Pharmacokinetic Study of Cabotegravir and Rilpivirine Long-acting Intramuscular Injections in Healthy Adult Participants

Study Overview
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Brief Summary
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This is a phase 1, open label study in healthy participants to assess the pharmacokinetics of cabotegravir and rilpivirine in plasma following the administration of a single 600 milligram (mg) and a 900 mg intramuscular (IM) injection respectively, to separate vastus lateralis muscles on each leg. Cabotegravir is an integrase inhibitor being developed in combination with rilpivirine, a non-nucleoside reverse transcriptase inhibitor, for the treatment of human immunodeficiency virus (HIV). The objective is to evaluate pharmacokinetics, tolerability, and safety of cabotegravir long acting plus rilpivirine long acting administered concomitantly as two separate IM injections in the vastus lateralis muscle of adult healthy participants. The screening phase will be of 30 days, oral lead-in (OLI) phase of 28 days, there will be washout period of 10-14 days, followed by an injection phase and follow-up period will be up to 52-weeks. Approximately 15 adult healthy participants will be enrolled.

Official Title
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A Phase 1, Open-Label Study to Evaluate the Pharmacokinetics and Tolerability of Cabotegravir and Rilpivirine Long-Acting Injections Following Intramuscular Administration in the Vastus Lateralis Muscle of Healthy Adult Participants

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Cabotegravir Tablets
* Drug: Rilpivirine Tablets
* Drug: Cabotegravir extended release suspension for injection (long-acting)
* Drug: Rilpivirine extended release suspension for injection (long-acting)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent. Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. A participant with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range may be included only if the investigator in consultation with the medical monitor agree and document that the finding is unlikely to introduce additional risk and will not interfere with the study procedures. A single repeat of a procedure or laboratory parameter is allowed to determine eligibility. Participants who are negative on two consecutive tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19), performed at Screening and on Day -1 of admission to the Phase I unit, using an approved molecular test (polymerase chain reaction or antigen test). Body weight >=40 kilogram (Kg) and body mass index (BMI) within the range 18 to 35 kg per square meter (inclusive). Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least 52 weeks after the last dose of study intervention; refrain from donating sperm plus either be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception/barrier as detailed; agree to use a male condom when having sexual intercourse with a woman of childbearing potential who is not currently pregnant, agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person. Female participants: a female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies; is not a woman of childbearing potential (WOCBP) or is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of less than 1 percent (%,) during the intervention period and for atleast 52 weeks after the last dose of study intervention; the investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention; a WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 30 days of the first dose of study intervention, if a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive; the investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form. Exclusion Criteria: Signs and symptoms which in the opinion of the investigator are suggestive of COVID-19 (example; fever, cough etc) within 14 days of inpatient admission Contact with known COVID-19 positive person/s in the 14 days prior to inpatient admission History or presence of/significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data. Abnormal blood pressure as determined by the investigator. Alanine transaminase (ALT) greater than 1.5 times upper limit of normal (ULN). Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%). 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 ongoing or clinically relevant seizure disorder within the previous 2 years, including participants who have required treatment for seizures within this time period. A prior history of seizure, with a seizure free period of at least 2 years, off anti-epileptics, may be considered for enrollment 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 enrollment. QT interval corrected for heart rate (QTc) greater than 450 millisecond for male participants and greater than 470 milliseconds for female participants A participant, who has an underlying skin disease or disorder (i.e. infection, inflammation, dermatitis, eczema, drug rash, drug allergy, psoriasis, food allergy, urticaria). A participant, who is considered to have insufficient musculature to allow safe administration of cabotegravir or rilpivirine in the opinion of the investigator will be excluded. Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication to the completion of the follow-up visit unless in the opinion of the Investigator and ViiV medical monitor the medication will not interfere with the study procedures or compromise participant safety. Participation in the study would result in loss of blood or blood products in excess of 500 mililiter within 56 days. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention. Positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention. Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. Presence of the Hepatitis B core antibody (HBcAb) should also lead to exclusion from the study even if HBsAg is negative. Positive pre-study drug/alcohol screen Positive human immunodeficiency virus (HIV) antibody test Regular use of known drugs of abuse 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. One unit is equivalent to 8 grams of alcohol: a half-pint ( 240 milliliter) of beer, 1 glass (125 milliliter) of wine or 1 (25 milliliter) measure of spirits. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices) within 6 months prior to screening. Participant, who has a tattoo or other dermatological condition overlying the thigh region which may interfere with interpretation of injection site reactions. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates their participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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
Intervention Model: Single Group Assignment
Interventional Model Description: Eligible participants will receive orally, tablets of cabotegravir plus rilpivirine for 28 days. There will be 10 to 14 days wash out period followed by an IM injection of cabotegravir long-acting plus rilpivirine long-acting.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OLI phase followed by Injection phase<br>Participants will be administered cabotegravir at a dose of 30 mg plus rilpivirine dose of 25 mg once daily with meal on Day 1 to Day 28 in OLI phase. There will be 10 to 14 days wash out period after OLI. This will be followed by an injection phase, wherein participants will receive 600 mg cabotegravir long acting given as one 3 milliliter (mL) IM injection plus 900 mg rilpivirine long acting given as one 3 mL IM injection on Day 1. | Drug: Cabotegravir Tablets<br>* Cabotegravir tablets will be white to almost white oval shaped film coated tablets with a unit dose of 30 mg and will be administered orally.<br>Drug: Rilpivirine Tablets<br>* Rilpivirine tablets will be off-white, round, biconvex film coated tablets with a unit dose of 25 mg and will be administered orally.<br>Drug: Cabotegravir extended release suspension for injection (long-acting)<br>* Cabotegravir long-acting will be a sterile white to slightly pink suspension containing 200 mg per mL of GSK1265744 as free acid for administration by intramuscular injection.<br>Drug: Rilpivirine extended release suspension for injection (long-acting)<br>* Rilpivirine long-acting will be a sterile white suspension containing 300 mg per mL of rilpivirine as the free base for administration by intramuscular injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) for cabotegravir (injection phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22 and Day 28 | 
| Time of Cmax (Tmax) for cabotegravir (injection phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22 and Day 28 | 
| Area under the plasma concentration-time curve from time zero to time (AUC[0-t]) for cabotegravir (injection+follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22, Day 28, Week 8, Week 12, Week 24, Week 36 and Week 52 | 
| Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC[0-infinity]) for cabotegravir (injection+follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22, Day 28, Week 8, Week 12, Week 24, Week 36 and Week 52 | 
| Apparent terminal phase half-life (t1/2) for cabotegravir (follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | One post-dose sample at Week 8, Week 12, Week 24, Week 36, and Week 52 | 
| Absorption rate constant for cabotegravir (follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of cabotegravir. | One post-dose sample at Week 8, Week 12, Week 24, Week 36, and Week 52 | 
| Cmax for rilpivirine (injection phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22 and Day 28 | 
| Tmax for rilpivirine (injection phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22 and Day 28 | 
| AUC(0-t) for rilpivirine (injection+follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22, Day 28, Week 8, Week 12, Week 24, Week 36 and Week 52 | 
| AUC(0-infinity) for rilpivirine (injection+follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | Day 1 (Pre-dose, 1 hour, 2 hours) and one post-dose sample on Day 2, Day 4, Day 5, Day 7, Day 10, Day 15, Day 17, Day 22, Day 28, Week 8, Week 12, Week 24, Week 36 and Week 52 | 
| t1/2 for rilpivirine (follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | One post-dose sample at Week 8, Week 12, Week 24, Week 36, and Week 52 | 
| Absorption rate constant for rilpivirine (follow-up phase) | Blood samples will be collected at indicated time points for pharmacokinetic analysis of rilpivirine. | One post-dose sample at Week 8, Week 12, Week 24, Week 36, and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cabotegravir, rilpivirine, HIV, Pharmacokinetics, intramuscular injection