Materials and Methods
Study Design and Participants
POLAR is a Phase 2b, open-label, multicenter (Canada and the USA), nonrandomized rollover study assessing the efficacy and safety of i.m. CAB+RPV long-acting Q2M in ART-experienced adults living with HIV-1 who received once-daily oral CAB+RPV treatment in the Phase 2b LATTE study (Figure 1a). The full study protocol is available at ClinicalTrials.gov: NCT03639311. In brief, eligible participants were at least 18 years of age, virologically suppressed, and had completed at least 300 weeks of the LATTE study with plasma HIV-1 RNA less than 50 copies/ml at Week 300. If participants had plasma HIV-1 RNA greater than or equal to 50 copies/ml at Week 300, a single repeat test to determine eligibility was allowed after consultation with the medical monitor. Participants from LATTE were excluded if they had two or more sequential plasma HIV-1 RNA greater than or equal to 50 copies/ml or any plasma HIV-1 RNA greater than or equal to 200 copies/ml in the last 6 months.
Figure 1.
Study design, screening, and treatment. aParticipants in LATTE received daily oral CAB (30 mg) + RPV (25 mg). bOne individual failed screening with the primary reason being "not meeting the inclusion or exclusion criteria." cParticipants received CAB LA 600 mg + RPV LA 900 mg at Day 1 and Month 2, then Q2M thereafter. To be accessed commercially once CAB+RPV LA Q2M is approved. Any participant who received at least one dose of CAB LA and/or RPV LA and discontinued the CAB+RPV LA regimen for any reason entered a 52-week Long-Term Follow-Up Phase and transitioned to an alternative ART regimen. dTo be accessed longer term via a commercial route. Participants will continue to receive DTG/RPV if located in a region where not commercially available. Figure 1a was presented previously at IDWeek; October 21–25, 2020; Virtual; Oral. ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; LA, long-acting; Q2M, every 2 months; RPV, rilpivirine.
The study included a Maintenance Phase (Day 1 until CAB+RPV long-acting is commercially available locally) and a Long-Term Follow-Up Phase (LTFU, 52 weeks) for participants who discontinued for any reason after receiving at least one dose of CAB long-acting and/or RPV long-acting. Participants entered the study on Day 1 and elected to transition from daily oral CAB+RPV to either i.m. CAB+RPV long-acting Q2M (long-acting arm; CAB long-acting 600 mg and RPV long-acting 900 mg) or daily oral single-tablet dolutegravir (DTG) 50 mg/RPV 25 mg (DTG/RPV arm) for 12 months. To cover preplanned, short-term interruptions of long-acting dosing, investigators could provide daily oral CAB 30 mg and RPV 25 mg as an oral therapy following consultation with the medical monitor. Participants in the long-acting arm will continue to receive CAB+RPV long-acting Q2M until the regimen is approved and commercially available within the local sector (including through local public/government health sectors), the participant no longer derives clinical benefit, or the participant meets a protocol-defined reason for discontinuation. DTG/RPV tablets were provided via commercial routes. Any participant who received at least one dose of CAB long-acting and/or RPV long-acting and discontinued CAB+RPV long-acting for any reason entered a 52-week LTFU Phase and remained on an alternative suppressive ART regimen for at least 52 weeks after the last dose. The cut-off date for this analysis predates the COVID-19 2020 pandemic. POLAR was conducted in accordance with the principles founded in the Declaration of Helsinki and with Good Clinical Practice.[21,22] All participants provided written informed consent, and the protocol was approved by an institutional review board or ethics committee.
Endpoints and Assessments
The primary objective of the study was to demonstrate the antiviral activity of CAB+RPV long-acting Q2M in suppressed HIV-1-infected ART-experienced participants. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 as per the Food and Drug Administration (FDA) Snapshot algorithm. Secondary endpoints assessed at Month 12 included the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml at Month 12 as per the FDA Snapshot algorithm; the incidence of protocol-defined confirmed virologic failure (CVF; two consecutive plasma HIV-1 RNA measurements of ≥200 copies/ml); incidence of treatment-emergent genotypic and phenotypic resistance; absolute values and changes in CD4+ cell count over time; incidence and severity of adverse events and laboratory abnormalities; proportion of participants who discontinue treatment due to adverse events; change from Baseline in laboratory parameters over time; and treatment satisfaction, as measured by the 12-item HIV Treatment Satisfaction Questionnaire status (HIVTSQs) and change (HIVTSQc) versions at Baseline, Month 6, and Month 12. HIVTSQ responses are rated on 6-point Likert scales, with the HIVTSQs total score ranging from 0 (very dissatisfied) to 66 (very satisfied), and the HIVTSQc total score ranging from –33 (much less satisfied now) to 33 (much more satisfied now). An exploratory endpoint evaluating participant preference for CAB+RPV long-acting compared with their prior daily oral CAB+RPV regimen was also included (single-item questionnaire) at Month 12. The pharmacokinetic profiles of CAB and RPV were not investigated in the study as they have been extensively characterized in previous Phase 2 and Phase 3 studies of the daily oral regimen and the i.m. therapy given every 4 or 8 weeks.[17–19,23]
Statistical Analysis
No statistical hypotheses of treatment comparisons were tested within this study due to the nonrandomized nature of the study and the unbalanced number of participants between comparator arms. Consequently, all presented data are descriptive.
AIDS. 2022;36(2):195-203. © 2022 Lippincott Williams & Wilkins
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