An Study to Investigate the Recovery, Excretion, and Pharmacokinetics of 14C-GSK1265744 Administered as a Single Oral Dose and a Study to Describe the Pharmacokinetics of a Supratherapeutic Dose of GSK1265744 in Healthy Adult Subjects

Study Description

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Brief Summary:

This will be a two-part study in healthy adults. Part A is a phase 1, non-randomized, open label, single-dose, single-centre mass balance study utilizing a radiolabeled dose to investigate the recovery, excretion, and pharmacokinetics of oral GSK1265744 in a cohort of 6 healthy adult male subjects. Subjects will undergo a pre-study screening visit within 30 days of the first dose and those who successfully pass pre-study assessments and meet eligibility criteria will be enrolled into the study to receive the equivalent of a 30 mg dose of GSK1265744 as an oral solution, containing approximately 70 microcuries (mcg Ci) [0.96 millisieverts (mSv)] of radioactivity under fasted conditions. Blood, urine and fecal samples will be collected for a maximum of 504 hours (21 days) following study drug administration. In Part B, approximately 10 healthy male and female subjects will be enrolled to evaluate the single-dose safety, tolerability and PK of supratherapeutic dose of GSK1265744 150 mg compared with placebo. Each subject will receive a single dose of GSK1265744 150 mg or placebo on Day 1 under fasting conditions in the morning. Blood, urine and fecal samples will be collected for 336 hours (14 days) following dosing.

Condition or disease	Intervention/treatment	Phase
HIV-associated Lipodystrophy Syndrome	Drug: GSK1265744B (sodium salt) containing 14C-GSK1265744B; Drug: 150 mg GSK1265744B; Drug: Placebo	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	16 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	An Open Label, Non-Randomized, Mass Balance Study to Investigate the Recovery, Excretion, and Pharmacokinetics of 14C-GSK1265744 Administered as a Single Oral Dose and a Placebo-Controlled, Randomized Study to Describe the Pharmacokinetics of a Supratherapeutic Dose of GSK1265744 in Healthy Adult Subjects
Study Start Date :	May 2013
Actual Primary Completion Date :	July 2013
Actual Study Completion Date :	July 2013

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Part A: 14C-GSK1265744 Arm; Each subject will receive a single 30 mg oral solution dose of GSK1265744 containing 14C-GSK1265744 of approximately 70 mcgCi (0.96 MSv) of radioactivity.	Drug: GSK1265744B (sodium salt) containing 14C-GSK1265744B; A white to slightly colored nonsterile crystalline powder for oral solution
Experimental: Part B: GSK1265744 Arm; In Part B - 8 subjects will be randomised to receive a single dose of GSK1265744 150 mg	Drug: 150 mg GSK1265744B; This is GSK1265744B (sodium salt of GSK1265744), lactose monohydrate, Microcrystalline cellulose, hypromellose, sodium lauryl sulfate, croscarmellose sodium, magnesium stearate, Opadry film-coating, white OY-S-28876 tablet
Placebo Comparator: Part B: Placebo Arm; In Part B - 2 subjects will be randomised to receive a single dose of placebo	Drug: Placebo; Microcrystalline cellulose, Opadry film-coating, white OY-S-28876 tablet

Outcome Measures

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Primary Outcome Measures :

1. Part A: Percent recovery of total radioactive [14C] GSK1265744 in urine and feces. [ Time Frame: Up to 21 days ]
   Measurement of total radioactivity present in individual samples (plasma, urine, and feces) collected for a minimum of 336 hours (14 days) post dose up to a maximum of 504 hours (21 days).
2. Part A: Composite of plasma GSK1265744 PK parameters to access total radioactivity in blood [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 288, 312 and 336 hours post dose. ]
   The PK parameters will include: Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a profile [AUC (0-t)], Area under the concentration-time curve from time zero (predose) extrapolated to infinite time [AUC (0-infinity)], Maximum observed concentration (Cmax), Time of occurrence of Cmax (tmax), Terminal phase elimination rate constant (lambda z), apparent terminal phase half-life (t1/2), and oral clearance (CL/F) of plasma GSK1265744 and total radioactivity in plasma and blood following single dose.
3. Part B: Number of participants with the use of concurrent medication as a measure of safety and tolerability [ Time Frame: Up to 14 days ]
4. Part B: Absolute values and changes over time of hematology as a measure of safety and tolerability. [ Time Frame: Up to 14 days ]
5. Part B: Absolute values and changes over time of clinical chemistry as a measure of safety and tolerability. [ Time Frame: Up to 14 days ]
6. Part B: Absolute values and changes over time of urinalysis as a measure of safety and tolerability. [ Time Frame: Up to 14 days ]
7. Part B: Absolute values and changes over time of vital signs as a measure of safety and tolerability. [ Time Frame: Up to 14 days ]
8. Part B: Absolute values and changes over time of ECG intervals and ECG rhythm as a measure of safety and tolerability. [ Time Frame: Up to 14 days ]
9. Part B: Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Up to 14 days ]
10. Part B: Composite of plasma GSK1265744 PK parameters [ Time Frame: Up to 14 days ]
    Plasma GSK1265744PK parameters following a single-dose administration of 150 mg under fasted conditions will include: AUC (0-t)], AUC (0-infinity), Cmax, tmax, lambda z, t1/2, and oral clearance (CL/F) of plasma

Secondary Outcome Measures :

1. Part A: Blood: Plasma ratio of total drug-related material (radioactivity) [ Time Frame: Up to 21 days ]
   The blood: plasma ratio of total radioactivity (Cb/Cp) will be calculated at each time point by Clinical Statistics at GSK.
2. Part A: Percent of total radioactivity associated with red blood cells [ Time Frame: Up to 21 days ]
   Percent of total radioactivity associated with red blood cells will be calculated based on radioactivity concentration in plasma and blood and hematocrit count.
3. Part A: Absolute values and changes over time of hematology as a measure of safety and tolerability. [ Time Frame: Up to 21 days ]
4. Part A: Absolute values and changes over time of clinical chemistry as a measure of safety and tolerability. [ Time Frame: Up to 21 days ]
5. Part A: Absolute values and changes over time of urinalysis as a measure of safety and tolerability. [ Time Frame: Up to 21 days ]
6. Part A: Absolute values and changes over time of vital signs as a measure of safety and tolerability. [ Time Frame: Up to 21 days ]
7. Part A: Absolute values and changes over time of ECG intervals and ECG rhythm as a measure of safety and tolerability. [ Time Frame: Up to 21 days ]
8. Part A: Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Up to 21 days ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Part A: Male subjects between 30 and 55 years of age at the time of signing the informed consent.
• Part B: Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.
• Parts A and B male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in protocol. This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication.
• Part B: A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, bilateral salpingo-oophorectomy or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. Woman with child-bearing potential and is abstinent or agrees to use one of the contraception methods listed in protocol for an appropriate period of time prior to the start of dosing. Female subjects must agree to use contraception until 14 days after the last dose of study medication
• Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin <= 1.5xUpper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• Body weight >= 50 kilogram (kg) and body mass index (BMI) within the range 18.5-31.0 kg/meter square (m^2) (inclusive).
• Capable of giving written informed consent
• Part A only: Available to complete the study (maximum of 21 days confinement in the clinical research unit).
• Part A only: A history of regular bowel movements (averaging one or more bowel movements per day).

Exclusion Criteria:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
• 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.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• 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 GlaxoSmithKline (GSK) Medical Monitor contraindicates their participation.
• Part A only: Subjects who have received a total body radiation dose of greater than 5.0 mSv or exposure to significant radiation (e.g. serial X-ray or computerised topography (CT) scans, barium meal etc.) in the 12 months prior to this study.
• Part A only: Any condition that could interfere with the accurate assessment and recovery of radioactivity [14C].
• Part A only: Participation in a clinical trial involving administration of 14C-labelled compound(s) within the last 12 months.
• Part A only: 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. Subjects with a history of cholecystectomy must be excluded.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
• A positive test for human immunodeficiency virus (HIV) antibody.
• Part B only: Pregnant or lactating females as determined by positive serum or urine Human Chorionic Gonadotropin (hCG) test at screening or prior to dosing.
• The subject's systolic blood pressure is outside the range of 90-140 millimetre of mercury (mmHg), or diastolic blood pressure is outside the range of 45-90 mmHg.
• History of clinically significant cardiovascular disease including: Heart rate <45 and >100 beats per minute in males and <50 and >100 beats per minute in females. QRS duration >120 milliseconds (msec) and corrected QT interval (QTc) interval B >450 msec in both males and females. Evidence of previous myocardial infarction, history/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PCTA) or any clinically significant cardiac disease, any conduction abnormality [including but not specific to left or right complete bundle branch block, atrioventricular (AV) block [2nd degree (type II) or higher], Wolf Parkinson White [WPW] syndrome) or 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. Nonsustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• 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
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days 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.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Kansas
GSK Investigational Site
Overland Park, Kansas, United States, 66211

Sponsors and Collaborators

ViiV Healthcare

GlaxoSmithKline

Investigators

Study Director:	GSK Clinical Trials	ViiV Healthcare

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	ViiV Healthcare
ClinicalTrials.gov Identifier:	NCT01848340 History of Changes
Other Study ID Numbers:	117008
First Posted:	May 7, 2013
Last Update Posted:	November 4, 2013
Last Verified:	October 2013

Keywords provided by ViiV Healthcare:

mass balance; GSK1265744; supratherapeutic; integrase inhibitor; healthy volunteer

Additional relevant MeSH terms:

HIV-Associated Lipodystrophy Syndrome; HIV Infections; Lipodystrophy; Skin Diseases, Metabolic; Skin Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Lentivirus Infections	Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases