| Protocol No: | ECCT/23/05/08 | Date of Protocol: | 30-06-2022 |
| Study Title: | A Phase 3, multicenter, randomized, double-blind, 24-week study of the clinical and antiviral effect of S-217622 compared with placebo in non-hospitalized participants with COVID-19 |
| Study Objectives: | 1. STUDY OBJECTIVES The main intent of the study is to evaluate the efficacy of S-217622 vs. placebo. The study will be conducted in the setting of locally available standard of care COVID-19 treatment. High-risk and low-risk participants will be analyzed together for the primary analysis and separately for secondary analyses. The following primary, secondary, and exploratory objectives will be addressed in the modified intent-to-treat (mITT) population, except for the safety analyses, which will be analyzed in the Safety population, and pharmacokinetic (PK) analyses, which will be analyzed in the PK population 1.1. Primary Objective To determine if S-217622 will reduce the time to sustained symptom resolution through Day 29. Time to sustained symptom resolution is defined as the time from start of study intervention to the first day of 4 consecutive days with complete resolution of 13 COVID-19 symptoms on participant self-assessment AND alive and without hospitalization for any reason by Day 29. Hospitalization is 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 1.2. Secondary Objectives 1.2.1. Key secondary objective: To determine the effect of S-217622 compared with placebo on the change from baseline in quantitative log10 SARS-CoV-2 RNA levels by PCR on NP swab at Day 4. 1.2.2. Key secondary objective: To determine whether S-217622 reduces COVID-19- related hospitalization (adjudicated) and all deaths regardless of occurrence outside of hospital or during hospitalization (not adjudicated) through Day 29. 1.2.3. To determine if S-217622 will decrease the proportion of participants with detectable SARS-CoV-2 viral culture on NP swab at Day 4. 1.2.4. To explore differences between S-217622 and placebo in time to sustained symptom resolution through Day 29 among subgroups, including by high risk vs. low risk at enrollment, by COVID-19 vaccination status, by receipt of COVID-19 treatments, and by time from symptom onset at enrollment. 1.2.5. To explore differences between S-217622 and placebo in the proportion of participants with detectable SARS-CoV-2 by viral culture from NP swab at Day 4 among subgroups, including by high risk vs. low risk at enrollment, by COVID-19 vaccination status, by receipt of COVID-19 treatments, and by time from symptom onset at enrollment. 1.2.6. To determine whether S-217622 reduces all-cause hospitalization and all deaths regardless of occurring prior to hospitalization (not adjudicated) through Day 29. 1.2.7. To determine if S-217622 will decrease the proportion of participants with detectable SARS-CoV-2 by viral culture from NP swab at Day 8. 1.2.8. To determine the efficacy of S-217622 to increase the proportion of participants with NP SARS-CoV-2 RNA levels by quantitative polymerase chain reaction (PCR) below the lower limit of quantification (LLoQ) on Days 4 and 8. 1.2.9. To determine whether S-217622 reduces levels of SARS-CoV-2 RNA by quantitative PCR in NP swabs from participants on Days 4 and 8. 1.2.10. To determine whether S-217622 results in a shorter time to return to pre-COVID-19 health compared with placebo throughDay 29. 1.2.11. To evaluate the efficacy of S-217622 compared with placebo based on the assessment of symptoms using the World Health Organization (WHO) ordinal scale (1-8) (see Section 6.3.16). 1.2.12. To determine the efficacy of S-217622 to maintain pulse oximetry measurement of ≥96% through Day 29. 1.2.13. To evaluate the safety of S-217622. 1.2.14. To explore measures of psychological health, functional health, and health-related quality of life in participants through end of study follow-up (Week 24). 1.2.15. To determine whether S-217622 reduces death due to any cause through end of study follow-up (Week 24). 1.2.16. To determine the PK of S-217622. 1.3. Exploratory Objectives 1.3.1. To evaluate whether S-217622 reduces a COVID-19 Severity Ranking Scale score based on COVID-19-associated symptom burden (severity and duration), hospitalization, and death through Day 29. 1.3.2. To explore the impact of S-217622 on participant-reported rates of new SARS-CoV-2 positivity of household contacts through Day 29. 1.3.3. To explore whether baseline and follow-up laboratory markers are associated with clinical and virologic outcomes in relation to S-217622 use. 1.3.4. To explore baseline and emergent viral resistance to S-217622 through Day 16. 1.3.5. To explore differences between S-217622 and placebo in NP SARS-CoV-2 RNA levels among subgroups, including by high risk vs. low risk at enrollment, by COVID-19 vaccination status, by receipt of COVID-19 treatments, and by time from symptom onset at enrollment 1.3.6. To explore possible predictors of outcomes, including death and hospitalization, across the study population, including by time from symptom onset, symptoms at baseline, sex assigned at birth, demographic characteristics, geographic region, and vaccination status. 1.3.7. To explore and develop a model for the interrelationships between virologic outcomes and clinical outcomes in each study group. 1.3.8. To explore the association between viral genotypes and phenotypic susceptibility to S217622 and clinical outcomes and virologic response to S-217622. 1.3.9. To explore the prevalence, severity, and types of persistent symptoms and clinical sequelae in participants through end-of-study follow-up (Week 24). 1.3.10. To explore relationships between exposure of S-217622 with laboratory markers and clinical outcomes. 1.3.11. To evaluate the safety of S-217622 in the high-risk and low-risk subpopulations. 1.3.12. To explore differences between S-217622 and placebo in death due to any cause through end of study follow-up (Week 24) in the high-risk and lowrisk subpopulations. 1.3.13. To explore the frequency of symptomatic viral rebound, defined as an increase in quantitative NP SARS-CoV-2 viral culture or NP SARS-CoV-2 RNA levels by quantitative PCR after Day 4 in the setting of new or worsening clinical symptoms, in both study groups. 1.3.14. To explore the frequency of viral rebound in both treatment arms, defined as an increase in quantitative NP SARSCoV-2 viral culture or NP SARS-CoV-2 RNA levels by quantitative PCR after Day 4. 1.3.15. To explore differences between S-217622 and placebo to reduce levels of SARS-CoV-2 RNA by quantitative PCR in NP swabs from participants on Days 4 and 8 among participants who have a positive culture at baselin
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| Laymans Summary: | The COVID-19 outbreak in the human population was first reported in Wuhan City, Hubei Province, China in December 2019. The rapid increase in the number of cases led to a declaration by the World Health Organization (WHO) on 11 March 2020 that the disease had spread to the whole world. As of May 2, 2021, the virus had been detected in more than 200 countries and infected more than 151 million people, causing more than 3.1 million deaths worldwide. In Kenya, as of May 10, 2021, more than 163 thousand cases and over 2,900 deaths had been reported. The signs and symptoms of COVID-19 presents differently in people. In the majority of people who are infected, it is mild, or the person may not have any symptoms of sickness. However, among patients with symptoms, typical presentations include fever, cough, muscle aches and shortness of breath. More severe cases have difficulty in breathing requiring admission in a hospital and this results in death in some patients. For majority of people, it does not require treatment but symptoms such as tiredness and shortness of breath appear to persist up to 2 months even after the virus has cleared. Several vaccines against COVID-19 have become available for use, and vaccinations have been initiated in many countries for the older people and the ones at high risk like doctors and nurses. These vaccines appear to be effective in preventing COVID-19 but we currently don’t know if the vaccines will work well long-term. In many middle- or low-income countries like Kenya, there is a shortage in the supply of these vaccines and this is expected to remain the case well beyond 2021. Some treatment options like steroids for patients with severe disease requiring admission in hospital have become available. Still, new treatments that can be given early after infection to prevent disease progression and long-term complications are urgently needed. Recent studies show that the treatments are beneficial in patients treated within the first 7 days after symptoms starts, reducing the need for subsequent hospital and doctors visit. |
| Abstract of Study: | COVID-19 pandemic has caused global suffering, mortality, and severe economic pressures. New variants of SARS-CoV-2 have been identified some of which increase the load of virus shed from an infected person, resulting in an increase in viral transmission and potentially severity of illness. There is no proven COVID-19 treatment for people who are not sick enough to be hospitalized. There is an urgent need to rapidly assess treatments in an outpatient setting, to prevent disease progression, and reduce serious complications or death. This trial will be a Phase-3, multi-center, randomized, double-blind, to evaluate safety and efficacy of S-217622 versus placebo among a global sample of approximately 1490 (745 on S-217622 and 745 on placebo) will be randomized into the study. Outpatient adults ( ≥ 18 years) with: a) documented positive SARS-CoV-2 nucleic acid or antigen test from a sample collected ≤120 hours (5 days) prior to randomization, b) onset of symptoms of COVID-19 ≤ 5 days prior to randomization, c) presence of 1 or more select COVID-19 symptoms within 24 hours prior to randomization. Participants will be eligible regardless of vaccination status and will be classified as either high risk or low risk. High-risk participants: defined as aged ≥65 years or those with presence of highrisk conditions. Low-risk participants: defined as those not meeting the high-risk definition. We target to initially enrol about 100 participants, but this will depend on how quickly the enrolment target is reached across all sites. Participants will be randomized into the study using an IRT, and stratified by geographic region, regardless of COVID-19 vaccination status. Participants’ demographics will be collected, medical history and physical examination done, vital signs and lab tests conducted as well as adverse events reported. The main intent of the ACTIV-2d/A5407 study is to evaluate the efficacy of S-217622 vs. placebo. The study will be conducted in the setting of locally available standard of care COVID-19 treatment. High-risk and low-risk participants will be analyzed together for the primary analysis and separately for secondary analyses. There will be safety analyses, which will be analyzed in the Safety population, and pharmacokinetic (PK) analyses, which will be analyzed in the PK population. The study duration will be from days 1 through 29 intensive study, followed by limited study through 24 weeks |