A Study to Investigate Pharmacokinetics, Safety and Tolerability of Long-Acting Cabotegravir Plus Recombinant Human Hyaluronidase PH20 in Healthy Adult Participants

Study Overview
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Brief Summary
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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) and CAB 400 mg/mL without rHuPH20 (Part C) and CAB 400 mg/mL with rHuPH20 (Part D). Part A of the study (CAB 200 mg/mL with rHuPh20) has been closed to further enrolment based on preliminary results.

Official Title
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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

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Cabotegravir 200 mg/mL
* Drug: Cabotegravir 400 mg/mL
* Drug: Recombinant human hyaluronidase PH20 (rHuPH20)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At the time of obtaining informed consent, participants age should be equal to or greater than (=>)18 years and equal to or less than (=<) 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 1. 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Participants receiving CAB 200 mg/mL with rHuPH20<br>Part A of the study (CAB 200 mg/mL with rHuPh20) has been closed to further enrolment based on preliminary results. | Drug: Cabotegravir 200 mg/mL<br>* CAB 200 mg/mL will be administered.<br>Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br>* rHuPH20 will be administered.<br>|
| Experimental: Part C: Participants receiving CAB 400 mg/mL<br> | Drug: Cabotegravir 400 mg/mL<br>* CAB 400 mg/mL will be administered.<br>|
| Experimental: Part D: Participants receiving CAB 400 mg/mL with rHuPH20<br> | Drug: Cabotegravir 400 mg/mL<br>* CAB 400 mg/mL will be administered.<br>Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br>* rHuPH20 will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of Cabotegravir |  | Up to Week 52 | 
| Time of maximum observed plasma concentration (tmax) of Cabotegravir |  | Up to Week 52 | 
| Area under the concentration - time curve from time zero to infinity (AUC[0-inf]) of Cabotegravir |  | Up to Week 52 | 
| 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 Cabotegravir |  | Up to Week 52 | 
| Plasma Concentration of Cabotegravir at Week 4 |  | Week 4 | 
| Plasma Concentration of Cabotegravir at Week 8 |  | Week 8 | 
| Plasma Concentration of Cabotegravir at Week 12 |  | Week 12 | 
| Plasma Concentration of Cabotegravir at Week 24 |  | Week 24 | 
| Apparent terminal phase half-life (t1/2) of Cabotegravir |  | Up to Week 52 | 
| Apparent long-acting absorption rate constant (KA-LA) of Cabotegravir |  | Up to Week 52 | 
| Number of Participants with Non-serious Adverse Events (non-SAEs) and Serious Adverse Events (SAEs) |  | Up to Week 52 | 
| Number of Participants with AEs by Severity |  | Up to Week 52 | 
| Absolute value of Hematology parameter: Platelet count (cells per microliter) |  | Up to Week 52 | 
| Absolute values of Hematology parameters: Reticulocytes (Percentage of reticulocytes) |  | Up to Week 52 | 
| Absolute values of Hematology parameters: Hematocrit (Proportion of red blood cells in blood) |  | Up to Week 52 | 
| Absolute values of Hematology parameters: Hemoglobin (Hgb) (grams per deciliter) |  | Up to Week 52 | 
| Absolute value of Hematology parameter: Red Blood Cell Count (RBC) (million cells per microliter) |  | Up to Week 52 | 
| Absolute value of Hematology parameter: Mean Corpuscle Volume (MCV) (Femtoliters) |  | Up to Week 52 | 
| Absolute value of Hematology parameter: Mean Corpuscle Hemoglobin (MCH) (Picograms) |  | Up to Week 52 | 
| Absolute values of Hematology parameters: Differential count of Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils (giga cells per liter) |  | Up to Week 52 | 
| Absolute values of Clinical Chemistry parameters: Glucose (fasting), Blood Urea Nitrogen (BUN), Creatinine, Sodium, Potassium, Calcium, Direct Bilirubin and Total Bilirubin (milligrams per deciliter) |  | Up to Week 52 | 
| Absolute values of Clinical Chemistry parameters: AST/SGOT, ALT/ SGPT, ALP and CPK (International Units per liter) | 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. | Up to Week 52 | 
| Absolute values of Clinical chemistry parameters: Albumin and Total Protein (Grams per deciliter) |  | Up to Week 52 | 
| Change from Baseline in Hematology parameter: Platelet count (cells per microliter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameters: Reticulocytes (Percentage of reticulocytes) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameters: Hematocrit (Proportion of red blood cells in blood) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameters: Hgb (grams per deciliter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameter: RBC Count (million cells per microliter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameter: MCV (Femtoliters) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameter: MCH (picograms) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Hematology parameters: Differential count of Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils (Giga cells per liter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Clinical Chemistry parameters: Glucose (fasting), BUN, Creatinine, Sodium, Potassium, Calcium, Direct Bilirubin and Total Bilirubin (milligrams per deciliter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Clinical Chemistry parameters: AST/SGOT, ALT/ SGPT, ALP and CPK (International Units per liter) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Clinical chemistry parameters: Albumin and Total Protein (Grams per deciliter) |  | Baseline (Day 1) and up to Week 52 | 
| Number of participants with maximum toxicity grades increase from Baseline in hematology and clinical chemistry |  | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose proportionality of Cabotegravir based on AUC(0-inf) |  | Up to Week 52 | 
| Dose proportionality of Cabotegravir based on AUC(0-t) |  | Up to Week 52 | 
| Dose proportionality of Cabotegravir based on Cmax |  | Up to Week 52 | 
| Dose proportionality of Cabotegravir 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 Week 52 | 
| 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 Week 52 | 
| 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 | Number of participants with worst case post-baseline values relative to potential clinical importance criteria compared to baseline will be categorized into change to low, change to within range or no change, and change to high. | Up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cabotegravir (CAB), Long-Acting Injection, Pharmacokinetics, Safety, Tolerability