Pharmacokinetics Study of GSK1265744 in Subjects With Severe Renal Impairment

NCT02354937 | Completed Phase 1

• 1 other identifier: 201480
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

GSK1265744 (744) is an integrase strand transfer inhibitor (INSTI) currently in development for both the treatment and prevention of human immunodeficiency virus (HIV) infection. Renal elimination of unchanged 744 is extremely low, with no parent 744 detected in the urine after a single 30 mg radiolabeled dose. Despite the minimal contribution of renal clearance on overall 744 elimination, renal impairment may potentially inhibit some pathways of hepatic and gut drug metabolism and transport, and as a result may impact 744 pharmacokinetics. The current Food and Drug Administration (FDA) draft guidance for renal impairment studies suggests that a pharmacokinetic (PK) study in patients with renal impairment be conducted even for those drugs primarily metabolized or secreted in bile. The study will be comprised of two cohorts (severe renal impairment and normal renal function) of 8 subjects each. Upon enrolment, each subject will be admitted to the study center and undergo serial PK sampling following a single dose of oral 744 30 milligrams (mg). Subjects will return to the clinic for follow-up evaluations 10-14 days after the 744 30 mg dose.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Keywords

Pharmacokinetics; GSK1265744; Severe Renal Impairment

Outcome Measures

Primary Outcomes (1)

• Composite of PK parameters evaluated by measurement of AUC (0-infinity) and Cmax following single oral dose.

  To compare effect of severe renal impairment on PK parameters for 744 assessed by Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinity\]) and Maximum observed concentration (Cmax)

  Samples will be collected at pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120 and 168 hours post dose.

Secondary Outcomes (6)

• Unbound concentration and unbound fraction in plasma of GSK1265744 at 2 and 24 hours post dose

  Samples will be collected at 2 and 24 hours post dose.

• Composite of PK parameters for GSK1265744 evaluated by measurement of Plasma AUC(0-t), %AUCex, C24, t1/2, CL/F, tlag, tmax and Vz/F following a single oral dose

  Samples will be collected at pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120 and 168 hours post dose.

• Number of participants with adverse events as measure of safety and tolerability

  Day -1 to Day 15

• Safety and tolerability of single oral dose of 744 assessed by clinical laboratory tests

  14 Days

• Safety and tolerability of single oral dose of 744 assessed by12-Lead electrocardiogram

  2 Days

Study Arms (2)

Subjects with renal impairment

EXPERIMENTAL

Subjects with severe renal impairment will receive single oral dose of 744 30 mg

Drug: GSK1265744 30 mg

Subjects with normal renal function

ACTIVE COMPARATOR

Subjects with normal renal function will receive single oral dose of 744 30 mg

Drug: GSK1265744 30 mg

Interventions

GSK1265744 30 mg DRUG

White to almost white coated oval tablets with unit dose strength of 30 mg for oral administrations.

Subjects with normal renal function; Subjects with renal impairment

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (2)

GSK Investigational Site

Lakewood, Colorado, 80228, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Parasrampuria R, Ford SL, Lou Y, Fu C, Bakshi KK, Tenorio AR, Trezza C, Spreen WR, Patel P. A Phase I Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Adults With Severe Renal Impairment and Healthy Matched Control Participants. Clin Pharmacol Drug Dev. 2019 Jul;8(5):674-681. doi: 10.1002/cpdd.664. Epub 2019 Feb 27.

  PMID: 30809978 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections; Renal Insufficiency

Interventions

cabotegravir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Male Urogenital Diseases

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2015
• First Posted: February 3, 2015
• Study Start: July 13, 2015
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: August 28, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (2)