A Sub-study of Cabotegravir (CAB) and Rilpivirine (RPV) in Human Immunodeficiency Viruses (HIV)-Infected Participants

ViiV Healthcare118 enrolled

Overview

This sub-study will assess the pharmacokinetics (PK), safety, tolerability, virologic efficacy and health outcomes of CAB (GSK1265744) and RPV long acting (LA) in HIV-infected adult participants currently enrolled in the Antiretroviral Therapy as Long Acting Suppression every 2 Months (ATLAS2M \[A2M\]) study (NCT03299049).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

118

Conditions

Human Immunodeficiency Virus Type 1 (HIV-1)

Interventions

Cabotegravir Injectable SuspensionDRUG

CAB LA injectable suspension is a sterile white to slightly pink suspension containing 200 milligrams per milliliter (mg/mL) of GSK1265744 as free acid for administration by IM injection. CAB LA injectable suspension is to be stored at up to 30 degree Celsius and should not be frozen.

Rilpivirine Injectable SuspensionDRUG

RPV LA injectable suspension is a sterile white suspension containing 300 mg/mL of RPV as the free base for administration by IM injection. RPV LA injectable suspension should be kept in the outer package and stored at 2-8 degree Celsius and should not be frozen. RPV LA should also be protected from light.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Sub-study specific Inclusion Criteria: * Capable of giving sub-study specific informed consent. * Eligible participants must have been on CAB LA + RPV LA regimen for a minimum of 152 weeks while on the ATLAS2-M study. Any disruptions in dosing during ATLAS2-M must be discussed with the Medical Monitor for a final determination of eligibility into the sub-study. * Plasma HIV-1 RNA \<50 copies/mL at Sub-Study Screening. Inclusion criteria detailed for the ATLAS-2M main study apply to the sub-study: * A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin \[hCG\] test) not lactating, and at least one of the following conditions applies: 1. Non-reproductive potential defined as: * Pre-menopausal females with one of the following: i. Documented tubal ligation ii. Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion iii. Hysterectomy iv. Documented Bilateral Oophorectomy * Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. 2. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication, throughout the study, for at least 30 days after discontinuation of all oral study medications, and for at least 52 weeks after discontinuation of CAB LA and RPV LA. * The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception. Exclusion Criteria: Sub-study specific Exclusion Criteria: * Participants with more than 1 plasma HIV-1 RNA measurement \>=50 copies/mL to \<200 copies/mL (virologic blip) within 24 weeks prior to sub-study Screening visit. * Any Suspected Virologic Failure (HIV-RNA greater than \[\>\]200 copies/mL as defined in during ATLAS-2M study. * Participants planning to require oral bridging during participation in the ATLAS-2M sub-study. * The participant has a tattoo or any dermatological condition overlying the thigh region which may interfere with interpretation of injection site reactions. * Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to receive study medication. Exclusion criteria detailed for the ATLAS-2M main study apply to the sub-study: * Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during the study. * Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3 disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy, and Cluster of Differentiation 4 positive (CD4+) counts \<200 cells per microliter are not exclusionary. * Participants with moderate to severe hepatic impairment. * Any pre-existing physical or mental condition (including substance use disorder) which, in the opinion of the Investigator, may interfere with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant. * Participants determined by the Investigator to have a high risk of seizures, including participants with an unstable or poorly controlled seizure disorder. A participant with a prior history of seizure 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. * Participants who, in the investigator's judgment, pose a significant suicide risk. Participant's recent history of suicidal behavior and/or suicidal ideation should be considered when evaluating for suicide risk. * Unstable liver disease (as defined by any of the following: presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice or cirrhosis), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). * History of liver cirrhosis with or without hepatitis viral co-infection. * Ongoing or clinically relevant pancreatitis. * Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically significant cardiac disease. * Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the participant prior to randomization. * Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to receive study medication. * History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. In addition, if heparin is used during PK sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled. * Current or anticipated need for chronic anti-coagulation with the exception of the use of low dose acetylsalicylic acid lesser than or equal to (\<=)325 mg or hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand Disease. * Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening phase to verify a result. * Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the participant's participation in the study of an investigational compound. * Participant has estimated creatine clearance \<50mL per minute per 1.73 square meter via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Method. * Alanine aminotransferase (ALT) \>=3 × upper limit of normal (ULN) at Screening. * Exposure to an experimental drug (with the exception of those in the ATLAS-2M study including CAB, CAB LA, and RPV, RPV LA) or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to Day 1 of this study. * Treatment with any of the following agents within 28 days of Screening: i. radiation therapy; ii. cytotoxic chemotherapeutic agents; iii. tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid \[INH\]); iv. anti-coagulation agents; v. Immunomodulators that alter immune responses such as chronic systemic corticosteroids, interleukins, or interferons * Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. * Use of medications which are associated with Torsade de Pointes. * Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication.

Locations (32)

Outcomes

Primary Outcomes

Concentration at End of Dosing Interval (Ctau) of CAB LA Following Administration of CAB LA + RPV LA Q8W

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis.

Time frame: Weeks -8,-7,-4 and Pre-dose on Day 1(Pre-Thigh Gluteal Injection);2 Hours post-dose on Day 1,Pre-dose on Week 8,Weeks 1 and 4 post-dose(First Thigh Injection);2 Hours post-dose on Week 8 and Weeks 9, 12 post-dose,Pre-dose on Week 16(Last Thigh Injection)

Concentration at End of Dosing Interval (Ctau) of RPV LA Following Administration of CAB LA + RPV LA Q8W

Blood samples were collected for PK analysis.

Maximum Plasma Concentration (Cmax) of CAB LA Following Administration of CAB LA + RPV LA Q8W

Blood samples were collected for PK analysis.

Maximum Plasma Concentration (Cmax) of RPV LA Following Administration of CAB LA + RPV LA Q8W

Blood samples were collected for PK analysis.

Area Under the Concentration Curve From 0 Hours to the Time of Next Dosing (AUC [0-tau]) of CAB LA Following Administration of CAB LA + RPV LA Q8W

Blood samples were collected for PK analysis.

Data from ClinicalTrials.gov

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Secondary Outcomes

Number of Participants With Injection Site Reactions (ISRs) by Maximum Severity Grade - Thigh Injection Phase

Severity of ISRs was analyzed using division of acquired immunodeficiency syndrome (DAIDS) grading scale. The severity is categorized into grades as following: Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4 - Potentially life threatening, Grade 5 - Death. Higher grade indicates more severe condition. Data for number of participants with maximum grade or intensity for overall ISRs were reported.

Time frame: Up to Week 16

Number of Participants With Adverse Events of Special Interest (AESI) Based on Maximum Severity Grade- Thigh Injection Phase

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Severity of AESI was analyzed using DAIDS grading scale. The severity is categorized into grades as following: Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4 - Potentially life threatening, Grade 5 - Death. Higher grade indicates more severe condition. Data for number of participants with common AESI based on maximum severity were reported.

Time frame: Up to Week 16

Number of Participants Who Discontinue Treatment Due to ISRs and AESIs-Thigh Injection Phase

Time frame: Up to Week 16

Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) Less Than (<)50 Copies Per Milliliter (Copies/mL) Using the Food and Drug (FDA) Snapshot Algorithm-Thigh Injection Phase

Percentage of participants with plasma HIV-1 RNA \< 50 copies/mL was obtained using the FDA snapshot algorithm. Baseline was the latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Percentage values are rounded off.

Time frame: Baseline (Day 1) and at Weeks 4, 8, 12, 16

Percentage of Participants With Plasma HIV RNA Greater Than or Equal to (>=)50 Copies/mL Over Time as Per the FDA Snapshot Algorithm- Thigh Injection Phase

Percentage of participants with plasma HIV 1 RNA \>= 50 copies/mL was obtained using the FDA snapshot algorithm. Baseline was the latest pre-treatment assessment with a non-missing value, including those from unscheduled visits. Percentage values are rounded off.

Time frame: Baseline (Day 1) and at Weeks 4, 8, 12, 16

Percentage of Participants With Protocol-defined Confirmed Virologic Failure (CVF)- Thigh Injection Phase

Plasma samples were collected for quantitative analysis of HIV-1 RNA. CVF was defined as rebound as indicated by two consecutive plasma HIV-1-RNA levels \>=200 copies/mL after prior suppression to \<200 copies/mL. Percentage of participants with protocol-defined CVF were reported.

Time frame: Up to Week 16

Number of Participants With Treatment Emergent Genotypic Resistance - Thigh Injection Phase

Plasma samples were collected for drug resistance testing. Number of participants who met CVF criteria (two consecutive plasma HIV-1-RNA levels \>=200 copies/mL after prior suppression to \<200 copies/mL) with treatment emergent genotypic resistance were reported.

Time frame: Up to Week 16

Number of Participants With Treatment Emergent Phenotypic Resistance - Thigh Injection Phase

Time frame: Up to Week 16

Number of Participants With Post-injection Pain Using Numerical Rating Scale (NRS) on Day 1-Thigh Injection Phase

A numeric rating scale was used to assess the level of pain experienced following injections with CAB + RPV. The scale contains one item and the response scale is ranging from 0= "no pain" to 10= "extreme pain". NRS questionnaire included two questions regarding the maximum level of pain experienced with the most recent injections.

Time frame: Day 1

Number of Participants With Post-injection Pain Using Numerical Rating Scale (NRS) for CAB LA + RPV LA Q8W Arm on Week 8- Thigh Injection Phase

Time frame: Week 8

Number of Participants With Post-injection Pain Using Numerical Rating Scale (NRS) for CAB LA + RPV LA Q4W Arm on Week 12- Thigh Injection Phase

Time frame: Week 12

Number of Participants With Post-injection Pain Using Numerical Rating Scale (NRS)- Return to Gluteal Injection Phase

Time frame: Study Week 16

HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Total Score at Indicated Time Points-Thigh Injection Phase

HIVTSQ is a self-completion measure specifically designed to measure treatment satisfaction in HIV participants. HIVTSQs questionnaire comprises 1-12 questions and the total treatment satisfaction score is computed with items 1-11 and summed to produce a total score with a possible range of 0 to 66. Higher scores indicate a greater satisfaction and a lower score indicate dissatisfaction. Baseline was the latest pre-treatment assessment with a non-missing value, including those from unscheduled visits.

Time frame: Baseline (Day 1) and Week 16

HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Total Score at Indicated Time Points for CAB LA + RPV LA Q8W Arm -Return to Gluteal Injection Phase

HIVTSQ is a self-completion measure specifically designed to measure treatment satisfaction in HIV participants. HIVTSQs questionnaire comprises 1-12 questions and the total treatment satisfaction score is computed with items 1-11 and summed to produce a score with a possible range of 0 to 66. Higher scores indicate a greater satisfaction and a lower score indicate dissatisfaction.

Time frame: Study Week 24

HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Total Score at Indicated Time Points for CAB LA + RPV LA Q4W Arm -Return to Gluteal Injection Phase

HIVTSQ is a self-completion measure specifically designed to measure treatment satisfaction in HIV participants. HIVTSQs questionnaire comprises 1-12 questions and the total treatment satisfaction score is computed with items 1-11 and summed to produce a score with a possible range of 0 to 66. Higher scores indicate a greater satisfaction and a lower score indicate dissatisfaction.

Time frame: Study Week 20

Change From Baseline in HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Individual Item Score at Indicated Time Points- Thigh Injection Phase

HIVTSQs is a 12-item questionnaire and individual item scores on HIVTSQs scale are rated as 6(very satisfied) to 0(very dissatisfied).Higher scores represent greater satisfaction.Data was reported for each treatment satisfaction item based on(Item1=satisfaction with current treatment,Item2=level of HIV control based on treatment,Item3=any side effects of present treatment,Item4=demands made by current treatment,Item5=convenience in finding treatment,Item6=flexibility in finding treatment,Item7=understanding HIV,Item8=extent to which the treatment fits in with lifestyle, Item9=recommendation of present treatment to someone else,Item10=continuation with present form of treatment,Item11=easy or difficult treatment,Item12=amount of discomfort/pain involved with present form of treatment).Baseline was latest pre-treatment assessment with a non-missing value, including those from unscheduled visits.Change from Baseline was calculated by subtracting Baseline value from post-dose visit value.

Time frame: Baseline (Day 1) and up to Week 16

Change From Study Week 16 to Study Week 24 in HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Individual Item Score at Indicated Time Points for CAB LA + RPV LA Q8W Arm- Return to Gluteal Injection

HIVTSQs is a 12-item questionnaire and individual item scores on HIVTSQs scale are rated as 6 (very satisfied) to 0 (very dissatisfied). Higher scores represent greater satisfaction with each aspect of treatment. Data was reported for each treatment satisfaction item based on (Item 1=satisfaction with current treatment, Item 2=level of HIV control based on treatment, Item 3=any side effects of present treatment, Item 4=demands made by current treatment, Item 5=convenience in finding treatment, Item 6=flexibility in finding treatment, Item 7=understanding HIV, Item 8=extent to which the treatment fits in with lifestyle, Item 9=recommendation of present treatment to someone else, Item 10=continuation with present form of treatment, Item 11=easy or difficult treatment, Item 12=amount of discomfort/pain involved with present form of treatment). Change from Study Week 16 to Study Week 24 was calculated by subtracting the Study Week 16 value from the Study Week 24 value.

Time frame: Study Week 16 and Study Week 24

Change From Study Week 16 to Study Week 20 in HIV Treatment Satisfaction Questionnaire - Status Version (HIVTSQs) Individual Item Score at Indicated Time Points for CAB LA + RPV LA Q4W Arm- Return to Gluteal Injection Phase

HIVTSQs is a 12-item questionnaire and individual item scores on HIVTSQs scale are rated as 6(very satisfied) to 0(very dissatisfied).Higher scores represent greater satisfaction.Data was reported for each treatment satisfaction item based on(Item1=satisfaction with current treatment,Item2=level of HIV control based on treatment,Item3=any side effects of present treatment,Item4=demands made by current treatment,Item5=convenience in finding treatment,Item6=flexibility in finding treatment,Item7=understanding HIV,Item8=extent to which the treatment fits in with lifestyle, Item9=recommendation of present treatment to someone else,Item10=continuation with present form of treatment,Item11=easy or difficult treatment,Item12=amount of discomfort/pain involved with present form of treatment).Change from Study Week 16 to Study Week 20 was calculated by subtracting the Study Week 16 value from the Study Week 20 value.

Time frame: Study Week 16 and Study Week 20

HIV Treatment Satisfaction Questionnaire - Change Version (HIVTSQc) Total Score at Indicated Time Points- Thigh Injection Phase

HIVTSQ is a self-completion measure specifically designed to measure treatment satisfaction in HIV participants. Total treatment satisfaction change score is computed using items 1 to 11 and are summed to produce a score with a possible range of -33 to 33. Higher the score, greater the improvement in satisfaction with treatment; the lower the score, the greater the deterioration in satisfaction with treatment. A score of 0 represented no change.

Time frame: Up to Week 16

HIV Treatment Satisfaction Questionnaire - Change Version (HIVTSQc) Individual Item Score at Indicated Time Points- Thigh Injection Phase

HIVTSQc is a 12-item questionnaire to measure treatment satisfaction in HIV participants. Individual items were rated as +3 (much more satisfied) to -3 (much less satisfied). Higher the score, greater the improvement in satisfaction with each aspect of treatment and lower the score, greater the deterioration in satisfaction with each aspect of treatment. Data was reported for each treatment satisfaction item based on (Item 1=satisfaction with current treatment, Item 2=level of HIV control based on treatment, Item 3=any side effects of present treatment, Item 4=demands made by current treatment, Item 5=convenience in finding treatment, Item 6=flexibility in finding treatment, Item 7=understanding HIV, Item 8=extent to which the treatment fits in with lifestyle, Item 9=recommendation of present treatment to someone else, Item 10=continuation with present form of treatment, Item 11=easy or difficult treatment, Item 12=amount of discomfort/pain involved with present form of treatment).

Time frame: Up to Week 16

Number of Participants With Their Treatment Preference as Assessed Using Preference Questionnaire for CAB LA + RPV LA Q8W Arm

A preference questionnaire was used to assess participant's preference for the thigh injections compared with the gluteal injections. The "Preference" questionnaire included a single item question evaluating preference of HIV treatment. Participants were required to provide their response to Question, which stated "Which injection site do you prefer". The responses included Injections in the buttock, Injections in the thigh and No preference.

Time frame: Up to Study Week 24

Number of Participants With Their Treatment Preference as Assessed Using Preference Questionnaire for CAB LA + RPV LA Q4W Arm

Time frame: Up to Study Week 20