A Study to Investigate Cabotegravir Ultra Long-Acting (CAB ULA) Plus Rilpivirine Ultra Long-Acting (RPV ULA) in Adults and Adolescents With HIV Who Are Virologically Suppressed

Inclusion criteria:

Patient Study Participant (PSP) Inclusion criteria

• Adults and adolescents with HIV-1 infection aged 12 years or older, at the time of signing the informed consent.
• Weight >=35 kg.
• Documented evidence of at least 2 plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: 1 within the 6 to 12-month window, and 1 within 6 months prior to Screening.
• Must be on current daily oral antiretroviral regimen for at least 6 months uninterrupted prior to Screening.
• Any prior switch, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability/safety, access to medications, or convenience/simplification, and must NOT have been done for virologic treatment failure (HIV-1 RNA >=200 c/mL).

The addition, removal, or switch of a drug(s) that has been used to treat HIV based on antiretroviral properties of the drug constitutes a change in ART with the following limited exceptions:

• Historical changes in formulations of ART drugs or booster drugs will not constitute a change in ART regimen if the data support similar exposures and efficacy, and the change must have been at least 3 months prior to Screening.
• A change from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) will not be considered a regimen change.
• For participants who received historical maternal perinatal use of an Nucleoside Reverse Transcriptase Inhibitors (NRTI) when given in addition to an ongoing antiretroviral therapy (ART), this will not be considered a change in ART regimen.
• For participants who received historical administration of Antiretroviral (ARV) drugs as a newborn, prior to initiation of maintenance ART, this will not be considered a change to ART regimen.

• A change in dosing scheme of the same drug from twice daily to once daily will not be considered a change in ART regimen if data support similar exposures and efficacy.

  • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • All participants in the study should be counselled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission.
  • Participants of childbearing potential:

• A participant is eligible to participate if they are not pregnant or breast/chest feeding, and 1 of the following conditions applies:

  • Is not of childbearing potential OR
  • Is a person of childbearing potential (POCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, prior to, during the study intervention period, and for 52 weeks following the last dose of study intervention administered.
• A POCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) at screening, and on Day 1 before 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.

  • Contraception and barriers as well as pregnancy testing is required as appropriate for the age, sexual activity, and sexual maturity of adolescent participants and as required by local regulations.
  • The investigator, or a person designated by the investigator, will obtain written informed consent from each study participant and the participant's assent, when applicable, before any study-specific activity is performed. All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand.
• If of legal age or otherwise able to provide independent informed consent as determined by site standard operation procedures (SOPs) and consistent with site institutional review board/ ethical committee (IRB/EC) policies and procedures: Study participants must be capable of giving written informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

• If not of legal age or otherwise not able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: parent or legal guardian is willing and able to provide written informed consent for study participation and potential adolescent participant must also provide written assent for participation in the study. Note: As adolescent participants meet what is considered the age of majority in the country (e.g. 18 years of age), they must sign the currently approved informed consent form to continue in the study.

  • For participants enrolled in France: a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Staff study participant (SSP) inclusion criteria

As part of the implementation objectives, staff at the investigative sites will be invited to complete a questionnaire and possibly participate in an interview. To be eligible, the SSP must meet the following conditions:

• Be a delegated staff member for the study, either as a physician, nurse, injector, pharmacist, or other appropriate healthcare professional.
• Able to provide consent to participate and has the required resource for questionnaire completion and to participate in an interview.
• Have the cognitive ability to complete an online questionnaire and take part in an interview which may last up to 45 minutes.
• Able to read, write and fully understand the materials in the languages provided in the study.

Exclusion criteria:

Patient Study Participant (PSP) Exclusion criteria

• Significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological 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.
• Participants who are pregnant or breast/chest feeding or plan to become pregnant or breast/chest feed during the study.
• Any evidence of an active Center for Disease Control and Prevention (CDC) Stage 3 disease except cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/mm^3 are not exclusionary.
• 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), or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease.
• Individuals with both HIV and hepatitis B virus (HBV) will be excluded from participating in studies where they would not be able to receive appropriate therapy (e.g., tenofovir, lamivudine, or entecavir) for their HBV co-infection and therefore may be at risk of hepatitis B flare. History of liver cirrhosis with or without hepatitis viral co-infection.

• Participants with hepatitis c virus (HCV) co-infection will be allowed entry into this study if:

  • Liver enzymes meet entry criteria.
  • HCV disease has undergone appropriate work-up, and is not advanced, and will not require treatment prior to the primary endpoint (e.g., Month 11). Additional information (where available) on participants with HCV co-infection at screening should include results from any liver biopsy, Fibroscan, ultrasound, or other fibrosis evaluation, history of cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for HCV treatment and be discussed with the Medical Monitor.
  • In the event that recent biopsy or imaging data is not available or inconclusive, the Fibrosis 4 (Fib-4) score will be used to verify eligibility:
• Participants diagnosed with syphilis at screening (i.e., positive syphilis testing) should be treated as per local guidelines and would be eligible to enroll at any time regardless of the stage of disease. When rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) titers are high (i.e., >1:256), investigators should consider syphilis treatment before study enrolment, but may enroll 48 hours after treatment initiation.
• 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 pose a significant suicidality risk. Participant's history of suicidal behaviour and/or suicidal ideation should be considered when evaluating for suicide risk.

• Any ongoing symptomatic comorbidity

  • Clinically significant cardiovascular disease, as defined by history/evidence of congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting surgery or percutaneous transluminal coronary angioplasty or any clinically significant cardiac disease.
  • Uncontrolled malignancy is always excluded, whereas participants who have controlled malignancies may be included on agreement between the investigator and the medical monitor.
• History of sensitivity to any of the study medications or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• Any condition which may interfere with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to take oral or IM medication.
• Any preexisting physical or mental condition which, in the opinion of the investigator or the medical monitor, 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.
• alanine aminotransferase (ALT) >=3xUpper Limit of Normal (ULN).
• Total bilirubin >1.5xULN; For participants with Gilbert's syndrome can be included with total bilirubin >1.5xULN as long as direct bilirubin is <=1.5xULN.
• Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice.

Note: Stable non-cirrhotic chronic liver disease including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis C are acceptable if participant otherwise meets entry criteria.

• QT interval corrected for heart rate according to Fridericia's formula (QTcF) >450 msec.
• Use of concomitant medications which are associated with Torsades de Pointes. A list of these medications is available in the Pharmacy Manual.
• Any prior exposure to CAB and/or RPV for treatment or prevention of HIV-1 infection.
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening or any history of receiving long-acting therapy for HIV (including lenacapavir or broadly neutralizing antibodies).
• Current or anticipated need for chronic anticoagulants, with the exception of low dose acetylsalicylic acid (<=325 mg).

• Treatment with any of the following agents within 28 days of screening:

  • radiation therapy;
  • cytotoxic chemotherapeutic agents;
  • tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid, INH);
  • anti-coagulation agents, with the exception of the use of low dose acetylsalicylic acid (<=325 mg);
  • immunomodulators that alter immune responses such as chronic systemic corticosteroids, interleukins, or interferons. Note: Participants using short-term (e.g., <=21 days) systemic corticosteroid treatment; topical, inhaled and intranasal corticosteroids are eligible for enrolment.
• Exposure to an experimental drug or experimental vaccine within either 28 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 the first dose of investigational product (IP).
• Participants receiving any protocol-prohibited medication and who are unwilling or unable to switch to an alternate medication. Note: Any prohibited medications that decrease CAB or RPV concentrations should be discontinued for a minimum of 4 weeks or a minimum of 3 half-lives (whichever is longer) prior to the first dose in the Initiation Phase and any other prohibited medications should be discontinued for a minimum of 2 weeks or a minimum of 3 half-lives (whichever is longer) prior to the first dose.
• Current enrolment or past participation in any another investigational clinical study or any other type of medical research in which an investigational study intervention (e.g., drug, vaccine, invasive device) was administered within the last 90 days before signing of consent.
• Current enrolment or past participation in this clinical study.
• Within 6 months prior to Screening, any plasma HIV-1 RNA measurement >50 c/mL
• Within the 6 to 12-month window prior to Screening, any plasma HIV-1 RNA measurement >200 c/mL, or 2 or more plasma HIV-1 RNA measurements >50 c/mL
• 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.
• Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides, lipid abnormalities or creatine phosphokinase (CPK). A single repeat test is allowed during the screening period to verify a result.
• eGFR of <30 mL/min/1.73 m2 via refitted, race-neutral chronic kidney disease (CKD)-EPIcr_R method (adult participants) or <50 mL/min/1.73 m2 using the Bedside Schwartz equation (adolescent participants).
• Hemoglobin <9.0 g/dL
• Absolute neutrophil count (ANC) <600 mm3

• Any evidence of primary resistance based on the presence of any major known integrase inhibitors (INSTI) (including CAB) or non-nucleoside reverse transcriptase inhibitor (NNRTI) (including RPV) resistance-associated mutation that was obtained from analyses prior to screening, including any historical resistance test result.

  • Note: While no prior genotypic resistance testing (genotyping of plasma vRNA and/or PBMC vDNA) is required for entry into this study, if available, it must be provided to ViiV, after screening and before randomisation according to guidance in the pharmacy manual, to provide direct evidence of no pre-existing exclusionary resistance mutations. The potential study participant must wait for the study virologists to confirm the lack of exclusionary resistance mutations, which will be provided before the screening window closes. Details regarding baseline or prior resistance data must be noted in the source documentation.
  • If there is resistance data in the medical record using proviral DNA testing, the medical monitor, in consultation with the study virologist, will decide whether to allow the participant to enter study.
• Unwilling to receive injections, or unable to receive gluteal injections.
• The participant has gluteal implants or prosthesis; or a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
• Adolescents who are wards of the state or government. Staff study participant (SSP) exclusion criteria
• Not willing to be audio recorded during interviews (only for SSPs selected for interviews).