Clinical trial NCT05587894: OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial
Official title: OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial: the OPTICOV Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: COVID-19
Immunodeficiency
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: University Hospital, Geneva
First posted: 2022-10-20
Enrollment: 256
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: Inclusion Criteria:

1. Laboratory confirmed SARS-CoV-2 infection by RT-PCR or positive antigenic test
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;
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)

   * Severe immunosuppression (e.g., HIV infection with CD4 + T cell count \<350 / 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, 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
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 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 through Day 28 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 and French Speaking Transplantation society will be provided to guide investigators

Primary outcomes:
measure: 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.
timeFrame: Day 10
Secondary outcomes:
measure: 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
timeFrame: Day5, Day14 and Day21
measure: Percentage of patients with detectable SARS-CoV-2 viremia at Day5, Day10 and Day14
timeFrame: Assessed for 14 days from the date of randomisation at Day5, Day10 and Day14
measure: 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
timeFrame: Day5, Day10, Day14, Day21
measure: Number of de novo emergence of mutations on nasopharyngeal RT-PCR at Day5, Day10, Day14 and Day21 comparatively to screening
timeFrame: Day5, Day10, Day14 and Day21
measure: Time to first negative SARS-CoV-2 RT-PCR (CT<32) until Day90
timeFrame: Day90
measure: Absence of ability to cultivate virus from viral cultures from nasopharyngeal swabs at Day5, Day10 and Day21
timeFrame: Day5, Day10 and Day21
measure: 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
timeFrame: Day5, Day10, Day14, Day21 and Day28
measure: All-cause hospitalization and/or death at Day28
timeFrame: Day28
measure: Hospitalization at Day28
timeFrame: Day28
measure: Death at Day28
timeFrame: Day28
measure: Rate of Post-COVID19 condition at Day90 according to the WHO October 2021 definition
timeFrame: Day 90
measure: Percentage of participants with an adverse event (AE) or serious adverse event (SAE) or AE leading to treatment discontinuation up to Day28
timeFrame: Day 28
measure: Adherence to nirmatrelvir/r with patient-reported adherence and nirmatrelvir/r residual plasma dosage at Day5 and Day10
timeFrame: Day5 and Day10
measure: Number of DDIs who led to dosage adjustment of other patient's drugs
timeFrame: Assessed up to Day 10 from randomisation
measure: Percentage of patients with specific retreatment patients (by antiviral antiinflammatory drugs or convalescent plasma through Day90
timeFrame: Day90
measure: To assess the phenotypic resistance (IC50 increase) against treatment for viral strains cultured from nasopharyngeal swabs
timeFrame: Day5, Day10, Day14, Day21
measure: Immunosuppressors residual concentrations, if applicable
timeFrame: as needed
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Saint-André Hospital
city: Bordeaux
country: France
facility: Pellegrin Hospital
city: Dijon
country: France
facility: Francois Mitterrand Hospital
city: Lyon
country: France
facility: Croix Rousse Hospital
city: Montpellier
country: France
facility: La Colombière Hospital
city: Nantes
country: France
facility: Hotel Dieu Hospital
city: Paris
country: France
facility: Laribosière Hospital
city: Paris
country: France
facility: Saint Antoine Hospital
city: Paris
country: France
facility: Pitié-Salpêtrière Hospital
city: Paris
country: France
facility: Saint Louis Hospital
city: Paris
country: France
facility: Bichat Claude-Bernard Hospital
city: Reims
country: France
facility: Robert Debré Hospital
city: Toulouse
country: France
facility: Purpan Hospital
city: Tourcoing
country: France
facility: Tourcoing Hospital
city: Basel
country: Switzerland
facility: Basel University Hospital
city: Geneva
country: Switzerland
facility: University Hospitals of Geneva
city: Lausanne
country: Switzerland
facility: University Hospital CHUV
city: Zürich
country: Switzerland
facility: University Hospital Zurich
Study officials:
References: