The overall purpose of the trial is to evaluate the efficacy and safety of possible combination antiviral therapy direct antiviral agents (remdesivir + nirmatrelvir/r) versus the reference monotherapy (nirmatrelvir/r alone) and to assess the efficacy and safety of increasing the nirmatrelvir/r course from 5- to 10 days in immunocompromised patients diagnosed with asymptomatic or mild to moderate Coronavirus Disease 2019 (COVID-19).
This is a randomized, controlled, factorial, superiority trial to evaluate the viral efficacy of direct antiviral agent nirmatrelvir/r + direct antiviral agent remdesivir versus nirmatrelvir/r alone and of 5 days versus 10 days of nirmatrelvir/r in immunocompromised patients diagnosed with asymptomatic or mild to moderate COVID-19. The primary objective is to assess whether (i) a combination antiviral therapy of two antiviral agents (nirmatrelvir/r + remdesivir and/or (ii) an increase in nirmatrelvir/ r duration from 5 to 10 days improves viral efficacy by decreasing the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2) positivity rate by real time polymerase chain reaction (RT-PCR) (cycle threshold CT\<32) in nasopharyngeal swabs at day 10 (D10). Patients will be eligible if they are immunocompromised, have confirmed asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19, regardless of symptoms onset, provided that they have no contra-indication to any of the study drugs. A total of 256 patients will be recruited in Switzerland and in France, Italy and Norway (through the parallel protocol ANRS0176s OPTICOV). Participants not eligible for randomisation or who refuse to participate to the trial for any reason will be proposed to be included in an exploratory non comparative cohort (maximum 97 participants, active only in Switzerland).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
256
Nirmatrelvir/r 300mg/100 mg bid will be given for 5 days, orally. Nirmatrelvir/r is a combination of two molecules: nirmatrelvir which is a protease inhibitor (against 3CL) and ritonavir which has a booster role. Nirmatrelvir/r (marketed by Pfizer under the brand name Paxlovid®) is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19.
Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.
Basel University Hospital
Basel, Basel, Switzerland
RECRUITINGHôpitaux Universitaires de Genève
Geneva, Canton of Geneva, Switzerland
RECRUITINGCHUV
Lausanne, Canton of Vaud, Switzerland
RECRUITINGVirological
Percentage of patients with SARS-CoV-2 viral load \<32 cycle threshold (CT) by real-time RT-PCR in nasopharyngeal swabs at D10 after treatment initiation.
Time frame: Day 10
Virological
Percentage of patients with SARS-CoV-2 viral load \<32 CT by real-time RT-PCR in nasopharyngeal swabs at D5, D14 and D21 after treatment initiation
Time frame: Day 5, Day 14, Day 21
Virological
Percentage of patients with detectable SARS-CoV-2 viremia at D5, D10 and D14
Time frame: Day 5, Day 10, Day 14
Virological
Decrease of SARS-CoV-2 viral load measured by copies/ml by nasopharyngeal swab at D5, D10, D14, D21 and at D5, D10 and D14 in blood samples comparatively to screening
Time frame: Day 5, Day 10, Day 14, Day 21
Virological
Number of de novo mutations after sequencing on nasopharyngeal swabs at D5, D10, D14 and D21 comparatively to screening
Time frame: Day 5, Day 10, Day 14, Day 21
Virological
To assess the phenotypic resistance (Half maximal inhibitory concentration (IC50) increase) against treatment for viral strains cultured from nasopharyngeal swabs at D5, D10, D14 and D21 comparatively to screening
Time frame: Day 5, Day 10, Day 14, Day 21
Virological
Time to first negative SARS-CoV-2 RT-PCR (CT\<32) until D90
Time frame: Day 90
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
University Hospital Zurich
Zurich, Canton of Zurich, Switzerland
RECRUITINGVirological
Absence of ability to cultivate virus from viral cultures from nasopharyngeal swabs at D5, D10, D14 and D21
Time frame: Day 5, Day 10, Day 14, Day 21
Clinical
Percentage of patients with sustained resolution or abatement of symptoms defined as a inFLUenza Patient-Reported Outcome Plus (FLU-PRO-Plus) score ≤1 at D5, D10, D14, D21 and D28
Time frame: Day 5, Day 10, Day14, Day 21, Day 28
Clinical
All-cause hospitalization and/or death at D28
Time frame: Day 28
Clinical
Hospitalization at D28
Time frame: Day 28
Clinical
Death at D28
Time frame: Day 28
Clinical
inFLUenza Patient-Reported Outcome Plus (FLU-PRO-Plus) scale at D5, D10, D14, D21, D28 and D90. Scores range from 0 (symptom free) to 4 (very severe symptoms).
Time frame: Day 5, Day 10, Day 14, Day 21, Day 28, Day 90
Clinical
Rate of Post-COVID19 condition at D90 according to the World Health Organisation (WHO) October 2021 definition
Time frame: Day 90
Clinical
Percentage of participants with an adverse event (AE) or serious adverse event (SAE) or AE leading to treatment discontinuation up to D90
Time frame: Day 90
Clinical
Adherence to nirmatrelvir/r with patient-reported adherence and nirmatrelvir/r residual plasma dosage at D5 and D10, if applicable
Time frame: Day 5, Day 10
Clinical
Number of drud-drug interactions who led to dosage adjustment of other patient's drugs
Time frame: Day 10
Clinical
Immunosuppressors residual concentrations, if applicable
Time frame: Day 10
Clinical
Percentage of patients with specific retreatment (by antiviral, anti-inflammatory drug or convalescent plasma) through D90
Time frame: Day 90
Clinical
Number of drug-drug interactions (DDIs) which led to dosage adjustment of other patient's drugs
Time frame: Day 10