A Phase 3b, Randomized, Multicenter, Open-Label Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-Acting Cabotegravir Plus Long-Acting Rilpivirine From Current Antiretroviral Regimen in HIV-1 Infected, Virologically Suppressed Adults in Sub-Saharan Africa
PROTOCOL SUMMARY
Synopsis
A Phase 3b, Randomized, Multicenter, Open-Label Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-Acting Cabotegravir Plus Long-Acting Rilpivirine From Current Antiretroviral Regimen in HIV-1 Infected, Virologically Suppressed Adults in Sub-Saharan Africa
Cabotegravir And Rilpivirine: Efficacy and Safety (CARES) Study
Long-acting (LA) injectable therapy for the treatment of Human Immunodeficiency Virus (HIV)-1 infection offers a reduced dosing frequency and an additional option to the currently available triple-drug oral combinations. A parenteral LA formulation of rilpivirine (RPV) for intramuscular (IM) injection in combination with ViiV Healthcare’s parenteral LA formulation of the integrase inhibitor cabotegravir (CAB) may offer a better tolerability and resistance profile, as well as improved adherence and treatment satisfaction in virologically suppressed patients. The combination regimen has been developed for maintenance of viral suppression (HIV-1 RNA <50 copies/mL) in HIV-1 infected individuals previously treated with standard-of-care antiretroviral therapy.
OBJECTIVES AND ENDPOINTS
Primary Objectives
- To demonstrate the non-inferior antiviral activity of switching to IM CAB LA+RPV LA administered every 2 months compared with continuation of cART administered daily over 12 months in HIV-1 infected participants in a resource limited setting.
Endpoint
- Proportion of participants with a virologic response (plasma HIV-1 RNA <50 c/mL)* at Month 12
Secondary Objectives
- To demonstrate the antiviral and immunologic activity of switching to IM CAB LA+RPV LA every 2 months compared to continuation of cART over 12 and 24 months of follow-up
- To evaluate the safety and tolerability of switching to CAB LA+RPV LA every 2 months compared to continuation of cART.
- To assess viral resistance in participants experiencing protocol-defined confirmed virologic failure (plasma HIV-1 RNA ≥200 c/mL).
- To assess the incidence of on-treatment genotypic resistance to CAB, RPV and other on-study cART up to Month 12 and 24.
- To evaluate adherence to treatment.
Secondary Endpoint
- Proportion of participants with confirmed virologic failure (2 consecutive plasma HIV-1 RNA levels ≥200 c/mL)** at Month 12 and Month 24.
- Proportion of participants with non-response (plasma HIV-1 RNA ≥50 c/mL) at Month 12 and Month 24.
- Proportion of participants with virologic response(plasma HIV-1 RNA <50 c/mL) at Month 24.
- Change from baseline in CD4+ lymphocyte count at Month 12 and Month 24.
- Incidence of Grade 3 and Grade 4 AEs and laboratory abnormalities over time through Month 12 and Month 24.
- Proportion of participants who discontinue treatment due to Aes through Month 12 and Month 24.
- Absolute values and changes in laboratory parameters through Month 12 and Month 24.
- To assess and compare genotypic drug resistance in individuals with confirmed virologic failure between the CAB LA+RPV LA versus cART.
- Adherence, pill count for cART and dosing visits for CAB LA+RPV LA
Exploratory
- To evaluate the effects ofCAB LA+RPV LA every 2 months on BMI over time compared to continuation of cART over time.
- ToevaluatetheeffectofCABLA+RPV LA on trunk fat compared with cART
- To explore the effect of patient characteristics (eg, demographic factors, baseline disease characteristics) on the virologic and immunologic responses to CAB LA+RPV LA compared to continuation of cART.
- Retrospective analysis of archived resistance and virological outcomes using PBMCs at baseline.
- To evaluate the effect of CAB LA+RPV LA on well-being and health status.
- To evaluate the effect of CAB LA+RPV LA on quality of life.
- To assess participant satisfaction with the injectable intervention.
- To assess preference for CAB LA+RPV LA compared to oral cART.
- To evaluate pharmacokinetics in women who become pregnant on CAB LA+RPV LA.
- To evaluate MRU among participants in the study.
- To determine the prevalence of HBV DNA among participants on stable cART containing NRTI who test negative for HbsAg and positive for anti-HBc at screening
- To determine the prevalence of anti-HBs positivity among participants on stable cART containing NRTI who test negative for HbsAg and positive for anti-HBc at screening.
- Change from Baseline in BMI over time including Month 12 and Month 24.
- Change from baseline in trunk fat measured by DEXA scan at Month 12 and Month 24
- Proportion of participants by patient subgroup(s) (eg, by age, gender, BMI, HIV-1 subtype) with virologic response (<50 c/mL) over time including Month 12, and 24.
- Proportion of participants by patient subgroup(s) (eg, by age, gender, BMI, race, HIV-1 subtype, baseline CD4+ cell count) with plasma HIV-1 RNA >50 c/mL over time including Month 12, and 24.
- Investigate correlation of archived resistance and HIV-1 subtype determined in baseline PBMCs and virologic outcomes at Month 12 and 24.
- Change from baseline in EQ-5D-5L scores at Month 12 and Month 24.
- Change from baseline in MOS-HIV at Month 12 and Month 24.
- For participants in the CAB LA+RPV LA group, perception of injection and change from baseline in HIVTSQ scores at Month 12 and Month 24.
- For participants randomized to the CAB LA+RPV LA group, preference for CAB LA+RPV LA compared to oral cART regimen at Month 12 and Month 24 using a single dichotomous preference question.
- Measure antiretroviral plasma concentrations in patients on long-acting antiretrovirals who become pregnant during 1st, 2nd, 3rd trimester and postpartum.
- In both study groups, MRU over 24 months:
- Rates of opportunistic infections
- Rates of hospitalizations.
- Proportion of participants who test negative for HbsAg and positive for anti-HBc with a detectable HBV viral load at screening.
- Proportionofparticipantsatscreeningwhotestpositivefor anti-HBs among those who test negative for HbsAg and positive for anti-HBc at screening.
Abbreviations: AE: adverse event; BMI: body mass index; AIDS: Acquired immunodeficiency syndrome; CAB: cabotegravir; cART: combination retroviral therapy; c/mL: copies/milliliter; DEXA: dual energy X-ray absorptiometry; EQ-5D-5L: EuroQol 5 dimension 5 level; HIV: Human Immunodeficiency Virus; HIVTSQs: HIV Treatment Satisfaction Questionnaire; IM: intramuscular; LA: long-acting; MOS-HIV: Medical Outcomes Study HIV Health Survey; MRU: medical resource utilization; OLI: Oral lead-in; PBMC: Peripheral blood mononuclear cells; RPV: rilpivirine; RNA: ribonucleic acid
*HIV-1 RNA levels in the study will be analyzed using the Food and Drug Administration (FDA) Snapshot Algorithm.
