A Study to Evaluate Pharmacokinetic (PK) and Safety of GSK1265744 in Subjects With Hepatic Impairment and Control Healthy Volunteers

NCT02354950 | Completed Phase 1 FDA Drug

• 1 other identifier: 201479
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

This will be a Phase 1, open-label, parallel group, two-part, single-dose adaptive study in adults with moderate and mild (if needed) hepatic impairment and matched, healthy control subjects with normal hepatic function. In Part 1, healthy control subjects (n=8) matched to subjects with moderate (n=8) hepatic impairment will be enrolled. If the geometric mean total plasma area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinity\]) of GSK1265744 is increased by \>2-fold in moderately impaired subjects relative to matched controls, Part 2 will be conducted to evaluate GSK1265744 PK in subjects with mild hepatic impairment (n=8) and matched, control subjects (n=8). All subjects will receive a single 30 milligram (mg) oral dose of GSK1265744. The primary objective of the study is to compare plasma PK parameters of GSK1265744 in subjects with hepatic impairment to healthy controls matched in gender, age, and body mass index (BMI).

Conditions

HIV Infections

Keywords

GSK1265744; healthy controls; pharmacokinetic; Hepatic Impairment

Outcome Measures

Primary Outcomes (2)

• Plasma area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time [AUC(0-infinity)] following a single oral dose of GSK1265744

  Plasma PK samples (2 mL of blood per sample) will be collected to measure GSK1265744 at the following time points: pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose

  Pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose (Day 8)

• Maximum observed concentration (Cmax) following a single oral dose of GSK1265744

  Plasma PK samples (2 mL of blood per sample) will be collected to measure GSK1265744 at the following time points: pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose

  Pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose (Day 8)

Secondary Outcomes (6)

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

  Up to 24 hours post dose (Day 2)

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

  Pre-dose (within 15 minutes prior to dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose (Day 8)

• Adverse events (AEs) assessment

  Up to Day 14

• Composite of Clinical laboratory parameters including hematology, and clinical chemistry

  Up to Day 14

• Electrocardiogram (ECG) monitoring

  Up to Day 2

Study Arms (4)

Part 1 Cohort 1 (Moderate hepatic impairment subjects)

EXPERIMENTAL

Subjects with moderate hepatic impairment will receive GSK1265744 30mg as a single oral dose in the fasted state followed by pharmacokinetic sampling for total concentrations of GSK1265744 in plasma

Drug: GSK1265744 30mg

Part 1 Cohort 2 (Healthy control subjects)

EXPERIMENTAL

Healthy control subjects will receive GSK1265744 30mg as a single oral dose in the fasted state followed by pharmacokinetic sampling for total concentrations of GSK1265744 in plasma

Drug: GSK1265744 30mg

Part 2 Cohort 3 (Mild hepatic impairment subjects)

EXPERIMENTAL

Subjects with mild hepatic impairment will receive GSK1265744 30mg as a single oral dose in the fasted state followed by pharmacokinetic sampling for total concentrations of GSK1265744 in plasma

Drug: GSK1265744 30mg

Part 2 Cohort 4 (Healthy control subjects)

EXPERIMENTAL

Healthy control subjects will receive GSK1265744 30mg as a single oral dose in the fasted state followed by pharmacokinetic sampling for total concentrations of GSK1265744 in plasma

Drug: GSK1265744 30mg

Interventions

GSK1265744 30mg DRUG

GSK1265744 30mg tablets are white to almost white coated oval tablets. All subjects will receive GSK1265744 30mg as a single oral dose in the fasted state followed by PK sampling.

Part 1 Cohort 1 (Moderate hepatic impairment subjects); Part 1 Cohort 2 (Healthy control subjects); Part 2 Cohort 3 (Mild hepatic impairment subjects); Part 2 Cohort 4 (Healthy control subjects)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hepatic Impaired Subjects (Cohort 1 and 3)
• Between 18 and 70 years of age
• Part 1 subjects with Moderate Hepatic Impairment Only (Cohort 1):
• Subject is considered to have moderate hepatic impairment (of any etiology) and has been clinically stable for at least 1 month prior to screening. Having moderate hepatic impairment with a Child-Pugh score of 7-9 and previous confirmation of liver cirrhosis.
• Part 2 subjects with Mild Hepatic Impairment Only (Cohort 3):
• Subject is considered to have mild hepatic impairment (of any etiology) and has been clinically stable for at least 1 month prior to screening. Having mild hepatic impairment, with a Child-Pugh score of 5-6 and previous confirmation of chronic liver disease.
• Male or female: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and the protocol.
• Healthy control subjects will be matched for age +/-10 years to subjects in the respective hepatic impairment cohort but must also remain in the age range between 18 and 70 years inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator or medically qualified designee. Healthy control subjects will be matched for BMI +/-25 percent to subjects in the respective hepatic impairment cohort but must also remain in the range of: Body weight \>=50 kg and BMI within the range 19 - 41 kg/m\^2 (inclusive)
• Male or female: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

You may not qualify if:

• Presence of Grade 3 or 4 elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin; corrected QT interval (QTc) \> 480 milliseconds (msec);
• The subject's systolic BP is outside the range of 90-160 millimeter of mercury (mmHg), or diastolic BP is outside the range of 45-95mmHg or heart rate is outside the range of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male subjects
• 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
• Any significant arrhythmia.
• Non-sustained or sustained ventricular tachycardia.
• Evidence of recent infection with Hepatitis B and/or Hepatitis C within preceding 6 months. Subjects with chronic Hepatitis B or C (duration\>6 months)
• Subjects with a pre-existing condition (except hepatic impairment) interfering with normal gastrointestinal anatomy or motility that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy and inflammatory bowel disease should be excluded.
• Subjects with a history of peptic ulceration or pancreatitis within the preceding 6 months of screening should be excluded.
• Subjects with previous gastrointestinal (GI) surgery (except appendectomy more than three months prior to study) should be excluded.
• Subjects with creatinine clearance (CLCR) \<=60 milliliter per minute (mL/min) (calculated by the Modification of Diet in Renal Disease \[MDRD\] equation).
• Subjects with advanced ascites (Grade 3 or 4).
• Subjects with refractory encephalopathy as judged by the investigator or significant Central Nervous System (CNS) disease.
• History of gastric or esophageal variceal bleeding within the past 6 months;
• Subjects with Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement;

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (3)

GSK Investigational Site

Lakewood, Colorado, 80228, United States

Location

GSK Investigational Site

Orlando, Florida, 32809, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Shaik JSB, Ford SL, Lou Y, Zhang Z, Bakshi KK, Tenorio AR, Trezza C, Spreen WR, Patel P. A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls. Clin Pharmacol Drug Dev. 2019 Jul;8(5):664-673. doi: 10.1002/cpdd.655. Epub 2019 Feb 27.

  PMID: 30811880 BACKGROUND

MeSH Terms

Conditions

HIV Infections

Interventions

cabotegravir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: January 29, 2015
• First Posted: February 3, 2015
• Study Start: June 22, 2015
• Primary Completion: September 16, 2016
• Study Completion: September 16, 2016
• Last Updated: August 5, 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 (3)