OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial

Study Overview
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Brief Summary
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The overall purpose of the trial is to evaluate the efficacy and safety of possible combination antiviral therapy DAA (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 COVID-19.

Detailed Description
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This is a randomized, controlled, factorial, superiority trial to evaluate the viral efficacy of DAA (nirmatrelvir/r) + DAA (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 DAA (nirmatrelvir/r + remdesivir)∞ And/or (ii) an increase in nirmatrelvir/r duration from 5 to 10 days improves viral efficacy by decreasing the SARS-CoV-2 positivity rate by real time RT-PCR (CT<32) in nasopharyngeal swabs at 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 included in France and Switzerland.

Official Title
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OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial: the OPTICOV Study

Conditions
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COVID-19, Immunodeficiency

Intervention / Treatment
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* Drug: Paxlovid 5 days
* Drug: Paxlovid 10 days
* Drug: Veklury


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Laboratory confirmed SARS-CoV-2 infection by RT-PCR Asymptomatic or mild to moderate COVID-19 (WHO progression scale ≤5) ≥ 16 years of age; Body weight > 40 kg Immunocompromised as defined by ≥ 1 risk factors for severe COVID-19 as assessed by the FOPH list (criteria 5: diseases/treatments leading to immune suppression) Severe immunosuppression (e.g., HIV infection with CD4 + T cell count <200 / µl) Neutropenia (<1000 neutrophils / µl) ≥1 week Lymphocytopenia (<200 lymphocytes/µl) Hereditary immunodeficiencies Intake of drugs which suppress the immune system (e.g. glucocorticoids for a long time [an equivalent dose of prednisone >20 mg/day > 3 months], monoclonal antibodies, cytostatics, biological products, etc.) in the last 12 months Aggressive lymphomas (all types) Acute lymphatic leukemia Acute myeloid leukemia Acute promyelocytic leukemia T prolymphocytic leukemia Primary central nervous system lymphoma Stem cell transplantation Light chain amyloidosis Chronic lymphoid leukemia Multiple myeloma Sickle cell disease Bone marrow transplant Organ transplant Being on the waiting list for an organ transplant Willing and able to comply with study requirements and restrictions as described in the informed consent form (ICF) Enrolled in or a beneficiary of a Social Security program (State Medical Aid (AME) is not a Social Security program) Participant's or its legal representative's signature of the informed consent form Exclusion Criteria: SARS-CoV-2 PCR ≥30 CT at screening Hypersensitivity to study drugs (active substance(s) or excipients) Creatinine clearance <30ml/mn/.73m² (CKD-EPI) AST or ALT > 5 times the upper limit Is taking or is anticipated to require any prohibited therapies* Participation in another interventional clinical study through Day 28 with an investigational compound or device, including COVID-19 therapeutics Presence of any condition for which, in the opinion of the investigator, participation would not be in participant's best interest or that could prevent, limit, or confound the protocol-specified assessments Having received antiviral treatments against SARS-CoV-2 in the 14 days before the inclusion Pregnant or breastfeeding female Study SOPs based on recommendations from the Liverpool COVID-19 interactions, French Society for Pharmacology and Therapeutics and French Speaking Transplantation society will be provided to guide investigators

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nirmatrelvir/r 5 days alone<br> | Drug: Paxlovid 5 days<br>* 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.<br>* Other names: Nirmatrevlir/ritonavir;|
| Experimental: Nirmatrelvir/r 10 days alone<br> | Drug: Paxlovid 10 days<br>* Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.<br>* Other names: Nirmatrevlir/ritonavir;|
| Experimental: Nirmatrelvir/r 5 days + remdesivir s.d<br> | Drug: Paxlovid 5 days<br>* 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.<br>* Other names: Nirmatrevlir/ritonavir;Drug: Veklury<br>* Remdesivir flash, 200mg, intravenous. Remdesivir (marketed by Gilead under de brand name Veklury®) is indicated in patients with pneumonia requiring supplemental oxygen (inpatients), as well as in outpatients who are at increased risk of progressing to severe COVID-19. The mode of action characterize remdesivir as a direct-acting antiviral compound.<br>* Other names: remdesivir;|
| Experimental: Nirmatrelvir/r 10 days + remdesivir s.d<br> | Drug: Paxlovid 10 days<br>* Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.<br>* Other names: Nirmatrevlir/ritonavir;Drug: Veklury<br>* Remdesivir flash, 200mg, intravenous. Remdesivir (marketed by Gilead under de brand name Veklury®) is indicated in patients with pneumonia requiring supplemental oxygen (inpatients), as well as in outpatients who are at increased risk of progressing to severe COVID-19. The mode of action characterize remdesivir as a direct-acting antiviral compound.<br>* Other names: remdesivir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with SARS-CoV-2 viral load (threshold cicle (Ct) <32) by real-time RT-PCR in nasopharyngeal swabs at Day 10 after treatment initiation. | SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR | Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with SARS-CoV-2 viral load (threshold cicle <32 CT) by real-time RT-PCR in nasopharyngeal swabs at Day5, Day14 and Day21 after treatment initiation | SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR | Day5, Day14 and Day21 | 
| Percentage of patients with detectable SARS-CoV-2 viremia at Day5, Day10 and Day14 | SARS-CoV-2 viremia is measured from plasma samples by real-time RT-PCR | Assessed for 14 days from the date of randomisation at Day5, Day10 and Day14 | 
| Decrease of SARS-CoV-2 viral load measured by copies/ml by nasopharyngeal swab at Day5, Day10, Day14, Day21 and in blood samples at Day5, Day10 and Day14 comparatively to screening | SARS-CoV-2 viral load is measured in nasopharyngeal swabs and in blood samples by real-time RT-PCR | Day5, Day10, Day14, Day21 | 
| Number of de novo emergence of mutations on nasopharyngeal RT-PCR at Day5, Day10, Day14 and Day21 comparatively to screening | Emergence of mutations is measured in nasopharyngeal swabs by genotyping techniques | Day5, Day10, Day14 and Day21 | 
| Time to first negative SARS-CoV-2 RT-PCR (CT<32) until Day90 | SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR | Day90 | 
| Absence of ability to cultivate virus from viral cultures from nasopharyngeal swabs at Day5, Day10 and Day21 | Viral culture is performed from nasopharyngeal swabs samples | Day5, Day10 and Day21 | 
| Percentage of patients with sustained resolution or abatement of symptoms defined as a FLU-PRO-Plus score ≤1 at Day5, Day10, Day14, Day21 and Day28 | FLU-PRO-Plus score is measured via an arithmetic formula | Day5, Day10, Day14, Day21 and Day28 | 
| All-cause hospitalization and/or death at Day28 | Outcome measured during patients medical follow-up | Day28 | 
| Hospitalization at Day28 | Outcome measured during patients medical follow-up | Day28 | 
| Death at Day28 | Outcome measured during patients medical follow-up | Day28 | 
| Maximum WHO 11-point Clinical Progression Scale through Day28 | Outcome measured during patients medical follow-up | Day28 | 
| Any worsening of WHO 11-point Clinical Progression Scale through Day28 | Outcome measured during patients medical follow-up | Day 28 | 
| Rate of Post-COVID19 condition at Day90 according to the WHO October 2021 definition | Rate of Post-COVID19 condition at Day90 according to the WHO October 2021 definition: o Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time. | Day 90 | 
| Percentage of participants with an adverse event (AE) or serious adverse event (SAE) or AE leading to treatment discontinuation up to Day28 | Outcome measured during patients medical follow-up | Day 28 | 
| Adherence to nirmatrelvir/r with patient-reported adherence and nirmatrelvir/r residual plasma dosage at Day5 and Day10 | Outcome measured by patient-reported adherence and drug residual dosage using dried spot (DBS) | Day5 and Day10 | 
| Number of DDIs who led to dosage adjustment of other patient's drugs | Outcome measured during patients medical follow-up | Assessed up to Day 10 from randomisation | 
| Percentage of patients with specific retreatment patients (by antiviral antiinflammatory drugs or convalescent plasma through Day90 | Outcome measured during patients medical follow-up | Day90 |