A Safety, Tolerability, Acceptability, and Pharmacokinetic (PK) Study of Cabotegravir (CAB) in Healthy Human Immunodeficiency Virus (HIV)-Uninfected Chinese Men

Overview

The pre-exposure prophylaxis (PrEP) is an important component in the overall strategy for prevention of HIV infection. Cabotegravir (CAB) is an integrase strand transfer inhibitor currently in development for treatment and prevention of HIV infection. CAB possesses attributes that allow formulation and delivery as a LA parenteral product. CAB is being developed as both oral and long acting (LA) injectable formulations. This study is designed to evaluate the PK, safety, tolerability, and acceptability of CAB LA in adult HIV uninfected Chinese male subjects at low risk for HIV acquisition. Eligible subjects will receive oral CAB during oral phase of the study followed by CAB LA intramuscular (IM) injection during injection phase of the study. Approximately 60 subjects will be screened, of which, approximately 48 subjects will enter the oral phase and 40 subjects will enter the injection phase of the study. The maximum study duration will be approximately 89 weeks including oral phase, injection phase and follow-up phase.

Full Title of Study: “An Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir (CAB; GSK1265744) in HIV Uninfected Chinese Men”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 20, 2020

Interventions

  • Drug: Oral CAB
    • CAB tablet will be formulated as white to almost white, oval shaped, film coated 30 mg tablets, administered orally once daily. The CAB tablets will be packaged in bottles containing 30 tablets each.
  • Drug: CAB LA
    • CAB LA is a sterile white to slightly colored suspension containing 200 mg/mL of CAB as free acid for administration by IM injection in gluteus medius.

Arms, Groups and Cohorts

  • Experimental: Subjects receiving CAB
    • Eligible subjects will receive oral doses of CAB 30 milligrams (mg) tablets once daily for 4 weeks followed by IM injectable suspension of CAB LA 600 mg at Week 5, Week 9, Week 17, Week 25 and Week 33. There will be an approximately 1-week washout period between the last oral dose and the first injection of CAB at Week 5.

Clinical Trial Outcome Measures

Primary Measures

  • Number of subjects with adverse events (AEs): Injection phase
    • Time Frame: Up to 623 days
    • An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Number of subjects with serious AEs (SAEs): Injection phase
    • Time Frame: Up to 653 days
    • Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
  • Number of subjects with abnormal clinical chemistry laboratory parameters: Injection phase
    • Time Frame: Up to 623 days
    • Clinical chemistry parameters will be analyzed including blood urea nitrogen (BUN), creatinine, glucose (non-fasting), total carbon dioxide (CO2), albumin, potassium, sodium, calcium, gamma glutamyl transferase (GGT), chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, creatinine clearance, total bilirubin, direct bilirubin, total protein, creatine phosphokinase (CPK) and uric acid.
  • Number of subjects with abnormal hematology laboratory parameters: Injection phase
    • Time Frame: Up to 623 days
    • Hematology parameters will be analyzed including platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), percent reticulocytes, mean corpuscular hemoglobin concentration (MCHC), neutrophils lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects with abnormal values for urinalysis: Injection phase
    • Time Frame: Up to 287 days
    • Urinalysis parameters will be analyzed including specific gravity and dipstick test will be used to analyze pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte esterase). Microscopic examination will be performed if blood or protein is abnormal.
  • Number of subjects withdrawn due to AEs: Injection phase
    • Time Frame: Up to 623 days
    • An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Number of subjects with abnormal values for blood pressure: Injection phase
    • Time Frame: Up to 623 days
    • Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal values for body temperature: Injection phase
    • Time Frame: Up to 623 days
    • Body temperature will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal pulse rate: Injection phase
    • Time Frame: Up to 623 days
    • Pulse rate will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal respiratory rate: Injection phase
    • Time Frame: Up to 623 days
    • Respiratory rate will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects experiencing injection site reactions (ISRs)
    • Time Frame: Up to 231 days
    • ISRs will be recorded via ISR diaries. All ISRs will be classified as serious or Grade 3 or higher that persists beyond 2 weeks.
  • Concentration of oral CAB in plasma at the end of the dosing interval (Ctau) from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Area under the plasma concentration time curve over the dosing interval (AUC [0-tau]) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Maximum observed concentration (Cmax) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Time of occurrence of Cmax (Tmax) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Oral clearance (CL/F) following dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Volume of distribution at steady state (Vss) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Terminal absorption elimination half-life (t1/2) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Apparent terminal phase rate constant (Lambda z) following oral dosing with CAB from Day 1 to Day 28
    • Time Frame: Pre-dose and 1, 2, 3, 4, 8 hours Post-dose on Day 27; 24 hours Post-dose on Day 28
    • Blood samples will be collected for pharmacokinetic analysis of oral CAB.
  • Ctau following IM dosing with CAB LA from Day 35 to Day 287
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • AUC(0-tau) following IM dosing with CAB LA from Day 35 to Day 287
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Cmax following IM dosing with CAB LA from Day 35 to Day 287
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Tmax following IM dosing with CAB LA from Day 35 to Day 287
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.

Secondary Measures

  • Ctau following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • AUC (0-tau) following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Cmax following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Tmax following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • CL/F following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Vss following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • T1/2 following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Lambda z following IM dosing with CAB LA from Day 35 to Day 623
    • Time Frame: Pre-dose on Day 35, 63, 119,175, 231 and Post-dose on Day 42, 70, 126, 182, 238, 259, 287; Day 371, 455, 539, and 623
    • Blood samples will be collected for pharmacokinetic analysis of CAB LA.
  • Number of subjects with AEs: oral phase
    • Time Frame: Up to 28 days
    • An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Number of subjects with SAEs: oral phase
    • Time Frame: Up to 58 days
    • Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
  • Number of subjects with abnormal clinical chemistry laboratory parameters: oral phase
    • Time Frame: Up to 28 days
    • Clinical chemistry parameters will be analyzed including BUN, creatinine, Glucose (non-fasting), total CO2, albumin, potassium, sodium, calcium, GGT, chloride, AST, ALT, alkaline phosphatase, creatinine clearance, total bilirubin, direct bilirubin, total protein, CPK and uric acid.
  • Number of subjects with abnormal hematology laboratory parameters: Oral phase
    • Time Frame: Up to 28 days
    • Hematology parameters will be analyzed including platelet count, RBC count, hemoglobin, hematocrit, WBC count, reticulocyte count, MCV, MCH, percent reticulocytes, MCHC, neutrophils lymphocytes, monocytes, eosinophils and basophils.
  • Number of subjects withdrawn due to AEs: Oral phase
    • Time Frame: Up to 28 days
    • An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.
  • Number of subjects with abnormal values for blood pressure: Oral phase
    • Time Frame: Day 1
    • Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal values for body temperature: Oral phase
    • Time Frame: Day 1
    • Body temperature will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal pulse rate: Oral phase
    • Time Frame: Day 1
    • Pulse rate will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with abnormal respiratory rate: Oral phase
    • Time Frame: Day 1
    • Respiratory rate will be measured in a semi-supine position after 5 minutes rest.
  • Number of subjects with injection discontinuation rate
    • Time Frame: Up to 287 days
    • The number of subjects with injection discontinuation rate will be determined.
  • Number of subjects with severity of ISRs
    • Time Frame: Up to 231 days
    • The severity of ISRs will be recorded via ISR diaries. All ISRs will be classified as serious or Grade 3 or higher that persists beyond 2 weeks.
  • Number of subjects displaying relationship between CAB concentration-effect with safety parameter
    • Time Frame: Up to 623 days
    • The relationship between significant safety and tolerability parameters and CAB PK will be evaluated.

Participating in This Clinical Trial

Inclusion Criteria

  • Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
  • Subjects are male at birth.
  • Subjects who have non-reactive point of care (POC) HIV test and undetectable HIV-1 ribose nucleic acid (RNA) at screening.
  • At risk of acquiring HIV, defined as having at least one casual male or female sex partner in the past 24 months.
  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring at the time of screening.
  • Capable of giving written informed consent.
  • Agree to appropriate use of contraceptive measures during heterosexual intercourse. All subjects should be counseled on safer sexual practices including the use and benefit/risk of effective barrier methods (example given (e.g.), male condom) to reduce the risk of sexually transmitted infections.
  • Willing to undergo all required study procedures.

Exclusion Criteria

  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
  • Active skin disease or disorder (that is [i.e.], infection, inflammation, dermatitis, eczema, drug rash, psoriasis, urticaria). Mild cases of localized acne or folliculitis or other mild skin condition may not be exclusionary at the discretion of the Investigator of Record or Medical Monitor.
  • Subjects determined by the Investigator to have a high risk of seizures, including subjects with an unstable or poorly controlled seizure disorder. A subject with a prior history of seizure may be considered for enrolment if the Investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the Medical Monitor prior to enrolment.
  • Any medical condition, including psychiatric conditions that in the judgment of the investigator would interfere with the subject's ability to complete study procedures.
  • Subjects who, in the investigator's judgment, poses a significant suicide risk.
  • Use of antiretroviral (ARV) therapy (e.g., for Post exposure prophylaxis [PEP] or PrEP) in the past 30 days.
  • Use of high dose aspirin or any other anticoagulant or antiplatelet medication that would interfere with the ability to receive IM injections.
  • Assessed by the Investigator of Record or designee as being at "high risk" for HIV infection. This may include one or more of the following: the negative partner in an HIV serodiscordant couple where the HIV infected partner is not suppressed; men who exchange sex for goods or money; men who have engaged in any condomless anal intercourse within the past 6 months; men who have had greater than 5 male or female sexual partners within the past 6 months; men who have had a sexually transmitted disease within the past 6 months; any other behavior assessed by the investigator as "high risk".
  • History of drug or alcohol consumption that in the opinion of the Principal Investigator will interfere with study participation.
  • Ongoing intravenous drug use – episodic use or any use in the past 90 days is exclusionary (as assessed by the study investigator).
  • One or more reactive HIV test results at screening or enrolment, even if HIV infection is not confirmed. Negative HIV RNA must also be documented at screening.
  • Co-enrolment in any other HIV interventional research study (provided by self-report or other available documentation) or prior enrolment and receipt of the active arm (i.e., NOT a placebo) of a HIV vaccine trial (provided by available documentation).
  • Any of the following laboratory values during the screening period: positive hepatitis C antibody result; positive Hepatitis B surface antigen (HBsAg); hemoglobin <11 grams per deciliter (g/dL); absolute neutrophil count <750 cells/ cubic millimeter (mm^3); platelet count <=100,000 cells/mm^3; presence of a coagulopathy as defined by an international normalized ratio(INR)>1.5 or a partial thromboplastin time (PTT) >45 seconds; calculated creatinine clearance <60 milliliter/minute (mL/minute) using the Cockcroft-Gault equation; a single repeat test is allowed during the screening period to verify a result, with the exception of HIV tests.
  • Subjects with an ALT, alkaline phosphatase or bilirubin >=1.5x Upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • The subject has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.

Gender Eligibility: Male

Healthy male subjects at low risk of HIV infection will be eligible to participate in this study.

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • ViiV Healthcare
  • Collaborator
    • PPD
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • GSK Clinical Trials, Study Director, ViiV Healthcare

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