Overview

Safety and Efficacy Study of GSK2838232 in Human Immunodeficiency Virus (HIV)-1 Infected Adults

Status:
Completed
Trial end date:
2018-04-23
Target enrollment:
0
Participant gender:
Male
Summary
GSK2838232 is a novel HIV-1 maturation inhibitor (MI) that is being developed for the treatment of HIV-1 infection in combination with other antiretroviral therapy (ART). This study will be a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose study. This study will be conducted in two Parts (Part A and Part B) consisting single daily doses of GSK2838232 and Cobicistat from Day 1 to Day 10. This proof of concept open-label study will be aimed to characterize the acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral activity, and safety of GSK2838232/cobi administered across a range of doses over 10 days in HIV-1 infected patients. A cohort of 10 subjects will be studied in Part I followed by interim (go/no-go) analysis of Part A data. On completion of an interim analysis of part A data, further cohorts of 8 subjects will then be studied in Part B in a parallel design in two or more cohorts (depending upon the data obtained in Part A). Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled during the study. 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 6 Weeks.
Phase:
Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
GlaxoSmithKline
Treatments:
Cobicistat
GSK-2838232
Criteria
Inclusion 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.

- 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.

Exclusion Criteria:

- 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).