Clinical trial NCT03422172: A Safety, Tolerability, Acceptability, and Pharmacokinetic (PK) Study of Cabotegravir (CAB) in Healthy Human Immunodeficiency Virus (HIV)-Uninfected Chinese Men
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: GSK1265744
Pre-Exposure Prophylaxis
Human immunodeficiency virus
Cabotegravir
Pharmacokinetics
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2018-02-05
Enrollment: 48
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Eligible subjects will receive oral doses of CAB for 4 weeks followed by IM dosing with CAB LA at Week 5, Week 9, Week 17, Week 25 and Week 33.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs): Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants With Maximum Toxicity Post-Baseline in Hematology Parameters-Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants With Maximum Toxicity Post-Baseline in Chemistry Parameters: Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants With Maximum Toxicity Post-Baseline in Urinalysis Parameters: Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants With Shift From Baseline in Vital Signs With Respect to Clinical Concern Range: Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants Withdrawn Due to AEs- Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants Experiencing Injection Site Reactions (ISR)-Injection Phase
timeFrame: Week 5 to 41
measure: Concentration of Cabotegravir in Plasma at the End of the Dosing Interval (Ctau)-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Dosing of Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Maximum Observed Concentration (Cmax) Following Oral Dosing With Cabogegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Time of Occurrence of Cmax (Tmax) Following Oral Dosing With Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Apparent Clearance Following Oral Dosing (CL/F) Following Dosing With Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Terminal Absorption Elimination Half-life (t1/2) Following Oral Dosing With Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Apparent Terminal Phase Rate Constant (Lambda z) Following Oral Dosing With Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Volume of Distribution at Steady State (Vss) Following Oral Dosing With Cabotegravir-Oral lead-in Phase
timeFrame: Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose
measure: Ctau Following IM Dosing With CAB LA During Injection Phase
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41
measure: AUC(0-tau) Following IM Dosing With CAB LA During Injection Phase
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41
measure: Cmax Following IM Dosing With CAB LA During Injection Phase
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41
measure: Tmax Following IM Dosing With CAB LA During Injection Phase
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41
Secondary outcomes:
measure: Ctau Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: AUC(0-tau) Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: Cmax Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: Tmax Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 7 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: CL/F Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 7, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: T1/2 Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: Lambda z Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: Vss Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases
timeFrame: Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41, 53, 65, 77, 89
measure: Number of Participants With Non-serious AEs and SAEs (Oral lead-in Phase)
timeFrame: Up to Week 4
measure: Number of Participants Withdrawn Due to AEs-oral lead-in Phase
timeFrame: Up to Week 4
measure: Number of Participants With Maximum Toxicity Post-Baseline in Chemistry Parameters: Oral lead-in Phase
timeFrame: Up to Week 4
measure: Number of Participants With Maximum Toxicity Post-Baseline in Hematology Parameters: Oral lead-in Phase
timeFrame: Up to Week 4
measure: Number of Participants With Abnormal Urinalysis Parameters: Oral lead-in Phase
timeFrame: Up to Week 4
measure: Number of Participants With Shift From Baseline in Vital Signs With Respect to Clinical Concern Range: Oral lead-in Phase
timeFrame: Up to Week 4
measure: Percentage of Participants With Injection Discontinuation-Injection Phase
timeFrame: Week 5 to 41
measure: Number of Participants With Grade 2 to 4 Injection Site Pain-Injection Phase
timeFrame: Week 5 to 41
measure: HIV-Prevention Treatment Satisfaction Total Score-Injection Phase
timeFrame: At Week 10
measure: Number of Participants With Acceptability of Cabotegravir for HIV Prevention
timeFrame: Up to Week 41
Other outcomes:
measure: Relationship Between Safety and Tolerability Parameters With Cabotegravir PK Parameters
timeFrame: Up to Week 41
Locations:
city: Hangzhou
country: China
facility: GSK Investigational Site
state: Zhejiang
city: Beijing
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Han K, Wannamaker P, Lu H, Zhu B, Wang M, Paff M, Spreen WR, Ford SL. Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0205721. doi: 10.1128/AAC.02057-21. Epub 2022 Feb 7.