Clinical trial NCT02354937 (phase 1, status: completed)
Conditions: infection, human immunodeficiency virus, hiv infections
ICD codes: Z21, Z21
Drugs: gsk1265744 30 mg
SMILES: C[C@H]1CO[C@@H]2CN3C=C(C(=O)NCC4=CC=C(F)C=C4F)C(=O)C(O)=C3C(=O)N12
Eligibility criteria:

        Inclusion Criteria:

        For Renally Impaired Subjects (Cohort 1)

          -  Between 18 and 70 years of age inclusive, at the time of signing the informed consent.

          -  Severe renal impairment, defined as individuals with a creatinine clearance of < 30
             milliliter (mL)/minute (min) as determined by a 24-hour urine creatinine clearance
             done at screening.

          -  Renally impaired subjects must have clinical laboratory test results that are
             considered clinically stable in the opinion of the principal investigator. Subjects
             with laboratory parameters outside the reference range may be included if, in the
             opinion of the investigator and medical monitor, these findings will not interfere
             with the study or introduce additional safety risk to the subject.

          -  Body weight >= 50 kilograms (kg) and body mass index (BMI) within the range 19 - 38
             kg/ meter (m)^2 (inclusive)

          -  Male or female A female subject is eligible to participate if she is not pregnant (as
             confirmed by a negative serum hCG test), not lactating. Women of child-bearing
             potential must be willing to practice acceptable methods of birth control.
             Pre-menopausal females defined as 12 months of spontaneous amenorrhea with one of the
             following: Documented tubal ligation, hysteroscopic tubal occlusion procedure with
             follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Bilateral
             Oophorectomy. Postmenopausal

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

        For Healthy Subjects (Cohort 2)

          -  Healthy control subjects will be matched for age +/-10 years to subjects in the renal
             impairment cohort but must also remain in the age range:

        Between 18 and 70 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.

          -  Healthy subjects are defined as individuals with a creatinine clearance >= 90 mL/min
             as determined by a 24-hour urine creatinine clearance done at screening.

          -  Healthy control subjects will be matched for BMI +/- 25% to subjects in the renal
             impairment cohort but must also remain in the range of:

        Body weight >=50 kg and BMI within the range 19 - 38 kg/m^2 (inclusive)

          -  Male or female A female subject is eligible to participate if she is not pregnant (as
             confirmed by a negative serum hCG test), not lactating. Women of child-bearing
             potential must be willing to practice acceptable methods of birth control.
             Pre-menopausal females defined as 12 months of spontaneous amenorrhea with one of the
             following: Documented tubal ligation, hysteroscopic tubal occlusion procedure with
             follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Bilateral
             Oophorectomy. Postmenopausal

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

        Exclusion Criteria:

        For Renally Impaired Subjects (Cohort 1)

          -  Alanine aminotransferase (ALT) and bilirubin >1.5x upper limit of normal (ULN)
             (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%).

          -  Current or chronic history of liver disease (including acute or chronic hepatitis B
             and C), or known hepatic or biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones).

          -  Corrected QT Interval (QTc) > 480 millisecond (msec)

        NOTES:

        The QTc is the QT interval corrected for heart rate according to Fridericia's formula
        (QTcF) machine-read or manually over-read.

        For purposes of data analysis, QT interval corrected for heart rate according to Bazette's
        formula (QTcB), QTcF, or a composite of available values of QTc will be used as specified
        in the Reporting and Analysis Plan (RAP).

          -  Systolic blood pressure outside the range of 90-160mmHg, or diastolic blood pressure
             outside the range of 45-95 millimeter of mercury (mmHg), or heart rate outside the
             range of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male
             subjects in the presence (or absence) of stabilized antihypertensive treatment.

          -  Evidence of previous myocardial infarction in the past 12 months or any clinically
             significant active cardiovascular disease that, in the opinion of the investigator,
             could interfere with the safety of the subject.

          -  Any clinically significant conduction abnormality (not including left or right
             complete bundle branch block) such as atrioventricular (AV) block [Mobitz type 2
             second degree or higher AV block], Wolf Parkinson White [WPW] syndrome or other
             aberrant pathways.

          -  Sinus Pauses >3 seconds.

          -  Any significant arrhythmia which, in the opinion of the principal investigator and GSK
             medical monitor, will interfere with the safety of the individual subject.

          -  Non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular
             ectopic beats).

          -  Signs of active infection that in the opinion of the investigator would interfere with
             the completion of study procedures or the safety of the subject.

          -  Fluctuating or rapidly deteriorating renal function, or currently receiving
             hemodialysis, peritoneal dialysis, or any other renal replacement therapy or other
             medical procedure that serves as a surrogate for renal function. Assessment of the
             stability of the subject's renal function will be determined by the investigator.

          -  History of renal transplant.

          -  History of inflammatory bowel disease.

          -  History of cholecystectomy or other gastrointestinal surgery (except appendectomy more
             than three months prior to study).

          -  History of peptic ulceration or pancreatitis within the preceding 6 months of
             screening.

          -  Any other medical condition (except renal impairment) which, in the judgment of the
             investigator and medical monitor, could jeopardize the integrity of the data derived
             from that subject or the safety of the subject. This includes but is not limited to
             any pre-existing condition that interferes with normal gastrointestinal anatomy or
             motility that could interfere with the absorption, metabolism, and/or excretion of the
             study drug.

          -  The use of any concurrent prohibited medications

          -  Subjects with a change in dose regimen of medically required medication within the 2
             weeks prior to dosing.

          -  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 millilitre [mL]) of beer, 5 ounces
        (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

          -  Inability or unwillingness to comply with lifestyle and/or dietary restrictions

          -  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. In addition, if heparin is used during
             PK sampling, subjects with a history of sensitivity to heparin or heparin-induced
             thrombocytopenia should not be enrolled.

          -  A pre-study screen positive for alcohol, cocaine, amphetamines, phencyclidine (PCP),
             and/or barbiturates. A positive drug screen is permitted if it is due to a prescribed
             medication, provided that medication is not a Prohibited Medication.

          -  A positive test for HIV antibody.

          -  A creatinine clearance <15 mL/min as determined by 24-hour urine collection.

          -  A clinically significant elevation in serum potassium at screening, that in the
             opinion of the investigator and GSK Medical Monitor will interfere with the study or
             introduce additional safety risk to the subject.

          -  A serum sodium level =<125 milliequivalent (mEq) /liter (L) at screening

          -  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).

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

        For Healthy Subjects (Cohort 2)

          -  ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35%).

          -  Current or chronic history of liver disease (including acute or chronic Hepatitis B
             and C), or known hepatic or biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones)

          -  QTc > 450 msec

        NOTES:

        The QTc is the QT interval corrected for heart rate according to Fridericia's formula
        (QTcF) machine-read or manually over-read.

        For purposes of data analysis, QTcB, QTcF, or a composite of available values of QTc will
        be used as specified in the RAP.

          -  Systolic blood pressure outside the range of 90-145 mmHg, or diastolic blood pressure
             outside the range of 45-95mmHg or heart rate outside the range of 50-100 bpm for
             female subjects or 45-100 bpm for male subjects.

          -  Evidence of previous myocardial infarction or any clinically significant active
             cardiovascular disease that, in the opinion of the investigator, could interfere with
             the safety of the subject.

          -  Any clinically significant conduction abnormality (not including left or right
             complete bundle branch block) such as AV block [Mobitz type 2 second degree or higher
             AV block], Wolf Parkinson White [WPW] syndrome or other aberrant pathways.

          -  Sinus Pauses > 3 seconds.

          -  Any significant arrhythmia which, in the opinion of the principal investigator and GSK
             medical monitor, will interfere with the safety for the individual subject.

          -  Non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular
             ectopic beats).

          -  Signs of active infection that in the opinion of the investigator would interfere with
             the completion of study procedures or the safety of the subject.

          -  Fluctuating or deteriorating renal function or creatinine clearance (CLCR) < 90 mL/min
             (determined by 24-hour urine collection) at screening. Assessment of the stability of
             the subject's renal function will be determined by the investigator.

          -  Subjects with a pre-existing condition interfering with normal gastrointestinal
             anatomy or motility, hepatic and/or renal function, that could interfere with the
             absorption, metabolism, and/or excretion of the study drugs.

          -  History of inflammatory bowel disease.

          -  History of cholecystectomy or other gastrointestinal surgery (except appendectomy more
             than three months prior to study).

          -  History of peptic ulceration or pancreatitis within the preceding 6 months of
             screening.

          -  The use of any concurrent prohibited medications.

          -  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 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.

          -  A history of regular use of tobacco- or nicotine-containing products within 30 days
             prior to screening.

          -  Inability or unwillingness to comply with lifestyle and/or dietary restrictions

          -  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. In addition, if heparin is used during
             PK sampling, subjects with a history of sensitivity to heparin or heparin-induced
             thrombocytopenia should not be enrolled.

          -  Presence of hepatitis B surface antigen (or positive hepatitis B core antibody with
             negative hepatitis B surface antibody) or positive hepatitis C antibody test result at
             any time prior to first dose of study treatment.

          -  A pre-study screen positive for alcohol, cocaine, amphetamines, PCP, and/or
             barbiturates.

          -  A positive test for HIV antibody.

          -  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).

          -  Unwillingness or inability to follow the procedures outlined in the protocol.