cohort |
| Safety as assessed by Blood pressure-Part 1 | 10 weeks | Systolic and diastolic blood pressure will be measured on Day 1, pre-dose (triplicate) and 1, 2, 4, 6, 8, 12, 24, 48, and 72hr post-dose during each visit. |
| Safety as assessed by Heart rate -Part 1 | 10 weeks | Heart rate will be measured on Day 1, pre-dose (triplicate) and 1, 2, 4, 6, 8, 12, 24, 48, and 72hr post-dose during each visit. |
| Safety as assessed by Blood pressure-Part 2 | 31 days in each cohort | Systolic and diastolic blood pressure will be measured on Day -1, Day 1 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose and at follow up during each cohort. |
| Safety as assessed by Heart rate -Part 2 | 31 days in each cohort | Heart rate will be measured on Day -1, Day 1 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11 at pre dose (triplicate), and 1hr, 4hr, 24hr, 48hr and 72hr post dose and at follow up during each cohort. |
| Safety as assessed by Electrocardiogram (ECG) parameters-Part 1 | Up to 10 weeks | 12-lead ECG will be conducted pre-dose on Day 1 (triplicate), and 1, 2, 4, 6, 8, 12, 24, 48 72 hour post dose. |
| Safety as assessed by ECG parameters-Part 2 | 31 days in for each cohort | A single 12-Lead ECG will be conducted at screening and Day -1, Day 1 at pre dose (triplicate), and 1 hour, 12 hour, 24hour, 48 hour and 72 hour post dose, Day 5, Day 8 and Day 11 at pre dose (triplicate), and 1 hr, 12 hour, 24 hour, 48 hour, and 72 hour post dose and at follow up during each cohort. |
| Area under the concentration-time curve from time zero (pre-dose) to 24 hours (AUC[0-24]), Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-inf]) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit | — |
| Apparent oral clearance (CL/F) for single dose GSK2838232 in Part 1A | Plasma samples will be collected pre-dose (within 15 minutes [min]prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit during Part 1A. | — |
| Area under the concentration-time curve over the dosing interval (AUC[0 tau]) for repeated dose GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose.On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose | — |
| Apparent oral clearance (CL/F) for repeated dose GSK2838232 in Part 2 | Plasma samples will be collected on Day 11; pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post dose. | — |
| Tmax for repeated dose GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose | — |
| Tlag for repeated dose GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose | — |
| T1/2 for repeated dose GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose | — |
| Tlast for repeated dose GSK2838232 in Part 2 | Day 1; pre-dose (within 15 min prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 hr post dose. On Day 11; pre-dose (within 15 min prior to dosing) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96,120 and 144 hr post dose | — |
Secondary
| Measure | Time frame |
|---|---|
| AUC (0-inf) in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit |
| Cmax in Part 1 | Plasma samples will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours post-dose at each study visit |
| AUC(0-tau) in Part 2 | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
| Cmax in Part 2 | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
| Pre-dose GSK2838232 plasma concentrations on Day 2-11 in Part 2 | Up to Day 11 |
| Accumulation ratios (Ro) for AUC (0-tau) | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
| Accumulation ratios (Ro) for Cmax | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
| Accumulation ratios (Ro) for Ctau (where tau is 24 hours) | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
| Ctau in Part 2 | Day 1 pre-dose; 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24 hr post dose. Days 3-10 pre-dose; Day 11; pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hr post dose; all pre-dose within 15 min prior to dosing |
Countries
United States
Outcome results
None listed