Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers

NCT02478463 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 201767
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

Brief Summary

Cabotegravir (CAB) long-acting (LA) is a promising candidate for human immunodeficiency virus (HIV) pre exposure prophylaxis (PrEP) due to its potent antiretroviral activity and infrequent dosing requirements. Currently, the CAB concentrations achieved in the anatomical sites associated with sexual HIV transmission following the proposed 600 milligram (mg) intramuscular (IM) PrEP dose are unknown. These data will enhance our understanding of CAB distribution to the anatomical mucosal tissue believed to be relevant to sexual HIV-1 transmission and supplement the data to support future PrEP clinical trial development. The primary objective is to determine the PK concentrations of CAB following LA administration in plasma and in vaginal tissue (VT), cervical tissue (CT), and cervicovaginal fluid (CVF) in healthy women and in rectal tissue (RT) and rectal fluid (RF) in healthy men and women following a single 600 mg IM dose. This will be a Phase 1, open label study in healthy subjects to assess the pharmacokinetics of CAB LA in the plasma and mucosal locations associated with sexual HIV-1 transmission: VT, CT, CVF, RT and RF. The study will consist of a screening period, a 28-day oral lead-in phase at a dose of 30 mg per day followed by a 14-42 day washout period, and a single dose of CAB LA 600 mg as an IM (intragluteal) injection with compartmental pharmacokinetic (PK) sampling for up to 12 weeks. Subjects will return for safety assessments and plasma PK sampling at Week 24 and Week 36 post-injection and undergo a follow-up/withdrawal visit at Week 52 post-injection.

Conditions

Infection, Human Immunodeficiency Virus; HIV Infections

Keywords

Cabotegravir; Pharmacokinetic; Healthy Adult Volunteers; GSK1265744

Outcome Measures

Primary Outcomes (6)

• Cabotegravir Concentration in Blood Plasma Following IM Administration

  Blood samples were collected to measure cabotegravir concentration in blood plasma following a single 600 mg IM dose at indicated time-points. Evaluable Pharmacokinetic (PK) Plasma Parameter Summary Population comprised of all participants who underwent plasma PK sampling following oral dose in treatment period 1 and IM injection in treatment period 2 and had evaluable PK parameters estimated and no major protocol deviation.

  Day 1: Pre-dose and 4 hours; one sample on Days 3, 5, 8, Weeks 4, 8, 12, 24, 36 and 52 post-dose

• Cabotegravir Concentration in Vaginal Tissue Following IM Administration (Female Participants)

  Vaginal tissue samples were collected to measure cabotegravir concentration following a single 600 mg IM dose at indicated time-points. Evaluable Tissue-Fluid and PK Parameter Population (Oral plus IM) comprised of all participants who underwent sampling following oral dose in treatment period 1 and IM injection in treatment period 2 and have both evaluable PK and evaluable tissues-fluid parameters estimated in vaginal tissue/cervical tissue/cervicovaginal fluid/rectal tissue/rectal fluid.

  One sample on Day 3 and Week 8 post-dose

• Cabotegravir Concentration in Cervical Tissue Following IM Administration (Female Participants)

  Cervical tissue samples were collected to measure cabotegravir concentration following a single 600 mg IM dose at indicated time-points.

  One sample on Days 3, 8, Weeks 4, 8 and 12 post-dose

• Cabotegravir Concentration in Cervicovaginal Fluid Following IM Administration (Female Participants)

  Cervicovaginal fluid samples were collected to measure cabotegravir concentration following a single 600 mg IM dose at indicated time-points.

  One sample on Days 3, 8, Weeks 4, 8 and 12 post-dose

• Cabotegravir Concentration in Rectal Tissue Following IM Administration

  Rectal tissue samples were collected to measure cabotegravir concentration following a single 600 mg IM dose at indicated time-points.

  One sample on Days 3, 8, Weeks 4, 8 and 12 post-dose

• Cabotegravir Concentration in Rectal Fluid Following IM Administration

  Rectal fluid samples were collected to measure cabotegravir concentration following a single 600 mg IM dose at indicated time-points.

  One sample on Days 3, 8, Weeks 4, 8 and 12 post-dose

Secondary Outcomes (105)

• Ratio of Cabotegravir Concentration in Vaginal Tissue to Cabotegravir Concentration in Blood Plasma Following IM Administration (Female Participants)

  One sample on Day 3 and Week 8 post-dose

• Ratio of Cabotegravir Concentration in Cervical Tissue to Cabotegravir Concentration in Blood Plasma Following IM Administration (Female Participants)

  One sample on Day 3, 8, Weeks 4, 8 and 12 post-dose

• Ratio of Cabotegravir Concentration in Cervicovaginal Fluid to Cabotegravir Concentration in Blood Plasma Following IM Administration (Female Participants)

  One sample on Day 3, 8, Weeks 4, 8 and 12 post-dose

• Ratio of Cabotegravir Concentration in Cervical Tissue to Cabotegravir Concentration in Cervicovaginal Fluid Following IM Administration (Female Participants)

  One sample on Day 3, 8, Weeks 4, 8 and 12

• Ratio of Cabotegravir Concentration in Vaginal Tissue to Cabotegravir Concentration in Cervicovaginal Fluid Following IM Administration (Female Participants)

  One sample on Day 3 and Week 8 post-dose

Study Arms (1)

Cabotegravir

EXPERIMENTAL

Subject will receive CAB 30 mg tablet once daily oral dose for 28 days (4 weeks) followed by a washout period of 14 to 42 days. After the washout, subject will receive a single dose of CAB LA 600 mg IM to gluteal region.

Drug: Cabotegravir tablet 30 mg once daily for 28 days.; Drug: Cabotegravir injection 3 mL (200 mg/mL) IM given once on Day 1.

Interventions

Cabotegravir tablet 30 mg once daily for 28 days. DRUG

GSK1265744B, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, Aquarius film-coating, white BP18237

Cabotegravir

Cabotegravir injection 3 mL (200 mg/mL) IM given once on Day 1. DRUG

Cabotegravir will be supplied as sterile suspension for injection 200 mg/mL vial. Each vial appears as sterile white to slightly colored suspension containing 200 mg/mL of CAB for administration by intramuscular (intragluteal) injection and will be administered as 1 × 3 mL Injections (3 mL \[600 mg\] total) IM given once on Day 1 of injection phase

Cabotegravir

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 55 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.

You may not qualify if:

• Body weight \>= 40 kilogram (kg) and body mass index (BMI) within the range 18.5 to 35 kg /meter square (inclusive).
• Male or female
• A female subject is eligible to participate if she is pre-menopausal, has an intact uterus and cervix, AND is not pregnant (as confirmed by a negative human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies: a) Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Documented Bilateral Oophorectomy. b)Reproductive potential and agrees to follow one of the options listed below in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer (can be up to 66 weeks on study) after the last dose of study medication and completion of the follow-up visit. Female subjects desiring pregnancy or foresee that they might wish to become pregnant within 52 weeks of receiving a CAB LA injection must be excluded. All subjects participating in the study must be counseled on safe sexual practices including the use of effective barrier methods to minimize risk of HIV transmission.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
• Liver Function: ALT or AST \> upper limit of normal (ULN)
• Total bilirubin \>ULN (isolated total bilirubin \>ULN is acceptable if total bilirubin is fractionated and direct bilirubin \<35%)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Corrected QT (QTc) Interval: QTc \> 450 milliseconds (msec):
• The subject's systolic blood pressure is outside the range of 90-140 millimeter (mm) mercury (Hg), or diastolic blood pressure is outside the range of 45-90 mmHg.
• History of clinically significant cardiovascular disease including:
• Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization); 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, AV block (2nd degree \[type II\] or higher), Wolf Parkinson White \[WPW\] syndrome); 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 (\>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia.
• History of ongoing or clinically relevant seizure disorder within the previous 2 years, including subjects who have required treatment for seizures within this time period. A prior history of seizure, with a seizure free period of at least 2 years, off anti-epileptics, 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
• Use of any concurrent prohibited medications as outlined in protocol
• 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 gram (g) of alcohol: 12 ounces (360 milliliter \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Sponsors & Collaborators

• ViiV Healthcare: lead

Study Sites (2)

GSK Investigational Site

Baltimore, Maryland, 21287-5554, United States

Location

GSK Investigational Site

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

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

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: June 18, 2015
• First Posted: June 23, 2015
• Study Start: February 27, 2017
• Primary Completion: July 25, 2019
• Study Completion: July 25, 2019
• Last Updated: June 22, 2020
• Results First Posted: June 22, 2020

Record last verified: 2020-06

Locations

US (2)