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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 214
- 试验地点
- 1
- 主要终点
- Maximum observed plasma concentration (Cmax) of CAB and RPV
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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).
- •Any significant arrhythmia which, in the opinion of the investigator or the medical monitor, will interfere with the safety for the individual participant.
- •One or more exclusionary values for a screening Electrocardiogram (ECG).
- •Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
- •Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent [%]).
- •Estimated Glomerular Filtration Rate (eGFR) <60 milliliter per minute (mL/min) using the Chronic Kidney Disease
- •Improved Prediction Equations (CKD-EPI) Creatinine Equation (2021).
- •Hemoglobin <12.5 gram per deciliter (g/dL) for men and <11 g/dL for women.
- •Positive pre-study drug/alcohol screen.
- •Regular use of tobacco- or nicotine-containing products within 3 months prior to screening; or urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g., nicotine patches or vaporizing devices).
- •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.
- •Regular use of known drugs of abuse.
- •Concurrent participation in another clinical trial (except imaging trials); or has participated in a clinical trial and received an investigational product within the following time period prior to the first dosing day in this 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.
- •Exposure to more than four (4) new chemical entities within 12 months prior to the first dosing day.
- •History of sensitivity to any of the study interventions (or components thereof), a history of drug allergy or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation, including a known hypersensitivity to hyaluronidases.
- •Current or anticipated need for chronic anti-coagulation therapy.
- •Hereditary coagulation and platelet disorders (e.g., hemophilia or Von Willebrand disease [VWD]).
- •Participant has a tattoo overlying the location of injection or an underlying skin disease or condition (e.g., infection, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria) that, in the opinion of the investigator, may interfere with interpretation of injection site reactions or administration of study intervention.
- •Any other clinical condition, behavior or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits.
- •Participant who in the investigator's judgment poses a significant suicidality risk. Participant's history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk.
研究组 & 干预措施
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.
干预措施: Cabotegravir 200 mg/mL (Drug)
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.
干预措施: rHuPH20 (Drug)
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
干预措施: Cabotegravir >=400 mg/mL (Drug)
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
干预措施: Cabotegravir Formulation I (Drug)
Part C: Participants receiving CAB >=400 mg/mL or CAB Formulation I or CAB Formulation J
干预措施: CAB Formulation J (Drug)
Part E: Participants receiving RPV
干预措施: RPV (Drug)
结局指标
主要结局
Maximum observed plasma concentration (Cmax) of CAB and RPV
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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)]
时间窗: Up to end of study (Week 72 for Cohort C10 [Part C])
Plasma Concentration of CAB and RPV at Week 4
时间窗: Week 4
Plasma Concentration of CAB and RPV at Week 8
时间窗: Week 8
Plasma Concentration of CAB and RPV at Week 12
时间窗: Week 12
Plasma Concentration of CAB and RPV at Week 16
时间窗: Week 16
Plasma Concentration of CAB and RPV at Week 24
时间窗: Week 24
Plasma Concentration of RPV at Week 32
时间窗: Week 32
Plasma Concentration of CAB at Week 36
时间窗: Week 36
Plasma Concentration of RPV at Week 40
时间窗: Week 40
Plasma Concentration of CAB and RPV at Week 48
时间窗: Week 48
Plasma Concentration of CAB
时间窗: At weeks 56, 64 and 72 for Cohorts C11 and C10 [Part C]
Plasma Concentration of RPV at Week 56
时间窗: Week 56
Plasma Concentration of RPV at Week 64
时间窗: Week 64
Plasma Concentration of RPV at Week 72
时间窗: Week 72
Apparent terminal phase half-life (t1/2) of CAB and RPV
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: 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])
次要结局
- 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]))