A Phase I, Multi-centre, Open-label, Single Dose Escalation Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Long-acting Cabotegravir Co-administered With Recombinant Human Hyaluronidase PH20 (rHuPH20) in Healthy Adult Volunteers
Overview
- Phase
- Phase 1
- Intervention
- Cabotegravir 200 mg/mL
- Conditions
- HIV Infections
- Sponsor
- ViiV Healthcare
- Enrollment
- 214
- Locations
- 1
- Primary Endpoint
- Maximum observed plasma concentration (Cmax) of CAB and RPV
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This is an open-label, dose-escalation study to investigate the safety, tolerability and pharmacokinetics (PK) of single subcutaneous (SC) administration of long acting (LA) Cabotegravir (CAB) 200 milligrams per milliliter (mg/mL) with Recombinant Human Hyaluronidase PH20 (rHuPH20) (Part A), a single-dose or repeat-dose SC or intramuscular (IM) administration of LA CAB (greater than or equal to) >=400 mg/mL (Part C), single-dose IM administration of LA CAB Formulation I (Part C Cohort C8) and LA CAB Formulation J (Part C Cohort C11), and a single-dose or repeat-dose IM administration of rilpivirine (RPV) (Part E). Part A of the study (CAB 200 mg/mL with rHuPh20) has been closed to further enrolment based on preliminary results. Part D of the study (CAB >=400 mg/mL with rHuPH20) will not be conducted due to changes in the study design.
Investigators
Eligibility Criteria
Inclusion Criteria
- •At the time of obtaining informed consent, participants age should be greater than or equal to (\>=)18 years and less than or equal to (\<=) 55 years.
- •Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- •Body weight \>=40 kilogram (kg) and body mass index (BMI) within the range \>=18 to \<=32 kilogram per meter square (kg/m\^2).
- •Participants who are negative on a single test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (approved molecular polymerase chain reaction \[PCR\] laboratory or point of care test), performed on the day of admission. A negative result is required prior to the administration of study intervention on Day
- •Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- •Capable of giving written informed consent.
Exclusion Criteria
- •Current presence or history of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders.
- •Current or chronic history of liver disease or known hepatic or biliary abnormalities.
- •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.
- •Positive SARS-CoV-2 polymerase chain reaction test, having signs and symptoms which in the opinion of the investigator are suggestive of coronavirus disease 2019 (COVID-19) (i.e., fever, cough etc) within 14 days of inpatient admission, or having contact with known COVID-19 positive person/s in the 14 days prior to inpatient admission.
- •Human immunodeficiency virus (HIV-1 or HIV-2) infection as indicated by positive antibody/antigen test.
- •History of or on-going high-risk behaviors that, in the opinion of the investigator, may put the participant at increased risk for HIV infection including, but not limited to, 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.
- •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.
- •Abnormal blood pressure.
- •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).
Arms & Interventions
Part A: Participants receiving CAB 200 mg/mL with rHuPH20
Part A of the study (CAB 200 mg/mL with rHuPh20) has been closed to further enrolment based on preliminary results.
Intervention: Cabotegravir 200 mg/mL
Part A: Participants receiving CAB 200 mg/mL with rHuPH20
Part A of the study (CAB 200 mg/mL with rHuPh20) has been closed to further enrolment based on preliminary results.
Intervention: rHuPH20
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
Intervention: Cabotegravir >=400 mg/mL
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
Intervention: Cabotegravir Formulation I
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
Intervention: CAB Formulation J
Part E: Participants receiving RPV
Intervention: RPV
Outcomes
Primary Outcomes
Maximum observed plasma concentration (Cmax) of CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Time of maximum observed plasma concentration (tmax) of Cabotegravir CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Area under the concentration - time curve from time zero to infinity (AUC[0-inf]) of CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Area under the concentration - time curve from time zero to time of last quantifiable concentration or 4 weeks following the injection whichever is earlier (AUC[0-t]) of CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Cohorts Part A, C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohort C10 [Part C])
Area under the concentration - time curve from time zero to last quantifiable time point or 8 weeks following the injection whichever is earlier [AUC(0-t)]
Time Frame: Up to end of study (Week 72 for Cohort C10 [Part C])
Plasma Concentration of CAB and RPV at Week 4
Time Frame: Week 4
Plasma Concentration of CAB and RPV at Week 8
Time Frame: Week 8
Plasma Concentration of CAB and RPV at Week 12
Time Frame: Week 12
Plasma Concentration of CAB and RPV at Week 16
Time Frame: Week 16
Plasma Concentration of CAB and RPV at Week 24
Time Frame: Week 24
Plasma Concentration of RPV at Week 32
Time Frame: Week 32
Plasma Concentration of CAB at Week 36
Time Frame: Week 36
Plasma Concentration of RPV at Week 40
Time Frame: Week 40
Plasma Concentration of CAB and RPV at Week 48
Time Frame: Week 48
Plasma Concentration of CAB
Time Frame: At weeks 56, 64 and 72 for Cohorts C11 and C10 [Part C]
Plasma Concentration of RPV at Week 56
Time Frame: Week 56
Plasma Concentration of RPV at Week 64
Time Frame: Week 64
Plasma Concentration of RPV at Week 72
Time Frame: Week 72
Apparent terminal phase half-life (t1/2) of CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Apparent long-acting absorption rate constant (KA-LA) of CAB and RPV
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Number of Participants with Non-serious Adverse Events (non-SAEs) and Serious Adverse Events (SAEs)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Number of Participants with AEs by Severity
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute value of Hematology parameter: Platelet count (cells per microliter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Hematology parameters: Reticulocytes (Percentage of reticulocytes)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Hematology parameters: Hematocrit (Proportion of red blood cells in blood)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Hematology parameters: Hemoglobin (Hgb) (grams per deciliter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C] , and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute value of Hematology parameter: Red Blood Cell Count (RBC) (million cells per microliter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C] , and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute value of Hematology parameter: Mean Corpuscle Volume (MCV) (Femtoliters)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C] , and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute value of Hematology parameter: Mean Corpuscle Hemoglobin (MCH) (Picograms)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Hematology parameters: Differential count of Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils (giga cells per liter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Clinical Chemistry parameters: Glucose (fasting), Blood Urea Nitrogen (BUN), Creatinine, Sodium, Potassium, Calcium, Direct Bilirubin and Total Bilirubin (milligrams per deciliter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Absolute values of Clinical Chemistry parameters: AST/SGOT, ALT/ SGPT, ALP and CPK (International Units per liter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Clinical chemistry parameters such as Aspartate Aminotransferase (AST) / Serum Glutamic-Oxaloacetic Transaminase (SGOT), Alanine Aminotransferase (ALT)/ Serum Glutamic-Pyruvic Transaminase and (SGPT), Alkaline phosphatase (ALP) and Creatinine Phosphokinase (CPK) will be analyzed.
Absolute values of Clinical chemistry parameters: Albumin and Total Protein (Grams per deciliter)
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameter: Platelet count (cells per microliter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameters: Reticulocytes (Percentage of reticulocytes)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameters: Hematocrit (Proportion of red blood cells in blood)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameters: Hgb (grams per deciliter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameter: RBC Count (million cells per microliter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameter: MCV (Femtoliters)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameter: MCH (picograms)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Hematology parameters: Differential count of Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils (Giga cells per liter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Clinical Chemistry parameters: Glucose (fasting), BUN, Creatinine, Sodium, Potassium, Calcium, Direct Bilirubin and Total Bilirubin (milligrams per deciliter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Clinical Chemistry parameters: AST/SGOT, ALT/ SGPT, ALP and CPK (International Units per liter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Change from Baseline in Clinical chemistry parameters: Albumin and Total Protein (Grams per deciliter)
Time Frame: Baseline (Day 1) and up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Number of participants with maximum toxicity grades increase from Baseline in hematology and clinical chemistry
Time Frame: Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C])
Secondary Outcomes
- Dose proportionality of CAB and RPV based on AUC(0-inf)(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))
- Dose proportionality of CAB and RPV based on AUC(0-t)(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))
- Dose proportionality of CAB and RPV based on Cmax(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))
- Dose proportionality of CAB and RPV based on plasma concentration(Weeks 4, 8, 12 and 24)
- Number of participants with maximum post-baseline QTc values compared to baseline by category (to <=450 milliseconds (msec) or no change, to >450 msec to <=480 msec, to >480 msec to <=500 msec, and to >500 msec)(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))
- Number of participants with maximum post-baseline increase in QTc values compared to baseline based on category (increase <=30 msec, increase of 31-60 msec, and increase of >60 msec)(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))
- Number of participants with worst case post-baseline values relative to potential clinical importance criteria compared to baseline for diastolic blood pressure (DBP), systolic blood pressure (SBP) and pulse rate(Up to end of study (Week 78 for Cohorts C1 and C3 [Part C], Week 52 for Part A, Cohorts C2, C4, C5, C6, C7, C8, C9 [Part C], and Week 72 for Part E and Cohorts C10 and C11 [Part C]))