OPTICOV: OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial
Study Details
Study Description
Brief Summary
The overall purpose of the trial is to evaluate the efficacy and safety of possible combination antiviral therapy (mAbs (T/C)∞ + 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Detailed Description
This is a randomized, controlled, factorial, superiority trial to evaluate the viral efficacy of DAA (nirmatrelvir/r) + mAbs (T/C)∞ 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 DAA (nirmatrelvir/r) and mAbs (T/C)∞ (ii) an increase in DAA 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Nirmatrelvir/r 5 days alone
|
Drug: Paxlovid 5 days
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.
Other Names:
|
| Experimental: Nirmatrelvir/r 10 days alone
|
Drug: Paxlovid 10 days
Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.
Other Names:
|
| Experimental: Nirmatrelvir/r 5 days + Evusheld s.d
|
Drug: Paxlovid 5 days
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.
Other Names:
Drug: Tixagevimab and Cilgavimab
T/C 300mg/300mg single dose, intramuscular. T/C (also known as AZD 7442 and marketed by AstraZeneca under the brand name Evusheld®) is a pair of mAbs with activity against SARS-CoV-2.
Other Names:
|
| Experimental: Nirmatrelvir/r 10 days + Evusheld s.d
|
Drug: Paxlovid 10 days
Nirmatrelvir/r 300mg/100 mg bid will be given for 10 days, orally.
Other Names:
Drug: Tixagevimab and Cilgavimab
T/C 300mg/300mg single dose, intramuscular. T/C (also known as AZD 7442 and marketed by AstraZeneca under the brand name Evusheld®) is a pair of mAbs with activity against SARS-CoV-2.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Measure of SARS-CoV-2 viral load (threshold cicle (Ct) <32) by real-time RT-PCR in nasopharyngeal swabs at Day 10 after treatment initiation. [Day 10]
SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR
Secondary Outcome Measures
- Measure of 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 [Day5, Day14 and Day21]
SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR
- Measure of SARS-CoV-2 viremia (detectable or not detectable) at Day5, Day10 and Day14 [Assessed for 14 days from the date of randomisation at Day5, Day10 and Day14]
SARS-CoV-2 viremia is measured from plasma samples by real-time RT-PCR
- Measure of SARS-CoV-2 viral load (indicated in copies/ml) in nasopharyngeal swab at Day5, Day10, Day14, Day21 and in blood samples at Day5, Day10 and Day14 comparatively to screening [Day5, Day10, Day14, Day21]
SARS-CoV-2 viral load is measured in nasopharyngeal swabs and in blood samples by real-time RT-PCR
- Number of de novo emergence of mutations on nasopharyngeal RT-PCR at Day5, Day10, Day14 and Day21 comparatively to screening [Day5, Day10, Day14 and Day21]
Emergence of mutations is measured in nasopharyngeal swabs by genotyping techniques
- Time to first negative SARS-CoV-2 RT-PCR (CT<32) until Day90 [Day90]
SARS-CoV-2 viral load is measured in nasopharyngeal swabs by real-time RT-PCR
- Absence of ability to cultivate virus from viral cultures from nasopharyngeal swabs at Day5, Day10, Day14 and Day21 [Day5, Day10, Day14 and Day21]
Viral culture is performed from nasopharyngeal swabs samples
- Sustained resolution or abatement or absence of signs or symptoms defined as a FLU-PRO-Plus score ≤1 at Day5, Day10, Day14, Day21 and Day28 [Day5, Day10, Day14, Day21 and Day28]
FLU-PRO-Plus score is measured via an arithmetic formula
- All-cause hospitalization and/or death at Day28 [Day28]
Outcome measured during patients medical follow-up
- Hospitalization at Day28 [Day28]
Outcome measured during patients medical follow-up
- Death at Day28 [Day28]
Outcome measured during patients medical follow-up
- Maximum WHO 11-point Clinical Progression Scale through Day28 [Day28]
Outcome measured during patients medical follow-up
- Any worsening of WHO 11-point Clinical Progression Scale through Day28 [Day 28]
Outcome measured during patients medical follow-up
- FLU-PRO-Plus (The InFLUenza Patient-Reported Outcome) scale at Day5, Day10, Day14, Day21, Day28 and Day90, where the minimum value 0 means "not at all" and the maximum value 4 means "very much" [Day5, Day10, Day14, Day21, Day28 and Day90]
Outcome assessed via a 32-item patient-reported questionnaire
- Rate of Post-COVID19 condition at Day90 according to the WHO October 2021 definition [Day 90]
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.
- Percentage of participants with an adverse event (AE) or serious adverse event (SAE) or AE leading to treatment discontinuation up to Day180 [Day 180]
Outcome measured during patients medical follow-up
- Adherence to nirmatrelvir/r with patient-reported adherence and nirmatrelvir/r residual dosage at Day5 and Day10 using dried blood spot [Day5 and Day10]
Outcome measured by patient-reported adherence and drug residual dosage using dried spot (DBS)
- Number of DDIs who led to dosage adjustment of other patient's drugs [Assessed up to Day 10 from randomisation]
Outcome measured during patients medical follow-up
- The need to retreat patients with antiviral drugs (evaluated by the treating physician) through Day90 [Day90]
Outcome measured during patients medical follow-up
Eligibility Criteria
Criteria
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) 53
-
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 prednisolone >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 ≥32 CT at screening
-
Contra-indication to T/C
-
Contra-indication to nirmatrelvir/r
• Study SOPs based on recommendations from Liverpool University (https://www.covid19-druginteractions.org/) will be provided to guide investigators
-
Creatinin clearance <30ml/mn/.73m² (CKD-EPI)
-
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
-
Previous exposure to T/C in the 6 months prior to randomization, or nirmatrelvir/r or other mAbs in the 28 days preceding randomization
-
Argument for the presence of a variant resistant against the reference mAbs, or, if variant identification is not available, the prevalence of variants resistant against the reference mAbs at inclusion is >10% in the study site's area
-
Pregnant or breastfeeding female, unless additional data are available for the use of the study drugs in this population
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- ANRS, Emerging Infectious Diseases
- University Hospital, Geneva
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ANRS 0176s OPTICOV
- CT-2022-501408-81-01