Ensitrelvir for Post-COVID Syndrome

(PREVAIL-LC Trial)

Overseen By PREVAIL-LC Study

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Timothy Henrich

Must not be taking: SARS-CoV-2 antivirals, Convalescent plasma

Disqualifiers: Cardiovascular disease, Stroke, HIV, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 61

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of an antiviral drug called Ensitrelvir for individuals with Long COVID. Researchers aim to determine if this treatment can reduce symptoms by blocking the virus from replicating, potentially causing ongoing issues after the initial COVID-19 infection. Participants will receive either Ensitrelvir or a placebo (a harmless pill with no active drug) to compare results. The trial seeks adults who have had a confirmed COVID-19 infection and are experiencing persistent, bothersome symptoms for at least 60 days. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received a SARS-CoV-2 antiviral or COVID-19 convalescent plasma treatment recently, and you should not plan to receive any investigational or approved SARS-CoV-2 vaccine or booster shortly before or during the trial.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot have received a SARS-CoV-2 antiviral or COVID-19 convalescent plasma treatment recently, and you should not plan to receive any COVID-19 vaccines or boosters during certain periods of the study.

Is there any evidence suggesting that Ensitrelvir is likely to be safe for humans?

Earlier studies have shown that Ensitrelvir has strong antiviral effects, effectively fighting viruses. In a large study, participants who took Ensitrelvir were 67% less likely to contract COVID-19 compared to those who did not. This suggests it might effectively and safely reduce the severity of infections. Although specific findings about its safety for Long COVID are not yet available, ongoing trials indicate some confidence in its safety. As Ensitrelvir is in a phase 2 trial for Long COVID, researchers believe it is generally well-tolerated in humans. However, more data is needed to fully understand all its effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Long COVID?

Ensitrelvir is unique because it's designed to target post-COVID syndrome, a condition with limited treatment options. Unlike many current treatments that focus on symptom relief, Ensitrelvir works by inhibiting a key enzyme of the virus, potentially stopping its activity. This targeted approach could mean faster and more effective relief for patients. Researchers are excited because it offers a new mechanism of action that could change how we manage post-COVID symptoms.

What evidence suggests that Ensitrelvir might be an effective treatment for Long COVID?

Research has shown that Ensitrelvir, an antiviral medication, can reduce the risk of contracting COVID-19 by 67% if taken after exposure to the virus. Users of Ensitrelvir also had a 14% lower chance of developing severe COVID-19 symptoms compared to those who did not take antiviral drugs. This medication stops the virus from multiplying, which may help ease symptoms in people with Long COVID. In this trial, participants will receive either Ensitrelvir or a placebo to evaluate its effectiveness in treating Long COVID symptoms. Although some studies have not found that Ensitrelvir speeds up recovery from symptoms, its ability to reduce infection risk and inhibit viral spread makes it a promising option for treating Long COVID symptoms. ^{1 2 3 4 5}

Who Is on the Research Team?

Timothy J Henrich, MD

Principal Investigator

University of California, San Francisco

Michael Peluso, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults aged 18-70 with a history of confirmed COVID-19, experiencing Long COVID symptoms for at least 60 days that are moderately to severely bothersome. Participants must not be known to have other causes for their symptoms and should have a BMI between 18 and 50 kg/m2. They must also agree to use contraception if they can bear children.

Inclusion Criteria

I have had a confirmed case of COVID-19.

Body mass index (BMI) 18 to 50 kilograms/meter squared (kg/m2), inclusive, at the time of screening

Participants who are of childbearing potential (CBP) and male participants with sexual partner(s) who are females of CBP must agree to use adequate contraception from study consent through 14 days after the last dose of study intervention

Exclusion Criteria

I do not have an active Hepatitis B or C infection.

Participation in a clinical trial with receipt of an investigational product within 28 days prior to Day 0

Severe anemia (hemoglobin <9 grams/deciliter (g/dL)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ensitrelvir or placebo orally for 5 days

1 week

1 visit (in-person) at baseline

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Multiple visits up to 60 days post-initiation

What Are the Treatments Tested in This Trial?

Interventions

• Ensitrelvir

Trial Overview The trial is testing Ensitrelvir, an antiviral drug, against a placebo to see if it's safe and effective in treating Long COVID by potentially blocking viral replication that could cause persistent symptoms.

How Is the Trial Designed?

Group I: Ensitrelvir (S-217622) Experimental Treatment 1 Intervention

Ensitrelvir fumaric acid (S-217622) given orally 375 mg on day 1 followed by 125 mg daily for 4 additional days

Group II: Placebo Placebo Group 1 Intervention

Placebo administered orally for 5 days

Ensitrelvir is already approved in Japan for the following indications:

Approved in Japan as Xocova for:

• COVID-19

Who Is Running the Clinical Trial?

Timothy Henrich

Lead Sponsor

Trials

1

Recruited

40+

Shionogi Inc.

Industry Sponsor

Trials

10

Recruited

760+

Published Research Related to This Trial

The investigational antiviral S-217622 shows strong potential against various SARS-CoV-2 variants, including new strains, by effectively inhibiting key replication enzymes like the main protease (Mpro), RNA-dependent RNA polymerase (RdRp), and exoribonuclease (ExoN) with very low effective concentrations (EC50 values of 0.17 and 0.27 μM).

S-217622's unique mechanism of action as a nucleoside analog allows it to target multiple coronavirus strains, suggesting its broad-spectrum efficacy and readiness for clinical evaluation as a treatment for COVID-19 and potentially other coronaviruses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir "S-217622": A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species. Eltayb, WA., Abdalla, M., Rabie, AM.[2023]

A phase 3 study is being conducted to evaluate the efficacy and safety of ensitrelvir, a novel oral protease inhibitor, in treating mild-to-moderate COVID-19 in patients regardless of their vaccination status or risk factors.

Preliminary results from a phase 2b study indicated that ensitrelvir reduced the time to resolution of COVID-19 symptoms compared to placebo, suggesting it may be an effective treatment option for patients with mild-to-moderate disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part). Yotsuyanagi, H., Ohmagari, N., Doi, Y., et al.[2023]

S-217622 (Ensitrelvir) is an approved treatment for SARS-CoV-2 that works by inhibiting a key enzyme (3CLpro) necessary for the virus's replication, and its analog YY-278 shows similar antiviral activity against this enzyme and the virus itself.

YY-278 not only retains favorable pharmacokinetic properties, such as good bioavailability, but also demonstrates broad anti-coronaviral activity against multiple coronaviruses, suggesting its potential for treating COVID-19 and other related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2. Yang, Y., Cao, L., Yan, M., et al.[2023]

Ensitrelvir (S-217622) is an effective antiviral treatment for COVID-19, demonstrating comparable activity against various SARS-CoV-2 variants, including the recently emerging omicron subvariants.

The drug effectively inhibits mutated forms of the SARS-CoV-2 3C-like protease (3CLpro), maintaining its efficacy against 11 major mutations identified globally, suggesting it could remain effective against future variants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants circulating globally. Kawashima, S., Matsui, Y., Adachi, T., et al.[2023]

In a phase 2b study involving 341 patients with mild-to-moderate COVID-19, ensitrelvir significantly reduced SARS-CoV-2 viral titers compared to placebo, indicating its antiviral efficacy.

While ensitrelvir did not show a significant difference in overall COVID-19 symptom scores compared to placebo, it did improve specific acute and respiratory symptoms, and most adverse events reported were mild, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study. Mukae, H., Yotsuyanagi, H., Ohmagari, N., et al.[2023]

Ensitrelvir, a small-molecule antiviral targeting the 3C-like protease of SARS-CoV-2, showed comparable antiviral activity to nirmatrelvir in vitro across multiple cell lines and effectively reduced virus levels in animal models.

In vivo, ensitrelvir demonstrated equal to or greater efficacy than nirmatrelvir at similar or slightly lower unbound-drug plasma concentrations, suggesting it could be a valuable treatment option for SARS-CoV-2 infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. Kuroda, T., Nobori, H., Fukao, K., et al.[2023]

Citations

1. cidrap.umn.edu cidrap.umn.edu/covid-19/trial-data-show-ensitrelvir-has-potent-antiviral-activity-against-covid-19

Trial data show ensitrelvir has potent antiviral activity ... The NDA submission was based on a phase 3 trial that found ensitrelvir demonstrated a 67% reduced risk of COVID-19 infection when taken after ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06161688

Study Details | NCT06161688 | Ensitrelvir for Viral ... This trial will study the safety and efficacy of Ensitrelvir (S-217622), an antiviral, to treat individuals with Long COVID in an adult population. Detailed ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39960062/

Results from the SCORPIO-HR, Phase 3 ... - PubMed Despite the evidence of antiviral activity with ensitrelvir, this trial did not demonstrate a significant difference in time to sustained symptom resolution.

4. shionogi.com shionogi.com/global/en/news/2025/11/20251105.html

New Clinical Data on the Efficacy of Antiviral Treatments ... For ensitrelvir alone, the risk was also significantly reduced by about 14% compared to non-antiviral treatment (adjusted risk ratio: 0.86 [95% ...

5. journals.plos.org journals.plos.org/plosone/article/asset?id=10.1371/journal.pone.0335609.PDF

A pro - Research journals - PLOS Ensitrel- vir fumarate, a novel oral antiviral agent, has demonstrated efficacy in treating of mild-to-moderate COVID-19. This study aims to ...