Safety and efficacy study of GSK2838232 in Human Immunodeficiency Virus (HIV)-1 infected adults
Trial overview
Maximum decline from Baseline (Day 1) in plasma HIV-1 ribonucleic acid (RNA)
Timeframe: Baseline (Day 1) and up to Day 11
Number of subjects with any adverse event (AE) and any serious adverse event (SAE)
Timeframe: Up to 3 Weeks
Safety as assessed by concurrent medications during the treatment period
Timeframe: Up to 3 Weeks
Number of subjects with abnormal hematology laboratory tests
Timeframe: Up to 3 Weeks
Number of subjects with abnormal clinical chemistry laboratory tests
Timeframe: Up to 3 Weeks
Number of subjects with abnormal routine urinalysis laboratory tests
Timeframe: Up to 3 Weeks
Number of subjects with abnormal electrocardiogram (ECG) findings
Timeframe: Up to 3 Weeks
Systolic and diastolic blood pressure (BP) as a measure of safety
Timeframe: Up to 3 Weeks
Pulse rate as a measure of safety
Timeframe: Up to 3 Weeks
Body temperature as a measure of safety
Timeframe: Up to 3 Weeks
Area under the plasma concentration-time curve (AUC) from time zero (Pre-dose) to over 24 hours time (AUC[0-24]) of GSK2838232 following dose administration on Day 1
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1
Maximum observed plasma concentration (Cmax) and concentration at 24 hours post dose (C24) of GSK2838232 on Day 1
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1.
Time to maximum observed concentration (Tmax) of GSK2838232 on Day 1
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1
Absorption lag time (Tlag) of GSK2838232 on Day 1
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1
Area under the concentration-time curve over the dosing interval (AUC[0-tau]) of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Pre dose concentration (C0) of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Concentration at the end of the dosing interval (Ctau) of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Cmax of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Tmax of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Terminal half-life (t1/2) of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Apparent oral clearance (CL/F) of GSK2838232 on Day 10
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Relationship of GSK2838232 PK parameter AUC(0-tau) (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11)
Timeframe: Up to 3 weeks
Relationship of GSK2838232 PK parameters Cmax (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11)
Timeframe: Up to 3 weeks
Relationship of GSK2838232 PK parameter Ctau (Day 10) with respect to change from baseline in HIV-1 RNA (Day 11)
Timeframe: Up to 3 weeks
Change from baseline in cluster of differentiation 4+ (CD4+) cell count
Timeframe: Up to Day 11
Relationship of GSK2838232 PK parameter Cmax (Day 10) with respect to change from baseline in CD4+ cell count
Timeframe: PD: Baseline (Day 1) and Day 11; PK: pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post- am dose on Day 1 and Day 10; pre dose on the mornings of Days 3, 4, 5, 8 and 9 and a single sample on Days 12 and 14.
Relationship of GSK2838232 PK parameter Ctau (Day 10) with respect to change from baseline in CD4+ cell count
Timeframe: PD: Baseline (Day 1) and Day 11; PK: pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post- am dose on Day 1 and Day 10; pre dose on the mornings of Days 3, 4, 5, 8 and 9 and a single sample on Days 12 and 14.
Number of participants with the emergence of drug resistance mutations
Timeframe: Baseline (Day 1) and Day 11
GSK2838232 Day 10 AUC(0-tau) compared to Day 1 AUC(0-24) to estimate accumulation ratio (R)
Timeframe: PK samples will be taken pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-am dose on Day 1 and Day 10. Pre dose PK samples will be taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
GSK2838232 Day 10 Cmax and Ctau compared to Day 1 Cmax and C24 to estimate accumulation ratio (R), respectively
Timeframe: PK samples will be taken pre dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-am dose on Day 1 and Day 10. Pre dose PK samples will be taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Pre-morning dose concentrations (C0) of GSK2838232 from Day 2 to Day 11
Timeframe: Pre dose on Days 1, 3, 4, 5, 8, 9 and 10
Day 1 AUC(0-24) and at different doses levels (20, 50, 100 and 200 milligram [mg]) for the assessment of dose proportionality
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Day 10 AUC(0-tau) at different doses levels (20, 50, 100 and 200 milligram [mg]) for the assessment of dose proportionality
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Day 1 and Day 10 Cmax
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Day 1 C24
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Day 10 Ctau
Timeframe: PK samples will be taken at pre dose and post dose at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours on Day 1 and Day 10. Pre dose PK samples will be taken on Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
Participation criteria
- Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
- Healthy (other than HIV infection) male or female as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring, defined as no other chronic medical conditions and taking no chronic medications.
- Alanine aminotransferase (ALT) and bilirubin (BIL) >1.5 x upper limit of normal (ULN), isolated BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35 percent.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); hepatitis B virus (HBV) and/or hepatitis C virus (HCV) positive.
- Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
- Healthy (other than HIV infection) male or female as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring, defined as no other chronic medical conditions and taking no chronic medications.
- 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 agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- A creatinine clearance >80 mL/minute as determined by Cockcroft-Gault equation creatinine clearance CLcr (mL/minute) = (140 – age) x weight (Wt) divided by (72 x serum creatinine [Scr]) (times 0.85 if female) where age is in years, Wt is in kilogram (kg), and Scr is in units of mg/decilitre (dL).
- Confirmed HIV positive; CD4+ cell count >=350 cells/millimetre (mm)^3 and plasma HIV-1 RNA >=5000 copies/mL at screening.
- No current and no prior ART.
- Body weight >=50 kg (110 pound [lbs.]) for men and >=45 kg (99 lbs) for women and body mass index (BMI) within the range 18.5-31.0 kg/meter^2 (inclusive)
- A female subject of reproductive or 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 at screening and prior to first dose), not lactating, and at least one of the following conditions applies: females of reproductive potential may only be enrolled if they are using two forms of complementary contraception, which must include one barrier method. They will be counselled on safer sex practices; there is no definitive drug-drug interaction (DDI) information with GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of contraception will be required; fertile females, who have an established, long-term lifestyle of sexual abstinence, or only same sex partners, require no other means of birth control. 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. 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; vasectomy with documentation of azoospermia; male condom plus partner use of one of the contraceptive options as: Contraceptive sub dermal implant including a <1 percent rate of failure per year; intrauterine device or intrauterine system including a <1 percent rate of failure per year; oral contraceptive, either combined or progestogen alone or 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.
- Alanine aminotransferase (ALT) and bilirubin (BIL) >1.5 x upper limit of normal (ULN), isolated BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35 percent.
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones); hepatitis B virus (HBV) and/or hepatitis C virus (HCV) positive.
- Subjects who have any other chronic medical condition, including cardiovascular (CV), respiratory, neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or dermatologic.
- Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
- 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 GSK medical monitor the medication will not interfere with the study procedures or compromise subject safety.
- History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
- Smoking is an exclusion criteria for this study. Subject having urinary cotinine levels indicative of smoking at screening.
- Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion criteria.
- 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 medical monitor, contraindicates their participation.
- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
- Screening or Baseline cardiac troponin I greater than the 99 percent cutoff (>0.045 nanogram [ng]/mL by the Dimension Vista cardiac troponin [CTN] I assay).
- A positive pre-study drug/alcohol screen.
- Prior history of receiving an HIV maturation inhibitor
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
- 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.
- Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
- Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
- An active Center for Disease Control and Prevention (CDC) category C disease except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
- Treatment with any vaccine within 30 days prior to receiving study medication.
- Exclusion criteria for 24-hour screening holter: any symptomatic arrhythmia (except isolated extra systoles); sustained cardiac arrhythmias (such as atrial fibrillation, flutter or supraventricular tachycardia [>=10 seconds]); non-sustained or sustained ventricular tachycardia (defined as >=3 consecutive ventricular ectopic beats); any conduction abnormality including but not specific to left or complete bundle branch block, atrioventricular (AV) block, high grade or complete heart block Wolff-Parkinson-White (WPW) syndrome etc.; sinus pauses >3 seconds.
- Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): heart rate <45 and >100 beats per minute (bpm) for males, and <50 and >100 bpm for females; PR Interval <120 and >220 milliseconds (msec); QRS duration <70 and >120 msec; corrected QT (QTc) interval >450 msec; Evidence of previous myocardial infarction (Does not include ST segment changes associated with repolarization); any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block [2nd degree or higher], WPW syndrome); sinus pauses >3 seconds; any significant arrhythmia which, in the opinion of the principal investigator or GSK medical monitor, will interfere with the safety for the individual subject; non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular ectopic beats).
Trial location(s)
Study documents
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.