Viral efficacy of early combination antiviral therapy versus antiviral monotherapy in Immunocompromised COVID-19 patients: a randomized controlled strategy trial: the OPTICOV study

Immunocompromised patients are a vulnerable population, less likely to be vaccine-responders, largely underrepresented in COVID-19 outpatient clinical trials, and overrepresented in ICUs worldwide. They have a higher viral load and a prolonged viral shedding, with often persistent infection. This results in a higher probability of variant selection, suggesting a particular interest for early antiviral strategies in this population, including monoclonal antibodies (mAbs) and/or direct active antivirals (DAAs). Treatment optimization has been truly transformative for viral diseases such as HIV or HCV and only achieved when antiviral drug combinations became the mainstay. Increasing treatment duration is another promising strategy. So far, no clinical trial has assessed the efficacy or safety of a combination of mAbs and DAA or of increasing treatment duration in COVID-19 immunocompromised patients.The main aim of this randomized factorial superiority phase 2/3 open clinical trial (OPTICOV) is to assess whether a combination antiviral therapy of oral DAA and mAbs compared to DAA monotherapy and whether an increase in DAA duration from 5 days to 10 days may improve viral efficacy in immunocompromised patients. To date, the best available DAA is nirmatrelvir/r (nirm/r) (2*300/100 mg/day for 5 days, orally) and tixagevimab/cilgavimab (T/C) (300/300 mg) the best mAb when considering BA.2 omicron subvariant predominance.Virtually, the four treatment arms will be: nirm/r 5 days + T/C; nirm/r 10 days + T/C; nirm/r 5 days alone; nirm/r 10 days alone.We will use a virological primary endpoint, with a recognized cut-off for infectiousness: SARS-CoV-2 viral load <32 CT by real-time RT-PCR in nasopharyngeal swabs at day 10 after treatment initiation. Viral load magnitude and duration predict clinical severity and are associated with infectiousness. Most efficient DAA treatments resulted in a significant viral load decrease. Thus, virological endpoints have the potential to be a surrogate marker.Secondary objectives and endpoints will be virological (assessment of the ability of combination therapy to decrease infectivity, viremia, viral rebound or the emergence of new variants/resistance at several timepoints) and clinical (assessment of the ability of combination therapy to increase the recovery rate, the 11-point WHO clinical progression scale score, and to decrease the rate of post-COVID-19 conditions by day 90).We will include immunocompromised patients aged 12 years or over and >40 kg, with asymptomatic or mild/moderate COVID-19 during the first 7 days of symptoms and no contraindication to each study drug. Standardized operating procedures will help investigators to assess if drug-drug interactions may contraindicate nirm/r. They will be followed over 90 days with 7 study visits (by phone or on site) after randomization.With 254 patients, we will be able to show a difference between both arms, assuming an incidence of the primary endpoint of 40% and 60% in combination vs. monotherapy and 10 days vs. 5 days, with a study power of 90% and an a risk of 5%. With this number of patients, we will be able to detect differences in clinical endpoints with sufficient power.The primary endpoint will be compared between study arms according to the intent-to-treat population using a log-log complementary model adjusted for the presence or absence of combination therapy for DAA duration and factors known to be associated with SARS-CoV-2 positivity.This proof-of-concept study will bring novel important clinical data not only on the viral efficacy of combination antiviral therapy, but also on the clinical efficacy. If combination therapy is proven efficient, it may support a change of standard of care in the early treatment of this fragile population. In public health terms, 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.