Viral efficacy of early combination antiviral therapy versus antiviral monotherapy in Immunocompromised COVID-19 outpatient: a randomized controlled pragmatic strategy trial (COMBINE study)

In the era of the omicron variant, the immunocompromised population is the main at-risk population for severe coronavirus disease 2019 (COVID-19). Several new early treatments administered within 7 days from symptom onset have been developed to prevent worsening to a severe disease in at-risk patients, such as direct acting antivirals (DAAs) (e.g., nirmatrelvir/ritonavir [nirmatrelvir/r]) and monoclonal antibodies (mAbs) (e.g., Evusheld). However, clinical trials have not included these fragile patients and current evidence on the effects of antivirals has been generated in populations with a robust immune system and therefore cannot be extrapolated. Combinations have the potential to lead to a better antiviral response and better clinical efficacy (individual benefit), but they also has the potential to reduce resistance and variant emergence by decreasing viral loads, infectivity, and the duration of viral shedding (public health benefit), especially in this vulnerable population. To date, these combinations have not been tested in the clinical setting.Therefore, we have designed in the clinical trial-experienced Geneva HIV unit (Principal investigator: Prof. Alexandra Calmy), a phase 2/3 randomized, controlled, academic clinical strategy trial to assess whether an early combination antiviral therapy of DAAs (nirmatrelvir/r 300/100 mg twice daily for 5 or 10 days) and mAbs ( tixagevimab/cilgavimab 300 mg/300mg, single injection) may improve viral, but also clinical efficacy, compared to nirmatrelvir/r alone for 5 or 10 days.The primary endpoint is a SARS-CoV-2 viral load cycle threshold (CT) <32 by real-time RT-PCR in nasopharyngeal swabs at day 10 after treatment initiation. There will be several virological (e.g., resistance and variant emergence under treatment, viral infectivity, viremia, duration of viral shedding) and clinical secondary endpoints, such as hospitalization, death, clinical symptom duration or World Health Organization (WHO)-defined post-COVID-19 condition rate, thus highlighting its translational essence. To attain these objectives, we will include 256 patients randomized in four arms of 64 patients that will be followed for 180 days. Follow-up will include virological, clinical and safety data. To reach our recruitment targets, which would be hardly feasible in Switzerland alone considering the specificity of the trial population, we plan to conduct the COMBINE trial both in Switzerland and in France. This will be a unique occasion to gather the expertise of those in the fields of COVID-19, immunocompromised patients and clinical trials, including clinical, virological and methodological experts. The trial will be fully academic as study drugs will be obtained through the public health circuit for the routine use of antiviral SARS-COV-2 medication.This proof-of-concept study will bring novel important clinical data not only about the viral efficacy, but also about the clinical efficacy of combination antiviral therapy. If combination therapy is proven efficient, it may support a change of standard of care in the early treatment of this fragile population in order to improve virological and clinical outcomes. In terms of public health, an effective antiviral strategy may promote a new prevention tool against future SARS-CoV-2 variants and resistance that are more likely to emerge from immunocompromised patients. Finally, the COMBINE study will add crucial information on how to protect, care, and monitor patients with an underlying immunosuppression and with COVID-19.