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

NCT03422172 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 206898
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 3

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.

Conditions

HIV Infections

Keywords

GSK1265744; Pre-Exposure Prophylaxis; Human immunodeficiency virus; Cabotegravir; Pharmacokinetics

Outcome Measures

Primary Outcomes (19)

• Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs): Injection Phase

  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.

  Week 5 to 41

• Number of Participants With Maximum Toxicity Post-Baseline in Hematology Parameters-Injection Phase

  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.

  Week 5 to 41

• Number of Participants With Maximum Toxicity Post-Baseline in Chemistry Parameters: Injection Phase

  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.

  Week 5 to 41

• Number of Participants With Maximum Toxicity Post-Baseline in Urinalysis Parameters: Injection Phase

  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.

  Week 5 to 41

• Number of Participants With Shift From Baseline in Vital Signs With Respect to Clinical Concern Range: Injection Phase

  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%.

  Week 5 to 41

• Number of Participants Withdrawn Due to AEs- Injection Phase

  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.

  Week 5 to 41

• Number of Participants Experiencing Injection Site Reactions (ISR)-Injection Phase

  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.

  Week 5 to 41

• Concentration of Cabotegravir in Plasma at the End of the Dosing Interval (Ctau)-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Dosing of Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Maximum Observed Concentration (Cmax) Following Oral Dosing With Cabogegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Time of Occurrence of Cmax (Tmax) Following Oral Dosing With Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Apparent Clearance Following Oral Dosing (CL/F) Following Dosing With Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Terminal Absorption Elimination Half-life (t1/2) Following Oral Dosing With Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Apparent Terminal Phase Rate Constant (Lambda z) Following Oral Dosing With Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Volume of Distribution at Steady State (Vss) Following Oral Dosing With Cabotegravir-Oral lead-in Phase

  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.

  Day 27: Pre-dose and at 1, 2, 3, 4, 8, 24 and 168 hours post-dose

• Ctau Following IM Dosing With CAB LA During Injection Phase

  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.

  Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41

• AUC(0-tau) Following IM Dosing With CAB LA During Injection Phase

  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.

  Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41

• Cmax Following IM Dosing With CAB LA During Injection Phase

  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.

  Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41

• Tmax Following IM Dosing With CAB LA During Injection Phase

  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.

  Pre-dose sample on Weeks 5, 9, 17, 25, 33; Post-dose sample on Weeks 6, 10, 18, 26, 34, 37, 41

Secondary Outcomes (18)

• 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

• 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

• 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

• 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

• 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

Other Outcomes (1)

• Relationship Between Safety and Tolerability Parameters With Cabotegravir PK Parameters

  Up to Week 41

Study Arms (1)

Subjects receiving CAB

EXPERIMENTAL

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.

Drug: Oral CAB; Drug: CAB LA

Interventions

Oral CAB DRUG

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.

Subjects receiving CAB

CAB LA DRUG

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.

Subjects receiving CAB

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: Healthy male subjects at low risk of HIV infection will be eligible to participate in this study.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• ViiV Healthcare: lead
• PPD Development, LP: collaborator

Study Sites (3)

GSK Investigational Site

Hangzhou, Zhejiang, 310000, China

Location

GSK Investigational Site

Beijing, 100069, China

Location

GSK Investigational Site

Shanghai, 201508, China

Location

Related Publications (1)

• 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.

  PMID: 35129374 DERIVED

MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus 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
• Masking Details: This will be an open-label study; hence, there will be no masking.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 30, 2018
• First Posted: February 5, 2018
• Study Start: April 10, 2018
• Primary Completion: April 20, 2020
• Study Completion: April 20, 2020
• Last Updated: May 13, 2021
• Results First Posted: May 13, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

CN (3)