Clinical trial NCT04484337: Study to Evaluate Pharmacokinetic (PK), Safety and Tolerability of Cabotegravir (CAB) 400 Milligrams Per Milliliter (mg/mL) Formulation in Healthy Adult Participants
Official title: A Phase 1, Two-part, Double-blind, Active-control, Randomized Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Repeat-Dose Cabotegravir (CAB 400 mg/mL Formulation) Long-Acting Injection Following Subcutaneous or Intramuscular Administration in Healthy Adult Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Cabotegravir
Long-Acting Injection
Pharmacokinetics
Safety
Tolerability
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2020-07-23
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Participants will receive repeat doses of long-acting CAB 400 mg/mL or CAB 200 mg/mL at four-weekly (Q4W) interval in Part 1 and at 12-weekly (Q12W) interval in Part 2.
Primary purpose: TREATMENT

Brief summary: This is an active control, randomized study to investigate the safety, tolerability and PK of repeat dose administration of long-acting CAB 400 mg/mL formulation intramuscular (IM) (gluteus medius and vastus lateralis) and subcutaneous (SC) (abdominal) injections in healthy adult participants.


Eligibility criteria: Inclusion Criteria:

* Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent.
* Participants who are overtly healthy as determined by medical evaluation.
* A participant with a clinical abnormality or laboratory parameters which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included if the investigator determines and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Participants who are negative on two consecutive tests for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), performed at Screening and within 5 days of admission to the Phase I unit, using an approved molecular test (Polymerase chain reaction \[PCR\]).
* Body weight more than or equal to (\>=)40 kilogram (kg) and body mass index (BMI) within the range 18 to 32 kilogram per square meter (kg/m\^2).
* Male participants are eligible to participate if they agree to use contraceptive methods and refrain from donating sperm.
* A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) or is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of less than (\<)1 percent(%).
* Capable of giving signed informed consent.

Exclusion Criteria:

* Signs and symptoms which in the opinion of the investigator are suggestive of Coronavirus disease 2019 (COVID-19) (that is \[i.e.\] fever, cough etc) within 14 days of inpatient admission.
* Contact with known COVID-19 positive person/s in the 14 days prior to inpatient admission.
* History or presence of/significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data.
* Abnormal blood pressure as determined by the investigator.
* Alanine transaminase (ALT) more than (\>)1.5 times upper limit of normal (ULN).
* Bilirubin \>1.5 times ULN (isolated bilirubin \>1.5 times ULN is acceptable if 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 interval (QTc) \>450 milliseconds (msec).
* A known hypersensitivity to hyaluronidases (Cohort 4h only).
* The participant has an underlying skin disease or disorder (infection, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria) that would interfere with assessment of injection sites.
* Current or anticipated need for chronic anti-coagulation with the exception of the use of low dose acetylsalicylic acid (less than or equal to \[\<=\]325 mg) or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease.
* Participants considered to have insufficient musculature to allow safe administration of CAB 400 mg/mL (gluteus medius or vastus lateralis).
* History of ongoing or clinically relevant seizure disorder within the previous 2 years, including participants who have required treatment for seizures within this time period.
* History of or on-going high-risk behaviors that may put the participant at increased risk for Human Immunodeficiency Virus (HIV) acquisition in the opinion of the investigator. This includes participants in HIV discordant relationships, or men who report current or prior unprotected anal sex with other men and those reporting prior or current injecting drug use.
* Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) 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).
* Participation in the study would result in loss of blood or blood products in excess of 500 mL within 56 days.
* The participant 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.
* Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
* A positive pre-study drug/alcohol screen.
* Exclusion criteria for screening electrocardiogram (ECG):

  1. Heart rate: For Males \<45 or \>100 beats per minute (bpm), for females \<50 or \>100 bpm.
  2. PR Interval: For males and females \<120 or \>220 msec.
  3. QRS duration: For males and females \<70 or \>120 msec.
  4. QT duration corrected for heart rate by Fridericia's formula (QTcF) interval: For males and females \>450 msec.
* Evidence of previous myocardial infarction.
* Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular \[AV\] block \[2nd degree or higher\], Wolff-Parkinson-White \[WPW\] syndrome).
* Sinus Pauses \>3 seconds.
* Any significant arrhythmia which, in the opinion of the Investigator or GlaxoSmithKline (GSK)/ViiV Medical monitor, will interfere with the safety for the individual participant.
* Non-sustained or sustained ventricular tachycardia (\>=3 consecutive ventricular ectopic beats).
* Positive HIV antibody/antigen test. Participants will be advised regarding safer sex. In the event a participant acquires HIV during the course of the study they will be required to withdraw from the study and will be referred urgently to an HIV treatment center for further management.
* Regular use of known drugs of abuse.
* Regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy.
* Participants with a history of intolerance to or with contraindications to the use of topical non-steroidal anti-inflammatory drugs (NSAIDs) or topical steroids will be excluded from participation in Cohort 4b.
* Regular alcohol consumption within 6 months prior to the study defined as: An average weekly intake of \>14 units for males or \>7 units for females.
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening.
* The participant has a tattoo or other dermatological condition overlying the location of injection or a prior history of silicone implants (gluteal) which may interfere with interpretation of injection site reactions or administration of CAB LA.

Primary outcomes:
measure: Maximum observed Plasma concentration (Cmax) for cabotegravir (Part 1 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 4
measure: Cmax for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Day 1 to Week 52 follow-up
measure: Cmax for cabotegravir (Part 2 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 12
measure: Cmax for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Day 1 to Week 52 follow-up
measure: Time of maximum observed plasma concentration (Tmax) for cabotegravir (Part 1 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 4
measure: Tmax for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Day 1 to Week 52 follow-up
measure: Tmax for cabotegravir (Part 2 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 12
measure: Tmax for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Day 1 to Week 52 follow-up
measure: Area under the concentration - time curve from time zero to last quantifiable time point (AUC[0-t]) for cabotegravir (Part 1 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 4
measure: AUC(0-t) for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Day 1 to Injection 2 Week 4
measure: AUC(0-t) for cabotegravir (Part 2 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 12
measure: AUC(0-t) for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Day 1 to Injection 2 Week 12
measure: Trough concentrations (Ctau) for cabotegravir (Part 1 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 4
measure: Ctau for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Day 1 to Injection 2 Week 4
measure: Ctau for cabotegravir (Part 2 Injection 1)
timeFrame: Injection 1 Day 1 to Injection 1 Week 12
measure: Ctau for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Day 1 to Injection 2 Week 12
measure: Apparent terminal phase half-life (T1/2) for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Week 4 to Week 52 follow-up
measure: T1/2 for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Week 12 to Week 52 follow-up
measure: Absorption rate constant (KALA) for cabotegravir (Part 1 Injection 2)
timeFrame: Injection 2 Week 4 to Week 52 follow-up
measure: KALA for cabotegravir (Part 2 Injection 2)
timeFrame: Injection 2 Week 12 to Week 52 follow-up
measure: Geometric mean ratio of plasma Ctau of CAB for Cohorts 1,2,3,4, 4b & 4h at Week4 (Part 1 Injection 1) compared to historical data of CAB 200 mg/mL IM (gluteus medius) (Week 8 Ctau following first injection at Week 4 in ATLAS [201585]/FLAIR [201584]Study)
timeFrame: At Injection 1 Week 4
measure: Geometric mean ratio of plasma Ctau of CAB for Cohorts 1,2,3,4, 4b at Week 4 (Part 1 Injection 2) compared to historical data of CAB 200 mg/mL IM (gluteus medius) (Week 12 Ctau following first injection at Week 8 in ATLAS [201585]/FLAIR [201584]Study)
timeFrame: At Injection 2 Week 4
measure: Geometric mean ratio of plasma Ctau of CAB for Cohorts 5 and 6 at Week 12(Part 2 Injection 1) compared to historical data of CAB 200 mg/mL IM (gluteus medius) (Week 8 Ctau following first injection at Week 4 in ATLAS [201585]/FLAIR [201584]Study)
timeFrame: At Injection 1 Week 12
measure: Geometric mean ratio of plasma trough concentration (Ctau) of cabotegravir at Week 4 (Part 1 Injection 1) for each pairwise comparison between Cohorts 1, 2, 3, 4, 4b and 4h
timeFrame: At Injection 1 Week 4
measure: Geometric mean ratio of plasma trough concentration (Ctau) of cabotegravir at Week 4 (Part 1 Injection 2) for each pairwise comparison between Cohorts 1, 2, 3, 4 and 4b
timeFrame: At Injection 2 Week 4
measure: Geometric mean ratio of Plasma AUC(0-t) of cabotegravir at Week 4 (Part 1 Injection 1) for each pairwise comparison between Cohorts 1, 2, 3, 4, 4b and 4h
timeFrame: At Injection 1 Week 4
measure: Geometric mean ratio of Plasma Cmax of cabotegravir at Week 4 (Part 1 Injection 2) for each pairwise comparison between Cohorts 1, 2, 3, 4 and 4b
timeFrame: At Injection 2 Week 4
measure: Geometric mean ratio of Plasma Cmax of cabotegravir at Week 4 (Part 1 Injection 1) for each pairwise comparison between Cohorts 1, 2, 3, 4, 4b and 4h
timeFrame: At Injection 1 Week 4
measure: Geometric mean ratio of Plasma AUC(0-t) of cabotegravir at Week 4 (Part 1 Injection 2) for each pairwise comparison between Cohorts 1, 2, 3, 4 and 4b
timeFrame: At Injection 2 Week 4
Secondary outcomes:
measure: Parts 1 and 2: Number of participants with adverse events (AEs)
timeFrame: Up to 52 weeks follow-up
measure: Number of participants with liver biochemistry abnormalities
timeFrame: Up to 52 weeks follow-up
measure: Cmax for cabotegravir following oral 30 mg administration
timeFrame: Up to Day 29
measure: Tmax for cabotegravir following oral 30 mg administration
timeFrame: Up to Day 29
measure: AUC(0-t) for cabotegravir following oral 30 mg administration
timeFrame: Up to Day 29
measure: Concentration at 24 hours (C24) for cabotegravir following oral 30 mg administration
timeFrame: At 24 hours
measure: Ctau for cabotegravir at Day 29 following oral 30 mg administration
timeFrame: Up to Day 29
measure: Cmax of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
measure: Tmax of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
measure: AUC(0-t) of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
measure: Ctau of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
measure: T1/2 of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
measure: KALA of cabotegravir for cohort 4h
timeFrame: Injection 1 Day 1 to Week 52 follow-up
Other outcomes:
Locations:
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Berlin
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Auckland
country: New Zealand
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: