Long COVID, Post Acute Sequelae of COVID-19, Post-Acute COVID-19
Conditions
Keywords
Antiviral, Viral Persistence
Brief summary
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.
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.
Interventions
DRUGEnsitrelvir
Those randomized to the experimental arm will receive Ensitrelvir, a protease inhibitor, taken orally for 5 days
OTHERPlacebo
Matching placebo for Ensitrelvir
Sponsors
Timothy Henrich
Shionogi Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score | Day 10 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score | Day 30 | 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. |
| Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Mental Health Summary Score | Day 10 | 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. |
| Quality of Life (Global Health Score) on a 100-point Visual-Analogue Scale | Day 10 | 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. |
| Quality of Life Score (5-Item EuroQol EQ-5D-5L) Index Value Score | Day 10 | 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. |
| Duke Activity Status Index (DASI) | Day 10 | 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. |
| Orthostatic Hypotension Questionnaire (OHQ) Composite Score | Day 10 | 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. |
| World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0) Questionnaire | Day 10 | 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. |
| Patient Global Impression of Change (PGIC) | Day 10 | 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. |
| Everyday Cognition Form (ECog-41) | Day 10 | 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. |
| 6 Minute Walking Test (6MWT) | Day 10 | 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. |
| Active Stand Test | Day 10 | 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. |
| Neurocognition Index (NCI) Score From the CNS-VS | Day 10 | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTimothy Henrich, MD
University of California, San Francisco
PRINCIPAL_INVESTIGATORMichael Peluso, MD
University of California, San Francisco
Participant flow
Pre-assignment details
40 people were randomized and received blinded study drug or placebo
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 43 years |
| BMI at Baseline <18.5 | 1 Participants |
| BMI at Baseline 18.5-24.9 | 11 Participants |
| BMI at Baseline 25.0-29.9 | 11 Participants |
| BMI at Baseline >=30 | 3 Participants |
| Days Since Infection To Which Long COVID Symptoms Are Attributed | 848 Days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 10 Participants |
| Time Since Most Recent SARS-CoV-2 Infection | 578 Days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 12 / 20 | 16 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
None listed