Ensitrelvir for Viral Persistence and Inflammation in People Experiencing Long COVID

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Day 10