Randomized Open‑Label Trial of Nirmatrelvir/Ritonavir Plus Remdesivir for Viral Clearance in Immunocompromised Patients with Persistent SARS‑CoV‑2 Infection

The primary objective is to evaluate viral clearance in immunocompromised participants with persistent SARS‑CoV‑2 infection following combined antiviral therapy with nirmatrelvir/ritonavir and remdesivir on days 15 and 22, addressing the clinical need to eradicate prolonged viral replication in this vulnerable population. Secondary objectives include:

• Assessment of safety of prolonged and/or combined antiviral treatment.
• Evaluation of viral clearance under extended nirmatrelvir/ritonavir therapy on days 15 and 22.
• Evaluation of viral clearance in severely immunocompromised participants on days 15 and 22.
• Measurement of changes in combined nose/throat swab viral load from baseline to days 5, 10, 15, 22, and 50.
• Determination of time to viral clearance.
• Comparison of the impact of combined antiviral treatment versus nirmatrelvir/ritonavir alone on clinical signs and symptoms and patient‑reported outcome measures.
• Assessment of symptoms and adverse clinical outcomes associated with viral persistence.

The trial enrolled adult participants of both sexes, all ≥ 18 years of age, who were classified as immunocompromised due to ongoing or residual effects of immunosuppressive therapy, hematopoietic stem cell or CAR‑T‑cell transplantation, primary immunodeficiency, high‑dose corticosteroid use, or HIV infection with CD4⁺ count < 200 cells/µL. Eligible individuals demonstrated persistent infection with SARS‑CoV‑2 for at least 28 days, confirmed by consecutive PCR tests with cycle‑threshold values ≤ 30. The sponsor did not provide the total number of participants enrolled. Selection was based on documented immunosuppression criteria and continuous viral positivity; participants were required to provide informed consent, be able to comply with study procedures, and, for women of child‑bearing potential, use effective contraception and have a negative pregnancy test. General health status was limited to the presence of the specified immunosuppressive conditions; no additional lifestyle requirements such as diet or physical activity were stipulated.

The study is an open‑label, randomized, phase IV trial evaluating the antiviral combination of nirmatrelvir/ritonavir (Paxlovid) and remdesivir (Veklury) in participants with long‑term persistence of SARS‑CoV‑2; participants are allocated to either the combination treatment arm or a control arm receiving standard care. Recruitment is planned to commence on 30 June 2026 and conclude on 5 April 2028, with each enrolled participant followed for up to 50 days after the first dose. The sequence of visits includes a screening visit to confirm eligibility and obtain informed consent, a baseline visit (Day 0) for randomization and initiation of therapy, subsequent study visits on Days 5, 15, 22, and 50 to collect nasopharyngeal swabs, safety laboratory data, and symptom diaries, and a final end‑of‑study visit at Day 50 for overall assessment. Participant involvement therefore spans approximately seven weeks. Early termination may occur if a participant experiences a serious adverse event, withdraws consent, fails to comply with protocol‑required procedures, or is lost to follow‑up, in which case the participant will be withdrawn from the study and appropriate safety follow‑up will be performed.

The investigational regimen includes Paxlovid 150 mg + 100 mg film‑coated tablets containing the active substance nirmatrelvir. The product is administered by oral route as a single dose of 6 U units per administration; the tablets are taken according to the study‑specified schedule.

The second investigational product is Veklury 100 mg powder for concentrate for solution for infusion, which provides the active antiviral agent remdesivir. It is reconstituted and delivered by intravenous infusion as a 200 mg dose of solution for infusion per administration, following the protocol‑defined timing.

No placebo or additional comparator therapy is employed in this open‑label trial; participants receive only the combination of the two experimental antivirals as described.

Administration of the combination therapy occurs on study days 15 and 22. Dosing compliance is monitored through documented intake records and infusion logs, with study staff verifying adherence at each visit.

The primary efficacy assessment will determine the percent of participants from group B with absence of SARS‑CoV‑2 (CT value > 30) using a combined nose/throat swab. Samples will be collected at day 15 and day 22, and participants must have negative results on both days to meet the endpoint.

Secondary efficacy evaluations include:

• Percentage of participants from group A with SARS‑CoV‑2 absence (CT value > 30) at day 15 and day 22.
• Percentage of severely immunocompromised participants from groups A and B with SARS‑CoV‑2 absence at day 15 and day 22.
• Quantitative SARS‑CoV‑2 RNA measurement from combined nose/throat swabs at baseline and changes from baseline to days 5, 15, 22, and 50.
• Mean time to first negative PCR (CT value > 30) in each treatment group.
• Assessment of acute COVID‑19 signs and symptoms using a patient‑reported diary and Global Impression Questions, with changes evaluated from baseline to days 5, 10, 15, 22, and 50, including any worsening or new onset of symptoms.
• Proportion of participants admitted to intensive care by day 50 and all‑cause mortality at day 50.