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

Phase 2RecruitingNCT05587894

ANRS, Emerging Infectious Diseases256 enrolled

Overview

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.

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. 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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

256

Conditions

Interventions

Paxlovid 5 daysDRUG

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.

Paxlovid 10 daysDRUG

Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.

VekluryDRUG

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.

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Laboratory confirmed SARS-CoV-2 infection by RT-PCR or positive antigenic test (commercialized assay) 2. Asymptomatic or mild to moderate COVID-19 (WHO progression scale \<5. Patients receiving oxygen therapy for reasons other than a pulmonary COVID-19 are eligible). 3. ≥ 16 years of age (for patients recruited in Italy and in Norway, ≥ 18 years of age); 4. 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) or other immunosuppression criteria such as Severe immunosuppression (e.g., HIV infection with CD4 + T cell count \<350 / µl) Neutropenia (\<1000 neutrophils / µl) ≥1 week Lymphocytopenia (\<200 lymphocytes/µl) On dialysis treatment 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, everolimus, mTOR inhibitors etc.) in the last 12 months Active cancer under cytostatics or targeted therapy known to be immunosuppressive (e.g., platinum salts, cyclophosphamide, anthracyclines, taxanes, 5-fluorouracil, gemcitabine, purine inhibitors, proteasome inhibitors) or associated with hematologic toxicity (neutropenia, lymphopenia), for example sunitinib, imatinib, regorafenib. 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 5. Willing and able to comply with study requirements and restrictions as described in the informed consent form (ICF) 6. Enrolled in or a beneficiary of a Social Security program (State Medical Aid (AME) is not a Social Security program) or holders of health insurance (LAF for participants recruited in Norway). 7. Participant's or its legal representative's signature of the informed consent form Exclusion Criteria: 1. SARS-CoV-2 PCR ≥30 CT at screening 2. Hypersensitivity to study drugs (active substance(s) or excipients) 3. Body weight \< 40 kg 4. AST and/or ALT \> 5 times the upper limit 5. Cirrhosis Child-Pugh score C 6. Is taking or is anticipated to require any prohibited therapies\*. 7. Participation in another interventional clinical study with an investigational compound or device, including COVID-19 therapeutics, where the study intervention is performed in the 28 days preceding the inclusion and the 10 days after the inclusion. Investigators of the different clinical studies should agree on participant's inclusion. 8. 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 9. Having received antiviral treatments against SARS-CoV-2 in the 14 days before the inclusion with exception of those having received one or two doses of nirmatrevir/r in the 24h preceding the inclusion in the study. 10. Pregnant or breastfeeding female * Study SOPs based on recommendations from the Liverpool COVID-19 interactions, French Society for Pharmacology and Therapeutics (https://sfpt-fr.org/recommandations-et-publications) and French Speaking Transplantation Society will be provided to guide investigators.

Locations (18)

Saint-André Hospital

Bordeaux, Bordeaux, France

RECRUITING

Pellegrin Hospital

Bordeaux, Bordeaux, France

RECRUITING

Francois Mitterrand Hospital

Dijon, Dijon, France

RECRUITING

Croix Rousse Hospital

Lyon, Lyon, France

RECRUITING

La Colombière Hospital

Montpellier, Montpellier, France

RECRUITING

Hotel Dieu Hospital

Nantes, Nantes, France

RECRUITING

Laribosière Hospital

Paris, Paris, France

RECRUITING

Saint Antoine Hospital

Paris, Paris, France

RECRUITING

Pitié-Salpêtrière Hospital

Paris, Paris, France

RECRUITING

Saint Louis Hospital

Paris, Paris, France

RECRUITING

...and 8 more locations

Outcomes

Primary Outcomes

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

Time frame: Day 10

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Day5, Day10, Day14, Day21 and Day28

All-cause hospitalization and/or death at Day28