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

Phase 1

Completed

Conditions: HIV Infections

Interventions: Drug: Oral CAB
Drug: CAB LA

Registration Number: NCT03422172

Lead Sponsor: ViiV Healthcare

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 48

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Subjects receiving CAB	CAB LA	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.
Subjects receiving CAB	Oral 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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs): Injection Phase	Week 5 to 41	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, or other situations as per investigator's judgement.
Number of Participants With Maximum Toxicity Post-Baseline in Hematology Parameters-Injection Phase	Week 5 to 41	Hematology parameters were graded according to Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Higher grade indicates more severity. Clinical hematology parameters included: Activated partial thromboplastin time (APTT) prolonged, hemoglobin (Hb) (increased), white blood cells (WBC) (decreased), lymphocytes count (decreased), neutrophils (decreased), platelets (decreased), prothrombin international normalized ratio (Pro.INR) (increased). Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Number of Participants With Maximum Toxicity Post-Baseline in Chemistry Parameters: Injection Phase	Week 5 to 41	Chemistry parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Higher grade indicates more severity. Clinical chemistry laboratory parameters included alanine amino transferase (ALT), albumin, alkaline phosphatase (ALP), Aspartate Aminotransferase (AST), bilirubin, calcium (hypercalcemia and hypocalcemia), carbon dioxide (CO2) (decreased), cholesterol (high), Creatine phosphokinase (CPK) increased, Creatinine increased, creatinine clearance (decreased), glucose (hyperglycemia and hypoglycemia), Hypophosphatemia, Potassium (Hyperkalemia and hypokalemia), Sodium (hypernatremia and hyponatremia), Hypertriglyceridemia, uric acid (increased). Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Number of Participants Experiencing Injection Site Reactions (ISR)-Injection Phase	Week 5 to 41	Injection site reactions were recorded via ISR diaries and managed through investigator assessment. Number of participants who experienced any injection site reaction (like pain, itching, bruising, bump, discoloration, redness, skin firmness, swelling, warm to touch etc.) is presented.
Number of Participants With Maximum Toxicity Post-Baseline in Urinalysis Parameters: Injection Phase	Week 5 to 41	Urinalysis parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Urinalysis parameters included: Protein. Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Number of Participants With Shift From Baseline in Vital Signs With Respect to Clinical Concern Range: Injection Phase	Week 5 to 41	Vital signs were measured after participants had rested in supine position for at least 5 minutes. Clinical concern ranges were: systolic blood pressure (SBP) (Low: \<85 millimeters of mercury \[mmHg\], High: \>160 mmHg), diastolic blood pressure (DBP) (Low: \<45 mmHg, High: \>100 mmHg), pulse rate (Low: \<40 mmHg, High: \>100 mmHg). Worst case results are presented. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, were recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Number of Participants Withdrawn Due to AEs- Injection Phase	Week 5 to 41	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Number of participants withdrawn from study due to AEs is presented.
Time of Occurrence of Cmax (Tmax) Following Oral Dosing With Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of Tmax following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Apparent Clearance Following Oral Dosing (CL/F) Following Dosing With Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of CL/F following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Terminal Absorption Elimination Half-life (t1/2) Following Oral Dosing With Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of t1/2 following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Concentration of Cabotegravir in Plasma at the End of the Dosing Interval (Ctau)-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of Ctau following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Dosing of Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of AUC(0-tau) following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Maximum Observed Concentration (Cmax) Following Oral Dosing With Cabogegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of Cmax following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Cmax Following IM Dosing With CAB LA During Injection Phase	Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41	Blood samples were collected at the indicated time points for the determination of Cmax following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Tmax Following IM Dosing With CAB LA During Injection Phase	Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41	Blood samples were collected at the indicated time points for the determination of Tmax following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Apparent Terminal Phase Rate Constant (Lambda z) Following Oral Dosing With Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of Lambda z following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Volume of Distribution at Steady State (Vss) Following Oral Dosing With Cabotegravir-Oral lead-in Phase	Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose	Blood samples were collected at the indicated time points for the determination of Vss following oral dose of Cabotegravir and was calculated by standard non-compartmental analysis.
Ctau Following IM Dosing With CAB LA During Injection Phase	Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41	Blood samples were collected at the indicated time points for the determination of Ctau following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
AUC(0-tau) Following IM Dosing With CAB LA During Injection Phase	Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41	Blood samples were collected at the indicated time points for the determination of AUC (0-tau) following IM dose of CAB LA and was calculated by standard non-compartmental analysis.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Maximum Toxicity Post-Baseline in Chemistry Parameters: Oral lead-in Phase	Up to Week 4	Chemistry parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Higher grade indicates more severity. Clinical chemistry laboratory parameters included ALT, albumin, ALP, AST, bilirubin, calcium (hypercalcemia and hypocalcemia), CO2 decreased, cholesterol, CPK increased, Creatinine increased, creatinine clearance (decreased), glucose (hyperglycemia and hypoglycemia), Hypophosphatemia, Potassium (Hyperkalemia and hypokalemia), Sodium (hypernatremia and hyponatremia), Hypertriglyceridemia, uric acid (increased). Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Ctau Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of Ctau following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
CL/F Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of CL/F following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Vss Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of Vss following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Lambda z Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of Lambda z following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
AUC(0-tau) Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of AUC(0-tau) following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Cmax Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of Cmax following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Tmax Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of Tmax following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
T1/2 Following IM Dosing With CAB LA Through Injection and Long-term Follow-up Phases	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	Blood samples were collected at the indicated time points for the determination of t1/2 following IM dose of CAB LA and was calculated by standard non-compartmental analysis.
Number of Participants With Non-serious AEs and SAEs (Oral lead-in Phase)	Up to Week 4	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent disability/incapacity, Is a congenital anomaly/birth defect, other situation as per investigator's judgement.
Number of Participants Withdrawn Due to AEs-oral lead-in Phase	Up to Week 4	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Number of participants withdrawn from study due to AEs is presented.
Number of Participants With Maximum Toxicity Post-Baseline in Hematology Parameters: Oral lead-in Phase	Up to Week 4	Hematology parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Higher grade indicates more severity. Clinical hematology parameters included: APTT prolonged, Hb (increased), WBC (decreased), lymphocytes count (decreased), neutrophils (decreased), platelets (decreased), prothrombin international normalized ratio (Pro.INR) (increased). Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Number of Participants With Abnormal Urinalysis Parameters: Oral lead-in Phase	Up to Week 4	Urinalysis parameters were graded according to DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events as Grade 0: none, Grade 1: mild; Grade 2: moderate; Grade 3: severe; and Grade 4: potentially life-threatening consequences. Urinalysis parameters included: Protein. Baseline was the last available assessment prior to the time of the first dose. Maximum toxicity grade reached by a participant post-Baseline was summarized.
Number of Participants With Shift From Baseline in Vital Signs With Respect to Clinical Concern Range: Oral lead-in Phase	Up to Week 4	Vital signs were measured after participants had rested in supine position for at least 5 minutes. Clinical concern ranges were: SBP (Low \<85 mmHg, High: \>160 mmHg), DBP (Low: \<45 mmHg, High: \>100 mmHg), pulse rate (Low: \<40 mmHg, High: \>100 mmHg). Worst case results are presented. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there was no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, were recorded in the 'To Normal or No Change' category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%.
Number of Participants With Grade 2 to 4 Injection Site Pain-Injection Phase	Week 5 to 41	Severity of injection site reactions was analyzed using DAIDS AE Grading Table. The severity is categorized into grades as following: Grade 1 (mild): causing no or minimal interference with usual social and functional activities, Grade 2 (moderate): causing greater than minimal interference with usual social and functional activities, Grade 3 (severe): causing inability to perform usual social and functional activities, Grade 4 (Potentially life threatening): causing inability to perform basic self-care functions or hospitalization indicated. Higher grade indicates more severe condition. Number of participants who had at least one Grade 2 to 4 Injection site reaction is presented.
HIV-Prevention Treatment Satisfaction Total Score-Injection Phase	At Week 10	HIV-Prevention Treatment Satisfaction Questionnaire (change) (HIV-PrevTSQc) was used to assess participant tolerability and satisfaction to the treatment. It consisted total 13 questions. The experience of HIV prevention treatment was assessed using a scale from 3 (much more satisfied/effective/convenient/ flexible/likely to recommend the treatment/likely to speak well of the treatment/easier now) to -3 (much less satisfied/effective/convenient/flexible/likely to recommend the treatment/likely to speak well of the treatment/easier now). Total score was calculated by taking sum of scores of all questions. It ranges from -39 to 39, with higher scores indicating more satisfaction.
Number of Participants With Acceptability of Cabotegravir for HIV Prevention	Up to Week 41	Number of participants who consider using cabotegravir for HIV prevention in the future is presented. Participants were asked if they would consider using cabotegravir for HIV prevention in the future and their answers to this question were recorded as 'Yes', 'No' or 'Missing'.
Percentage of Participants With Injection Discontinuation-Injection Phase	Week 5 to 41	Percentage of participants with injection discontinuation is presented.