Ensitrelvir for Viral Persistence and Inflammation in People Experiencing Long COVID (PREVAIL-LC)

Placebo-Controlled, Randomized Trial of Ensitrelvir (S-217622) for Viral Persistence and Inflammation in People Experiencing Long COVID (PREVAIL-LC)

Persistent viral infection with viral reservoirs and detection of circulating spike protein after the initial acute illness is one potential pathogenic mechanism for Long COVID. This mechanism may be susceptible to antiviral therapy that blocks viral replication, which has the potential to alleviate long COVID symptoms. This trial will study the safety and efficacy of Ensitrelvir (S-217622), an antiviral, to treat individuals with Long COVID in an adult population.

Study Overview

• Status: Active, not recruiting
• Conditions: Long COVID; Post-Acute COVID-19; Post Acute Sequelae of COVID-19
• Intervention / Treatment: Drug: Ensitrelvir; Other: Placebo

Detailed Description

The study will enroll approximately 40 participants who meet the World Health Organization (WHO) Long COVID criteria. Participants will be enrolled at a single center and randomized 1:1 to receive ensitrelvir fumaric acid (Ensitrelvir: S-217622), given orally for 5 days, or placebo. Subjects randomized to receive Ensitrelvir will take 375 mg on day 1, followed by 125 mg daily for 4 additional days. Evaluations will take place at baseline and at timepoints up to 60 days post-initiation of study drug.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • UCSF/Zuckerberg San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria (note, additional eligibility criteria not listed here will be assessed at Screening):

• ≥18 and <70 years of age at Screening.
• History of confirmed SARS-CoV-2 infection.
• Long COVID attributed to a SARS-CoV-2 infection
• At least two moderate symptoms or one severe symptom that are new or worsened since the time of a SARS-CoV-2 infection, not known to be attributable to another cause upon assessment by the PI. Symptoms must have been present for at least 60 days prior to screening and must be reported to be at least somewhat bothersome.
• 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 (note, additional eligibility criteria not listed here will be assessed at Screening):

• Previously received SARS-CoV-2 antiviral within 90 days prior to planned Day 0 or plan to receive such treatment before exiting the study
• Previously received COVID-19 convalescent plasma treatment within 60 days prior to planned Day 0 or plan to receive such treatment before exiting the study.
• Plans to receive any investigational or approved vaccine or booster for SARS-CoV-2 within 60 days prior to Day 0 or before Day 30 following Day 0.
• Active cardiovascular disease or recent (within 3 months) stroke.
• Recent (within 6 months) or planned major surgery.
• Currently hospitalized or recent (within 1 month) unplanned hospitalization.
• Active Hepatitis B or C infection.
• Known HIV infection.
• Severe coagulopathy (international normalized ratio ((INR) >2.0, history of hemophilia).
• Severe anemia (hemoglobin <9 grams/deciliter (g/dL)).
• Moderate or severe immunocompromise, according to the current NIH COVID-19 Treatment Guidelines as of March 6, 2023.
• History of anaphylaxis or hypersensitivity to any components of the intervention, prescription or non-prescription drugs, or food products in the past.
• Known prior diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), preceding and not related to SARS-CoV-2 infection and not worsened since SARS-CoV-2 infection
• Pregnant, breastfeeding, or unwilling to practice birth control abide by the contraception requirements outlined in the inclusion criteria.
• Participation in a clinical trial with receipt of an investigational product within 28 days prior to Day 0.
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ensitrelvir (S-217622); Ensitrelvir fumaric acid (S-217622) given orally 375 mg on day 1 followed by 125 mg daily for 4 additional days	Drug: Ensitrelvir; Those randomized to the experimental arm will receive Ensitrelvir, a protease inhibitor, taken orally for 5 days; Other Names: ensitrelvir fumaric acid
Placebo Comparator: Placebo; Placebo administered orally for 5 days	Other: Placebo; Matching placebo for Ensitrelvir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean PROMIS-29 Physical Health Summary Score at 10 post-[ADD]. PROMIS-29 is a validated scale assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, and pain. Each domain is scored on a 5-point scale (without any difficulty, with a little difficulty, with some difficulty, with much difficulty, unable to do). A T-score is calculated from each individual domain. A T score of 50 represents the mean for US general adult population, and 10 is the standard deviation. A lower T score indicates worse physical health.	Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean PROMIS-29 Physical Health Summary Score at Day 30 post-randomization. PROMIS-29 is a validated scale assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, and pain. Each domain is scored on a 5-point scale (without any difficulty, with a little difficulty, with some difficulty, with much difficulty, unable to do). A T-score is calculated from each individual domain. A T score of 50 represents the mean for US general adult population, and 10 is the standard deviation. A lower T score indicates worse physical health.	Day 30
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Mental Health Summary Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean PROMIS-29 Mental Health Summary Score at Day 10 post-randomization. PROMIS-29 is a validated scale assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, and pain. Each domain is scored on a 5-point scale (without any difficulty, with a little difficulty, with some difficulty, with much difficulty, unable to do). A T-score is calculated from each individual domain. A T score of 50 represents the mean for US general adult population, and 10 is the standard deviation. A lower T score indicates worse mental health.	Day 10
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Mental Health Summary Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean PROMIS-29 Mental Health Summary Score at Day 30 post-randomization. PROMIS-29 is a validated scale assessing physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social activities, and pain. Each domain is scored on a 5-point scale (without any difficulty, with a little difficulty, with some difficulty, with much difficulty, unable to do). A T-score is calculated from each individual domain. A T score of 50 represents the mean for US general adult population, and 10 is the standard deviation. A lower T score indicates worse mental health.	Day 30
Quality of Life (Global Health Score) on a 100-point Visual-Analogue Scale	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in the baseline adjusted mean Quality of Life 100-point Visual-Analogue-Scale at Day 10 post-randomization. 0 represents the worst health a person can imagine and 100 represents the best health a person can imagine.	Day 10
Quality of Life Score (5-Item EuroQol EQ-5D-5L) Index Value Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean Quality of Life (5-Item EuroQol EQ-5D-5L) Index Value Score at Day 10 post-randomization. 5-Item EuroQol EQ-5D-5L questions assess pain/difficulty in day-to-day activities over the past week. The 5-Item EuroQol EQ-5D-5L produces a score that typically ranges from 0 - 1, with a higher score indicating better quality of life.	Day 10
Duke Activity Status Index (DASI)	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean DASI at Day 10 post-randomization. The Duke Activity Status Index is a patient-reported estimate of functional capacity, maximal oxygen consumption (VO2 max) and maximum metabolic equivalent of tasks (METs). The DASI questionnaire produces a score between 0 and 58.2 points, which is linearly correlated with a patient's VO2 max and METs, as measured from cardiopulmonary exercise testing (CPET). It inquires about a person's ability to perform self-care, walk, climb stairs, run, do house and yard work, engage in sexual intercourse, and perform moderate recreational activities. A higher score indicates higher functional capacity.	Day 10
Orthostatic Hypotension Questionnaire (OHQ) Composite Score	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean OHQ composite score at Day 10 post-randomization. The Orthostatic Hypotension Questionnaire (OHQ) was developed as a psychometric tool to capture patients' experience quantifying symptomatic burden and functional limitations caused by neurogenic orthostatic hypotension The OHQ composite score range is 0 -10 with a higher score indicating higher burden.	Day 10
World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0) Questionnaire	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean WHO-DAS 2.0 score at Day 10 post-randomization. The World Health Organization Disability Assessment Schedule 2.0 questionnaire asks about difficulties due to health conditions. Health conditions include diseases or illnesses, other health problems that may be short or long lasting, injuries, mental or emotional problems, and problems with alcohol or drugs. The range is scored from 0-48, with a higher score indicating a higher level of disability.	Day 10
Patient Global Impression of Change (PGIC)	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo on the Patient Global Impression of Change (PGIC) scale at Day 10 post-randomization. The self-reported PGIC reflects a patient's belief about the efficacy of treatment. We used a modified PGIC scale which has been used to study pain syndromes and has been employed in other Long COVID clinical trials. It is a common data element developed by the National Institutes of Mental Health. The PGIC ranges from 0 (Much better) to 10 (Much Worse). A score of 5 indicates no change.	Day 10
Everyday Cognition Form (ECog-41)	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean ECog-41 score at Day 10 post-randomization. The ECog-41 is an instrument that measures the decline in everyday cognitive and functional abilities that map to six cognitive domains, adapted specifically to describe change in abilities since having COVID. A summary ECog-41 score is calculated scored with a range of 1-4, with a higher score indicating greater cognitive impairment.	Day 10
6 Minute Walking Test (6MWT)	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean distance walked on the 6MWT at Day 10 post-randomization. The 6MWT requires an individual to walk at their normal pace for 6 minutes on a marked track (for example, a hallway). Vital signs are assessed, and the total distance covered is the primary outcome of interest. A larger distance is regarded as better.	Day 10
Active Stand Test	The active standing test is a non-invasive tool to assess orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). In short, blood pressure and heart rate measurements were obtained after 5 minutes of resting supine and 1, 3, 5, and 10 minutes of continuous standing. A positive active stand test is defined as: those with a decline >20 mmHg in systolic or > 10 mmHg in diastolic blood pressure in at least two consecutive measurements, or those with an increase in heart rate > 30 bpm on two consecutive measurements. Here we evaluate positive active stand tests as a binary outcome (yes, no), comparing the difference in proportion of participants with a positive active stand test at baseline and day 10 between the group treated with Ensitrelvir versus placebo.	Day 10
Neurocognition Index (NCI) Score From the CNS-VS	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo in baseline adjusted mean NCI standard score from the CNS-VS at Day 10 post-randomization The CNS Vital Signs is a a computer-based neurocognitive assessment comprised of seven tests: verbal and visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention and the continuous performance test. The battery gives a summary neurocognition index (NCI) score averaging five domain scores (Composite Memory, Psychomotor Speed, Reaction Time, Complex Attention, and Cognitive Flexibility) and representing a global score of neurocognition. NCI scores are normalized scores (mean 100, standard deviation 15) that are age matched relative to other people in a normative sample. A higher score indicates better cognitive function.	Day 10

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Global Impression of Change (PGIC)	The self-report measure Patient Global Impression of Change (PGIC) reflects a patient's belief about the efficacy of their treatment. We will use a modified PGIC scale which has been used to study pain syndromes and has been employed in other Long COVID clinical trials. It is a common data element developed by the National Institutes of Mental Health.	At 4 days and 10 days following administration
Distance walked on 6 minute walk test (6MWT).	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo on 6MWT performance between baseline and at 3 months post-administration. The 6MWT requires an individual to walk at their normal pace for 6 minutes on a marked track (for example, a hallway). Vital signs are assessed, and the total distance covered is the primary outcome of interest.	Baseline and 10 days following administration
Global health score on a 100-point visual-analogue scale	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo on self-reported score on a 100-point visual-analogue scale, where 0 represents the worst health a person can imagine and 100 represents the best health a person can imagine.	Baseline and 10 days following administration
CNS-Vital Signs Global Neurocognitive Index	This measure will evaluate whether there is a difference between treatment with Ensitrelvir versus placebo on CNS-Vital Signs neurocognitive testing performance between baseline and at 60 days post-administration. CNS-VS is a computerized testing battery that participants will complete at baseline and follow-up visits. The global neurocognitive index is a summary score that comprises multiple domains.	Baseline and 10 days following administration

Collaborators and Investigators

• Sponsor: Timothy Henrich
• Collaborators: Shionogi Inc.
• Investigators: Principal Investigator: Timothy Henrich, MD, University of California, San Francisco; Principal Investigator: Michael Peluso, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2024
• Primary Completion (Actual): December 20, 2024
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 6, 2023
• First Submitted That Met QC Criteria: December 6, 2023
• First Posted (Actual): December 8, 2023

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Antiviral; Viral Persistence
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Post-Acute COVID-19 Syndrome; ensitrelvir
• Other Study ID Numbers: 23-38752

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No