SARS-CoV-2 Infection
Conditions
Brief summary
The main aim of this study is to evaluate the efficacy of S-217622 versus placebo among outpatient adults with mild and moderate COVID-19 starting intervention within 3 days of symptom onset.
Interventions
DRUGS-217622
Administered as a round tablet.
DRUGPlacebo
Administered as a round tablet.
Sponsors
Shionogi
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documentation of laboratory-confirmed active SARS-CoV-2 infection, as determined by a nucleic acid (for example, reverse-transcriptase PCR) or antigen test from any respiratory tract specimen (for example, oropharyngeal, NP or nasal swab, or saliva) collected ≤72 hours (3 days) prior to randomization. * Participants are expected to begin study intervention ≤3 days from self-reported date of onset of any of the COVID-19-related symptoms from the following list: * Cough * Shortness of breath or difficulty breathing * Feeling feverish * Chills * Fatigue * Body pain or muscle pain or aches * Diarrhea * Nausea * Vomiting * Headache * Sore throat * Nasal obstruction or congestion * Nasal discharge * Loss of taste * Loss of smell * One or more of the following signs/symptoms present within 24 hours prior to randomization: * Cough * Shortness of breath or difficulty breathing * Feeling feverish * Chills * Fatigue * Body pain or muscle pain or aches * Diarrhea * Nausea * Vomiting * Headache * Sore throat * Nasal obstruction or congestion * Nasal discharge * Participants at higher risk of progression to severe COVID-19 are defined as follows: * Age ≥65 years * Age ≥18 with 1 of the following: * Obesity (body mass index \[BMI\] ≥30 kilograms per square meter \[kg/m\^2\]). Note: BMI is rounded to the nearest whole number, for example 29.5 kg/m\^2 is rounded to 30 kg/m\^2. * Diabetes mellitus * Hypertension requiring daily prescribed therapy * Cardiovascular disease (requiring daily prescribed therapy or congenital heart disease) * Chronic lung disease (for example, chronic obstructive pulmonary disease, moderate to severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension) requiring daily prescribed therapy * Chronic kidney disease, defined as known current kidney impairment with a creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) \<60 milliliters (mL)/minute (min)/1.73 square meter (m\^2) within the past 12 months prior to randomization, as long as the participant does not have known CrCl \<30 mL/min by Cockcroft-Gault or require dialysis * Down syndrome * Sickle cell disease * One of the following immunocompromising conditions or immunosuppressive treatments: * Receiving chemotherapy or other therapies for cancer * Hematologic malignancy (active or in remission) * History of a hematopoietic stem cell or a solid organ transplant * Human immunodeficiency virus infection: not on antiretroviral therapy or with cluster of differentiation 4+ cell count \<200 cells per cubic millimeter * Combined primary immunodeficiency disorder * Taking immunosuppressive medications (for example, drugs to suppress rejection of transplanted organs or to treat rheumatologic and gastrointestinal conditions, such as anti-tumor necrosis factor agents, mycophenolate, and rituximab). Note: Current use of some corticosteroids is exclusionary, due to concern for possible drug-drug interaction (DDI) with S-217622.
Exclusion criteria
* History of hospitalization for the current SARS-CoV-2 infection (that is, prior hospitalization for a prior episode of SARS-CoV-2 infection is allowable) * For the current SARS-CoV-2 infection, any positive SARS-CoV-2 molecular (nucleic acid) or antigen test from any respiratory tract specimen (for example, oropharyngeal, NP, or nasal swab, or saliva) collected ˃72 hours (3 days) prior to randomization. Participants with reinfection, defined as prior SARS-CoV-2 infection that began \>90 days prior to the current onset of symptoms with interval resolution of symptoms are eligible as long as the current infection has not been present for more than 3 days prior to randomization. * Current need for hospitalization or immediate medical attention in the opinion of the investigator * Current use of any medications prohibited with the study intervention. Individuals who have used Paxlovid or any other oral, inhaled, or injectable medication intended to treat the current SARS-CoV-2 infection before randomization are excluded. After randomization, locally available SARS-CoV-2 treatment (including but not limited to molnupiravir, mAbs, outpatient IV remdesivir, convalescent plasma, inhaled budesonide, favipiravir, and fluvoxamine) will be permitted, as long as there are no concerns for DDIs. Note: Paxlovid use for a prior episode of COVID-19 is permitted. * Receipt of any investigational treatments for the current episode of SARS-CoV-2 at any time prior to randomization is exclusionary. Note: This does not include drugs approved for other uses and taken for those indications or COVID-19 vaccines. Note: Use of locally authorized or approved therapies to prevent COVID-19, such as mAbs given solely to prevent COVID-19, are not exclusionary. * Any co-morbidity requiring surgery within 7 days prior to randomization or that is considered life threatening in the opinion of the investigator within 28 days prior to randomization * Known allergy/sensitivity or any hypersensitivity to components of S-217622 or placebo for S-217622 * Known (within 12 months prior to randomization) renal impairment defined as CrCl \<30 mL/min by Cockcroft-Gault or requiring dialysis * Known history of cirrhosis or liver decompensation (including ascites, variceal bleeding, or hepatic encephalopathy) * Participants who have used any of the following drugs within 14 days prior to randomization: * Strong cytochrome P453A inducer * Products containing St. John's Wort
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sustained Symptom Resolution | Up to Day 29 | Time to sustained symptom resolution was defined as the time from start of study intervention to the first day of 2 consecutive days with complete resolution of COVID-19 symptoms on participant self-assessment and alive and without hospitalization for any reason by Day 29. Hospitalization was defined as ≥24 hours of acute care in a hospital or similar acute care facility, including emergency rooms, urgent care clinics, or facilities instituted to address medical needs of those with COVID-19. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Day 4 in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA Levels on Nasopharyngeal (NP) Swabs | Baseline, Day 4 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by quantitative log10 polymerase chain reaction (PCR). Results reported as log10 (RNA copies/milliliter \[mL\]). |
| Number of Participants Who Experienced Hospitalization (Adjudicated) or Death Due to Any Cause | Up to Day 29 | Hospitalization was defined as ≥24 hours of acute care in a hospital or similar acute care facility, including emergency rooms, urgent care clinics, or facilities instituted to address medical needs of those with COVID-19. Hospitalization was adjudicated to be COVID-19-related. All deaths regardless of occurrence outside of hospital or during hospitalization (not adjudicated) are reported. |
| Time to Sustained Symptom Resolution in the mITT1 Set | Up to Day 29 | Time to sustained symptom resolution was defined as the time from start of study intervention to the first day of 2 consecutive days with complete resolution of COVID-19 symptoms on participant self-assessment and alive and without hospitalization for any reason by Day 29. Hospitalization was defined as ≥24 hours of acute care in a hospital or similar acute care facility, including emergency rooms, urgent care clinics, or facilities instituted to address medical needs of those with COVID-19. Wald confidence interval reported. |
| Median Change From Baseline at Day 8 in SARS-CoV-2 RNA Levels on NP Swabs | Baseline, Day 8 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by quantitative log10 PCR. |
| Number of Participants With Persistent and/or Late-Onset Symptoms of COVID-19 at Week 12 | Week 12 | The number of participants with persistent and/or late-onset symptoms of COVID-19 at Week 12 based on participant assessment of the 5 symptoms specified by the World Health Organization (WHO) (fatigue, shortness of breath/difficulty breathing, difficulty with concentration/ thinking, difficulty reasoning/solving problems, and memory loss) plus taste disturbance and smell disturbance. |
| Time to Sustained Resolution of 6 Targeted Symptoms and Being Alive and Without Hospitalization for Any Reason by Day 29 | Day 1 through Day 29 | The time to sustained symptom resolution was defined as the first day of 2 consecutive days with complete resolution of COVID-19 symptoms on participant self-assessment and being alive and without hospitalization for any reason by Day 29. Data are reported for time (days) from start of ensitrelvir or placebo (Day 1) until sustained resolution based on assessments for 2 consecutive days of 6 targeted symptoms (nasal obstruction or congestion, nasal discharge, sore throat, cough, feeling feverish, and fatigue) and being alive and not hospitalized for any reason. Hospitalization was defined as ≥24 hours of acute care in a hospital or similar acute care facility, including emergency rooms, urgent care clinics, or facilities instituted to address medical needs of those with COVID-19. |
| Number of Participants Who Experienced Death Due to Any Cause | Baseline through Week 24 | All participants in the mITT set who experienced death due to any cause are reported. All deaths regardless of occurrence outside of hospital or during hospitalization (not adjudicated) are reported. |
| Plasma Concentration of Ensitrelvir at Day 4 | Day 4 (up to 90 minutes postdose) | Plasma samples were collected at specified timepoints to measure ensitrelvir levels. Results reported as micrograms/milliliter (ug/mL). |
| Time to Sustained Resolution of Targeted Symptoms (Excluding Loss of Taste and Loss of Smell) and Being Alive and Without Hospitalization for Any Reason by Day 29 | Day 1 through Day 29 | The time to sustained symptom resolution was defined as the first day of 2 consecutive days with complete resolution of COVID-19 symptoms on participant self-assessment and being alive and without hospitalization for any reason by Day 29. Time (days) from start of ensitrelvir or placebo (Day 1) until sustained resolution (where cough and fatigue were considered resolved if they remain mild) based on assessments for 2 consecutive days of all targeted symptoms excluding loss of taste and loss of smell (cough, shortness of breath or difficulty breathing, feeling feverish, chills, fatigue, body pain or muscle pain or aches, diarrhea, nausea, vomiting, headache, sore throat, nasal obstruction or congestion, and nasal discharge) and being alive and not hospitalized for any reason by Day 29. Hospitalization was ≥24 hours of acute care, in a hospital or similar acute care facility (emergency rooms, urgent care clinics, or facilities instituted to address medical needs of those with COVID-19). |
| Number of Participants With Undetectable SARS-CoV-2 on NP Swabs on Day 4 and Day 8 | Day 4 and Day 8 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by viral titer by culture. |
| Number of Participants Experiencing Hospitalization (All Cause) or Death Due to Any Cause | Up to Day 29 | Hospitalization was defined as ≥24 hours of acute care in a hospital or similar acute care facility, including emergency rooms, urgent care clinics, or facilities instituted to address medical needs. All deaths regardless of occurrence outside of hospital or during hospitalization (not adjudicated) are reported. |
| Number of Participants With NP SARS-CoV-2 RNA Levels Below the Lower Limit of Quantification on Day 4 and Day 8 | Day 4 and Day 8 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by log10 quantitative PCR. |
| Median Change From Baseline at Day 4 and Day 8 in SARS-CoV-2 RNA by Quantitative PCR in NP Swabs | Baseline, Day 4, Day 8 | NP swabs were collected by staff during in-person visits per protocol for measurement of log10 SARS-CoV-2 RNA levels by quantitative PCR. |
| Time to Self-Reported Return to Usual (Pre-COVID-19) Health | Day 1 up to Day 29 | Participants kept a log of symptoms and major events in their study diary. The time to self-reported return to health (in days) was derived as: (the date of self-reported return to usual \[pre-COVID-19 health\] - (the date of first dose of study intervention) + 1. |
| Number of Participants Reaching a Score ≥2, ≥3, ≥4, ≥5, ≥6, ≥7, or ≥8 on the WHO Ordinal Scale | Day 29 | The severity of COVID-19 disease was assessed using the WHO ordinal scale. The scale ranged from 1 to 8 and focuses primarily on the participant's oxygen need when they first came to the hospital. Scores include: 1 = no limitation of activities; 2 = limitation of activities; 3 = hospitalized no oxygen therapy; 4 = oxygen by mask or nasal prongs; 5 = non-invasive ventilation or high flow oxygen; 6 = intubation and mechanical ventilation; 7 = ventilation and additional organ support, pressors, renal replacement therapy, extra corporeal membrane oxygenation; 8 = death. Higher scores indicated greater severity of illness and a need for more intensive medical support. |
| Change From Baseline at Day 29 in Resting Peripheral Oxygen Saturation | Baseline, Day 29 | Resting peripheral oxygen saturation was measured as the percentage of oxygen transported throughout the participant's body. An increase in percentage indicated an increased oxygen supply throughout the body. |
| Number of Participants With Resting Peripheral Oxygen Saturation <96% Versus ≥96% | Up to Day 29 | Resting peripheral oxygen saturation was measured as the percentage of oxygen transported throughout the participant's body. Saturation levels at ≥96% indicated effective oxygen transportation throughout the body. A decrease in percentage indicated decreased oxygen supply throughout the body. |
| Severity of Persistent and/or Late-Onset Symptoms of COVID-19 at Week 24 | Week 24 | A participant was considered to have persistent and/or late-onset symptoms if either 1 of the following criteria was met: occurrence of at least 1 of the following symptoms at Week 24: difficulty with concentration/thinking, difficulty reasoning/solving problems, or memory loss; or occurrence of at least 1 of the following symptoms at Week 24: fatigue, shortness of breath/difficulty breathing, taste disturbance, or smell disturbance. Symptom severity assessed as: None; Mild; Moderate; Severe; At least Mild. |
| Number of Participants With Symptomatic Viral Rebound Between Day 6 and Day 29 | Day 6 up to Day 29 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by log10 quantitative PCR. Symptomatic viral rebound was defined as an increase in NP SARS-CoV-2 RNA levels by quantitative PCR or an increase in NP SARS-CoV-2 viral culture. |
| Number of Participants With Viral Rebound Between Day 6 and Day 29 | Day 6 up to Day 29 | NP swabs were collected by staff during in-person visits for measurement of SARS-CoV-2 RNA levels by quantitative PCR. Viral rebound was defined as an increase in quantitative NP SARS-CoV-2 viral culture or NP SARS CoV-2 RNA levels by quantitative PCR. |
| Change From Baseline at Week 24 in Short Form 36 Version 2.0 (SF-36 V2) Quality of Life Score | Baseline, Week 24 | The SF-36v2 is a 36-item, participant-reported survey of participant health that measures 8 scales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Each component was directly transformed into a 0 to 100 scale on the assumption that each question carried equal weight. A score of 0 was equal to maximum disability, and a score of 100 indicated no disability. Mean change could range from -100 to 100. A positive mean change indicated an improved outcome. |
| Change From Baseline at Week 24 in EuroQol-5 Dimension 5 Level (EQ-5D-5L): Visual Analog Scale (VAS) | Baseline, Week 24 | The EQ-5D-5L VAS is an instrument for self-reported assessment that ranks participant health status. Participants self-rate their health status using a scale of best health imaginable (100) to worst health imaginable (0). An increase in score indicates an improved health status. |
| Number of Participants With a Response as Measured by the Post-Acute COVID-19 Questionnaire | Week 24 | Participants completed a post-acute COVID-19 questionnaire at each scheduled visit. The questionnaire is a survey instrument used to help measure functional health and health-related quality of life post-acute COVID-19. One of the items the questionnaire captures was whether the participant sought urgent medical care at an emergency room or clinic for specified symptoms (answered 'Yes' or 'No'). Symptoms ranged from cough and shortness of breath or difficult breathing to difficulty reasoning and solving problems and memory loss (short or long term). The number of participants answering 'Yes' to this question is reported. |
Countries
Argentina, Brazil, Colombia, Ghana, India, Japan, Kenya, Malawi, Mexico, Pakistan, Peru, Philippines, Poland, South Africa, Thailand, Uganda, United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 13.74 |
| Coronavirus Disease 2019 (COVID-19) Vaccination Status Completed primary series with last vaccine ≤3 months prior to enrollment | 21 Participants |
| Coronavirus Disease 2019 (COVID-19) Vaccination Status Completed primary series with last vaccine >3 months prior to enrollment | 675 Participants |
| Coronavirus Disease 2019 (COVID-19) Vaccination Status Missing | 4 Participants |
| Coronavirus Disease 2019 (COVID-19) Vaccination Status Not vaccinated | 245 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 430 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1019 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants |
| Race (NIH/OMB) Asian | 387 Participants |
| Race (NIH/OMB) Black or African American | 169 Participants |
| Race (NIH/OMB) More than one race | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 128 Participants |
| Race (NIH/OMB) White | 403 Participants |
| Sex: Female, Male Female | 506 Participants |
| Sex: Female, Male Male | 405 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,037 | 2 / 1,048 |
| other Total, other adverse events | 472 / 1,037 | 474 / 1,048 |
| serious Total, serious adverse events | 11 / 1,037 | 13 / 1,048 |
Outcome results
None listed