Phase 3 Randomized Non‑Inferior Trial of Ultra‑Long‑Acting Cabotegravir + Rilpivirine vs Long‑Acting Formulations in Adults/Adolescents with Virologically Suppressed HIV

The primary objective is to demonstrate the non‑inferior antiviral activity of cabotegravir ultra‑long‑acting plus rilpivirine ultra‑long‑acting compared with cabotegravir long‑acting plus rilpivirine long‑acting in adults and adolescents who are virologically suppressed while receiving antiretroviral therapy for HIV, thereby supporting a less frequent dosing regimen without compromising viral control.

Secondary objectives include:

• Assess non‑inferior antiviral activity of the ultra‑long‑acting regimen administered every 4 months versus the long‑acting regimen every 2 months over a 23‑month period.
• Evaluate the antiviral activity of the two regimens independent of the dosing interval.
• Compare safety and tolerability between the ultra‑long‑acting and long‑acting dosing schedules.
• Characterize viral resistance patterns in participants experiencing protocol‑defined confirmed virologic failure.
• Determine plasma concentrations of cabotegravir and rilpivirine.
• Examine the effects of the ultra‑long‑acting regimen versus the long‑acting regimen specifically in adolescent participants.

The trial enrolled 483 individuals with HIV‑1 infection who were virally suppressed and experienced with antiretroviral therapy. Eligible participants were aged 12 years or older, encompassing both male and female subjects, and were required to have a body weight greater than 35 kg. Inclusion criteria mandated documented plasma HIV‑1 RNA < 50 copies/mL on at least two occasions in the preceding 12 months, continuous daily oral antiretroviral therapy for a minimum of six months, and, for those of childbearing potential, the use of a highly effective contraceptive method and a negative pregnancy test. Participants who were pregnant, breastfeeding, or had a history of virologic failure (HIV‑1 RNA ≥ 200 copies/mL) were excluded. Selection was based on these virologic and clinical parameters, with additional requirements for informed consent and, where applicable, assent. No specific lifestyle factors such as diet or physical activity were stipulated as eligibility criteria.

The study is a Phase 3, multicenter, parallel‑group, randomized, open‑label, non‑inferiority trial comparing cabotegravir ultra‑long‑acting plus rilpivirine ultra‑long‑acting with cabotegravir long‑acting plus rilpivirine long‑acting in adults and adolescents with HIV who are virologically suppressed on antiretroviral therapy. After a screening visit confirming eligibility (including two HIV‑1 RNA < 50 copies/mL in the prior 12 months and weight > 35 kg), participants receive the first intramuscular dose on Day 1 (baseline). Subsequent study visits are scheduled at regular injection intervals (e.g., every 2 months for the ultra‑long‑acting arm and every 4 months for the long‑acting arm), during which safety, tolerability, plasma drug concentrations, and virologic assessments are performed. Follow‑up continues through Month 23, with the primary efficacy assessment at Month 11 and additional secondary assessments at Month 23, after which an end‑of‑study visit concludes participant involvement, totaling approximately 23 months of follow‑up. Early termination may occur for confirmed virologic failure (≥200 copies/mL on two consecutive tests), pregnancy, drug‑related grade 2–5 adverse events, injection intolerance leading to discontinuation, or withdrawal of consent, in accordance with protocol‑defined criteria.

The investigational regimen consists of two intramuscular products. cabotegravir is supplied as a powder for suspension for injection and is administered as a prolonged‑release suspension following reconstitution. The second component, rilpivirine, is provided as a prolonged‑release suspension for injection (JNJ‑16150108). Both products are injected intramuscularly according to the dosing schedule defined in the study protocol, with intervals between administrations specified by the trial design.

The comparator arm utilizes two commercially available prolonged‑release suspensions for injection. Vocabria contains 600 mg of cabotegravir per dose and is administered intramuscularly. REKAMBYS provides 900 mg of rilpivirine per dose, also given intramuscularly. Dosing intervals for these agents follow the schedule outlined in the protocol, mirroring the administration frequency of the investigational products.

Administration procedures include preparation of the suspension, verification of dose, and documentation of injection site and time. Compliance is monitored through study visit assessments, injection logs, and pharmacokinetic sampling as required by the protocol to ensure adherence to the prescribed dosing schedule.

Efficacy will be evaluated primarily by the proportion of participants with Plasma HIV-1 RNA ≥ 50 copies/mL, determined using the FDA Snapshot algorithm at Month 11 (full analysis set). Secondary efficacy assessments include the same virologic threshold at Month 23, the proportion with plasma HIV-1 RNA < 50 copies/mL at Months 11 and 23, and the incidence of confirmed virologic failure (two consecutive HIV‑1 RNA values ≥ 200 copies/mL) through Months 11 and 23. Additional secondary measures comprise the occurrence of grade 2–5 drug‑related adverse events, treatment discontinuations, and the emergence of genotypic and phenotypic resistance to cabotegravir and rilpivirine. Pharmacokinetic evaluations will quantify plasma concentrations of cabotegravir and rilpivirine and calculate trough, peak, and area‑under‑the‑curve parameters when samples are evaluable. Immunologic response will be monitored by measuring absolute CD4+ cell counts and changes from baseline at each scheduled visit.

All virologic and immunologic specimens will be collected at baseline and at the pre‑specified study visits corresponding to Month 11 and Month 23 for both adult and adolescent cohorts. Laboratory analyses will be performed using validated quantitative assays in accordance with the FDA Snapshot algorithm and standard flow‑cytometry techniques for CD4+ enumeration. Data will be analyzed on the full analysis set, with efficacy outcomes expressed as proportions, incidence rates, and descriptive statistics for continuous variables.