OPtimisation of antiviral Therapy in Immunocompromised COVID-19 patients: a randomized factorial controlled strategy trial: the OPTICOV Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Inserm

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

4 Mar 2024 → ongoing

Decision date (initial)

2022-11-18

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministère de l’Enseignement supérieur, de la Recherche et de l’Innovation (MESRI)

External identifiers

EU CT number

2022-501408-81-01

ClinicalTrials.gov

NCT05587894

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

The primary objective is to assess whether
(iii) a combination antiviral therapy of two DAAs (nirmatrelvir/r + remdesivir∞)
(iv) an increase in nirmatrelvir 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.

Secondary objectives 16

1. Decrease SARS-CoV-2 positivity rate by real time PCR (CT<32) in nasopharyngeal swabs at D5, D14 and D21
2. Decrease the SARS-CoV-2 positivity rate by RT-PCR in blood samples (viremia) at D5, D10 and D14
3. Assess SARS-CoV-2 viral load decay at D5, D10, D14, D21 in nasopharyngeal swabs and at D5, D10 and D14 in blood samples
4. Limit SARS-CoV-2 de novo emergence of mutations at D5, D10, D14 and D21 comparatively to screening
5. Decrease the time to virus clearance (negative nasopharyngeal RT-PCR (CT<32))
6. Increase the rate of negative viral culture from nasopharyngeal swabs at D5, D10, D14 and D21
7. Increase the rate of clinical recovery (sustained resolution or abatement of symptoms using the FLU-PRO-Plus scale) at D5, D10, D14, D21 and D28
8. Decrease all-cause hospitalization and/or death rate at D28
9. Decrease patient’s maximum WHO 11-point Clinical Progression Scale and decrease patient’s reported COVID-19 signs and symptoms through D28
10. Decrease COVID-19 related signs or symptoms at D5, D10, D14, D21, D28 and D90 (using FLU-PRO-Plus scale)
11. Decrease the rate of post-COVID-19 condition at D90
12. Assess safety and adherence (self-reported and nirmatrelvir/r residual concentrations) through D90
13. Impacts nirmatrelvir/r plasma dosage at D5 and D10
14. Impacts immunosuppressive drugs dosage at D5 and D10, if applicable
15. Decrease the need for additional specific treatments (antiviral, anti-inflammatory drug or convalescent plasma) with antiviral drugs through D90
16. - Diminuer le taux de positivité du SARS-CoV-2 par RT-PCR (CT<32) dans les frottis nasopharyngés à J5, J14 et J21 - Diminuer le taux de positivité du SARS-CoV-2 par RT-PCR dans les échantillons de sang (virémie) à J5, J10 et J14 - Évaluer la décroissance de la charge virale du SARS-CoV-2 à J5, J10, J14, J21 dans les frottis nasopharyngés, et à J5, J10 et J14 dans les échantillons de sang - Limiter l'émergence de novo de mutations du SARS-CoV-2 à J5, J10, J14 et J21 par rapport au screening - Limiter l’augmentation de novo de l’IC50 aux traitements du SARS-CoV-2 reçus par le patient, à J5, J10, J14 et J21 comparativement au screening (étude exploratoire) - Diminuer le délai de clairance du virus (RT-PCR nasopharyngée négative (CT<32)) - Augmenter le taux de culture virale négative sur frottis nasopharyngé à J5, J10, J14 et J21 - Décrire l’évolution virologique chez des patients immunodéprimés qui ont une contre-indication pour le nirmatrelvir/r et/ou pour le remdesivir et qui recevront le standard de soins local dans le cadre d’une cohorte observationnelle Clinique : - Augmenter le taux de guérison clinique (taux de résolution ou d’atténuation des signes ou symptômes, selon l'échelle FLU-PRO-Plus) à J5, J10, J14, J21 et J28. - Diminuer le taux d'hospitalisation et/ou de décès, toutes causes confondues, à J28. - Diminuer les signes et symptômes COVID-19 rapportés par le patient jusqu'à J28. - Diminuer les signes ou symptômes liés au COVID-19 à J5, J10, J14, J21, J28 et J90 (en utilisant l'échelle FLU-PRO-Plus) - Diminuer le taux d’affection post-COVID-19 (« COVID-long ») à J90 - Evaluer la tolérance et l’observance du nirmatrelvir/r (auto-reportée et mesurée via le dosage du nirmatrelvir/r) jusqu'à J90 - Estimer le dosage plasmatique du nirmatrelvir/r à J5 et J10, si applicable - Estimer le dosage des immunosuppresseurs associés le cas échéant - D’évaluer la nécessité de recours à un traitement spécifique (antiviral, antiinflammatoire ou plasma de convalescent) supplémentaire jusqu'à J90, si applicable - Décrire l’évolution clinique chez des patients immunodéprimés qui ont une contre-indication pour le nirmatrelvir/r et/ou pour le remdesivir et qui recevront le standard des soins local dans le cadre d’une cohorte observationnelle

Conditions and MedDRA coding

Covid-19

Study design 1 period

Regulatory references

Plan to share IPD

Yes

IPD plan description

The data will be available following the article publication. The data include the individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures and appendices). Data will be shared with researchers who provide a methodologically sound proposal, that needs to be approved by the relevant ANRS or trial committee, and for analyses to achieve aims in the approved proposal. To gain access, data requestors will need to sign a data access agreement and comply with GDPR.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Laboratory confirmed SARS-CoV-2 infection by RT-PCR
2. Asymptomatic or mild to moderate COVID-19 (WHO progression scale ≤5)
3. ≥ 16 years of age (for patients recruited in Italy and in Norway, ≥ 18 years of age);
4. Body weight > 40 kg
5. Immunocompromised as defined by ≥ 1 risk factors for severe COVID-19 as assessed by the Swiss Federal Office of Public Health (FOPH) list (criteria 5: diseases/treatments leading to immune suppression)  HIV Infection with CD4 count< 200 cells/μL  Neutropenia (<1000 neutrophils / μl) ≥1 week  Lymphocytopenia (<200 lymphocytes/μl)  Hereditary immunodeficiencies  Intake of drugs which suppress the immune system (e.g., taking 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 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
6. Willing and able to comply with study requirements and restrictions as described in the informed consent form (ICF)
7. 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)
8. Participant’s or its legal representative's signature of the informed consent form (ICF)

Exclusion criteria 9

1. SARS-CoV-2 PCR ≥30 CT at screening
2. Hypersensitivity to study drugs (active substance(s) or excipients)
3. Creatinine clearance <30ml/mn/.73m² (CKD-EPI)
4. AST or ALT > 5 times the upper limit
5. Is taking or is anticipated to require any prohibited therapies
6. Participation in another interventional clinical study through Day 28 with an investigational compound or device, including COVID-19 therapeutics
7. 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
8. Having received antiviral treatments against SARS-CoV-2 in the 14 days before the inclusion
9. Pregnant or breastfeeding female, unless additional data are available for the use of the study drugs in this population

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients with SARS-CoV-2 viral load <32 CT by real-time RT-PCR in nasopharyngeal swabs at D10 after treatment initiation

Secondary endpoints 18

1. 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
2. Percentage of patients with detectable SARS-CoV-2 viremia at D5, D10 and D14
3. 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
4. Number of de novo emergence of mutations on nasopharyngeal RT-PCR at D5, D10, D14 and D21 comparatively to screening
5. Time to first negative SARS-CoV-2 RT-PCR (CT<32) until D90
6. Absence of ability to cultivate virus from viral cultures from nasopharyngeal swabs at D5, D10, D14 and D21
7. Percentage of patients with sustained resolution or abatement or absence of signs or symptoms defined as a FLU-PRO Plus score ≤1 at D5, D10, D14, D21 and D28
8. All-cause hospitalisation and/or death at D28
9. Hospitalization at D28
10. Death at D28
11. Maximum WHO 11-point Clinical Progression Scale through D28
12. Any worsening of WHO 11-point Clinical Progression Scale through D28
13. FLU-PRO-Plus scale at D5, D10, D14, D21, D28 and D90
14. Rate of post-COVID-19 condition at D90 according to the WHO October 2021 definition
15. Percentage of participants with an adverse event (AE) or serious adverse event (SAE) or AE leading to treatment discontinuation up to D90
16. Adherence to nirmatrelvir/r with patient-reported adherence (PRA) and nirmatrelvir/r residual dosage at D5 and D10 from plasma sample
17. Number of drug-drug interactions (DDIs) which led to dosage adjustment of other patient’s drugs
18. Percentage of patients with specific retreatment (by antiviral, anti-inflammatory drug or convalescent plasma) through D90

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Inserm

Sponsor organisation

Inserm

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Inserm

Contact name

Douae Ammour

Public contact point

Organisation

Inserm

Contact name

Douae Ammour

Sponsor responsibilities

Article 77 compliance

Inserm

Contact point sponsor

Inserm

Article 77 implementation

Inserm

Locations

3 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 36 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications