Clinical trial for the treatment of COVID-19 and COVID-like illness in primary care

Current primary outcome measure as of 23/07/2024:
The primary outcome will be Phase dependent. For Phase IIb/III type evaluations the primary outcome will be:
1. Time to first self-report of feeling fully recovered from symptoms related to COVID-19 or COVID-like illness (days), measured using self-report for 28 days (or months 3 and 6 if not recovered).

For Phase IIa type evaluations the primary outcome parameter will be:
2. Viral clearance assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention-specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.

Previous primary outcome measure from 03/02/2023 to 23/07/2024:
Primary study endpoints are dependent on the study phase and can be:
1. Time to first self-report of feeling fully recovered from symptoms related to COVID-19 or COVID-like illness (days), measured using self-report for 28 days (or months 3 and 6 if not recovered).
2. Viral clearance assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention-specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.

Previous primary outcome measure as of 04/01/2023 to 03/02/2023:
Primary study endpoints are dependent on the study phase and can be:
1. Time to first self-report of feeling recovered from symptoms related to COVID-19 or COVID-like illness (days), measured using self-report until the end of the study.
2. Viral clearance assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention-specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.

Previous primary outcome measure:
Primary study endpoints are dependent on the study phase and can be:
1. Time to first self-report of feeling fully recovered from symptoms related to COVID-19 or COVID-like illness (days), measured using self-report until the end of the study
2. Viral clearance assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention-specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.

Current secondary outcome measures as of 23/07/2024:
1. Sustained recovery, measured using self-report for 28 days
2. Time to first self-report of feeling fully recovered from individual symptoms of COVID-19 or COVID-like illness (days) (for Phase IIa type evaluation), measured using self-report for 28 days (or months 3 and 6 if not recovered).
3. Viral clearance (for Phase IIb and III type evaluation) assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention-specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.
4. Time to first self-report of return to usual daily activity (days), measured using self-report until the end of the study
5. Presence, duration and severity of individual respiratory symptoms (runny/congested nose, sore throat, cough, fever shortness of breath, fatigue/tiredness, sweats/chills, headache, muscle, joint and/or body aches, loss of taste/smell, diarrhoea, other) as: absent, mild, moderate, severe, measured using a daily diary at day 0-28.
6. Participant-reported overall wellbeing, reported by rating of how well participant feels (scale 0-10) at day 0-28, and after 3 months and 6 months
7. Evaluation of overall safety of the IP by monitoring of AEs for the duration of IP administration and a defined period after the IP administration finishes. The duration of investigational product administration is dependent on the investigational product and will be specified in the intervention-specific appendix, for the selected IPs only side effects will be measured, as safety data are already available.
8. The use of additional antiviral medication (yes/no, name of medication), using a daily diary on days 0-28
9. The use of other prescribed and/or OTC medication for the respiratory tract infection, yes/no, using a daily diary at days 0-28
10. Occurrence of complications (i.e. hospitalisation, death; all-cause, non-elective hospitalisation) measured using weekly diary on days 7, 14, 21 and 28 or Serious Adverse Event reporting during the entire duration of study participation.
11. Impact on usual daily activities (work/education, caring for (grand-) children, household activities, sports, social life), as: no, slight, moderate, severe, not applicable, measured at day 1- 28, after 3 and 6 months
12. Healthcare utilisation for COVID-19 or COVID-like-illness (GP and hospital visits) measured using participant diary on days 1-28, months 3 and 6
13. Long-term consequences of COVID-19 or COVID-like-illness (e.g. cough, shortness of breath and/or difficulty breathing, fast heart rate, fatigue, tiredness and/or loss of energy, sleep alterations, loss of smell and/or taste, emotional sensitivity, depression and/or anxiety, concentration problems and/or difficulty thinking, muscle aches and or generalised body pains, diarrhoea and/or stomach pain, other) measured using a follow-up call or electronic questionnaire after 3 and 6 months
14. The incidence of COVID-19 and COVID-like-illness in other members of the household, measured using participants' diaries and/or swabbing the symptomatic household member(s) at daily day 0 - 28, if this will be measured using swabs in household members then timepoint(s) will be specified in the intervention specific appendix

Exploratory parameters:
1. Emergence of mutations in causative pathogens in index cases and potentially in household members measured using combined pharyngeal/nasal swabs for participants swabs that are taken at Day 0, 4, 7 and 14 can be used, if this will be measured in household members then timepoint(s) will be specified in the intervention specific appendix
2. Experiences of researchers and network coordinators of setting up the trial in multiple countries, including views on optimising trial delivery, recruitment, and implementation (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with researchers and network coordinators will take place throughout the period of ECRAID-Prime prior to trial set-up through to the completion of recruitment and follow-up of patients. We will aim to include longitudinal interviews, interviewing the same participant at multiple timepoints, where possible, to gain insights into how researchers apply learning to improve trial processes throughout the study
3. Healthcare professionals’ views and experience of taking part in the trial (in the context of a pandemic), the novel trial design, recruiting patients and views on the intervention(s) (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with healthcare professionals will take place throughout the trial and will focus on key timepoints such as the start of recruitment and the introduction of a new intervention arm.
4. Patient views and experiences of taking part in the trial and trial interventions, including how they conceptualise their illness and recovery (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with patients participating in the trial will take place at a suitable timepoint after their initial consultation (depending on their diagnosis, likely recovery time and the regimen of any trial intervention), likely around 2 weeks, to understand their experience of being recruited to the trial, trial processes, their views of the intervention and intervention adherence (where relevant).


Previous secondary outcome measures from 03/02/2023 to 23/07/2024:
Secondary study parameters/endpoints include:
1. Time to first self-report of feeling fully recovered from symptoms related to COVID-19 or COVID-like illness (days) (for Phase IIa type evaluation), measured using self-report for 28 days (or month 3 and 6 if not recovered).
2. Viral clearance (for Phase IIb and III type evaluation) assessed using semi-quantitive PCR at baseline and on days 4, 7 and 14, and impact on biomarkers of illness severity (if this will be an outcome parameter, then this will be specified in the intervention-specific appendix). The impact on biomarkers, for example on illness severity or immunological response is dependent on the specific investigational product (also the method and timepoints are dependent on the investigational product). If this will be an outcome parameter, then this will be specified in the intervention specific appendix of that investigational product. So far, there are no compounds selected for which this will be an outcome parameter.
3. Time to first self-report of return to usual daily activity (days), measured using self-report until the end of the study
4. Presence and severity of COVID-19 or COVID-like-illness symptoms (runny/congested nose, sore throat, cough, fever shortness of breath, fatigue/tiredness, sweats/chills, headache, muscle, joint and/or body aches, loss of taste/smell, diarrhoea, other) as: absent, mild, moderate, severe, measured using a daily diary at day 0-28.
5. Participant-reported overall wellbeing, reported by rating of how well participant feels (scale 0-10) at day 0-28, and after 3 months and 6 months
6. Possible side effects of the IP measured using a daily diary at day 1-28
7. Evaluation of overall safety of the IP by monitoring of AEs for the duration of IP administration and a defined period after the IP administration finishes. The duration of investigational product administration is dependent on the investigational product and will be specified in the intervention specific appendix, for the selected IPs only side effects will be measured, as safety data are already available.
8. The use of additional antiviral medication (yes/no, name of medication), using a daily diary at day 0-28
9. The use of other prescribed and/or OTC medication for the respiratory infection (antibiotics, antiviral medication, ibuprofen, other pain/fever medication, inhaled medication, intranasal medication, other), yes/no, using a daily diary at day 0-28
10. Impact on usual daily activities (work/education, caring for (grand-) children, household activities, sports, social life), as: no, slight, moderate, severe, not applicable, measured at day 1- 28, after 3 and 6 months
11. Complications (i.e. hospitalisation, death) measured using weekly diary at day 7, 14, 21 and 28 or Serious Adverse Event reporting during the entire duration of study participation
12. Healthcare utilisation for COVID-19 or COVID-like-illness (GP and hospital visits) measured using participant diary at day 1-28, months 3 and 6
13. Long-term consequences of COVID-19 or COVID-like-illness (e.g. cough, shortness of breath and/or difficulty breathing, fast heart rate, fatigue, tiredness and/or loss of energy, sleep alterations, loss of smell and/or taste, emotional sensitivity, depression and/or anxiety, concentration problems and/or difficulty thinking, muscle aches and or generalised body pains, diarrhoea and/or stomach pain, other) measured using a follow-up call or electronic questionnaire after 3 and 6 months
14. The incidence of COVID-19 and COVID-like-illness in other members of the household, measured using participants' diaries and/or swabbing the symptomatic household member(s) at daily day 0 - 28, if this will be measured using swabs in household members then timepoint(s) will be specified in the intervention specific appendix

Exploratory parameters:
1. Emergence of mutations in causative pathogens in index cases and potentially in household members measured using combined pharyngeal/nasal swabs for participants swabs that are taken at Day 0, 4, 7 and 14 can be used, if this will be measured in household members then timepoint(s) will be specified in the intervention specific appendix
2. Experiences of researchers and network coordinators of setting up the trial in multiple countries, including views on optimising trial delivery, recruitment, and implementation (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with researchers and network coordinators will take place throughout the period of ECRAID-Prime prior to trial set up through to completion of recruitment and follow-up of patients. We will aim to include longitudinal interviews, interviewing the same participant at multiple timepoints, where possible, to gain insights into how researchers apply learning to improve trial processes throughout the study
3. Healthcare professionals’ views and experience of taking part in the trial (in the context of a pandemic), the novel trial design, recruiting patients and views on the intervention(s) (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with healthcare professionals will take place throughout the trial and will focus on key timepoints such as start of recruitment and introduction of a new intervention arm.
4. Patient views and experiences of taking part in the trial and trial interventions, including how they conceptualise their illness and recovery (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with patients participating in the trial will take place at a suitable timepoint after their initial consultation (depending on their diagnosis, likely recovery time and the regimen of any trial intervention), likely around 2 weeks, to understand their experience of being recruited to the trial, trial processes, their views of the intervention and intervention adherence (where relevant).


Previous secondary outcome measures as of 04/01/2023 to 03/02/2023:
Secondary study parameters/endpoints include:
1. Viral clearance (for Phase IIb and III type evaluation)
2. Time to first self-report of return to usual daily activity (days), measured using self-report until the end of the study
3. Presence and severity of COVID-19 or COVID-like-illness symptoms (runny/congested nose, sore throat, cough, fever shortness of breath, fatigue/tiredness, sweats/chills, headache, muscle, joint and/or body aches, loss of taste/smell, diarrhoea, other) as: absent, mild, moderate, severe,
measured using a daily diary at day 0-28.
4. Participant-reported overall wellbeing, reported by rating of how well participant feels (scale 0-10) at day 0-28, and after 3 months and 6 months
5. Possible side effects of the IP measured using a daily diary at day 1-28
6. Evaluation of overall safety of the IP by monitoring of AEs for the duration of IP administration and a defined period after the IP administration finishes. The duration of investigational product administration is dependent on the investigational product and will be specified in the intervention specific appendix, for the selected IPs only side effects will be measured, as safety data are already available.
7. Impact on usual daily activities (work/education, caring for (grand-) children, household activities, sports, social life), as: no, slight, moderate, severe, not applicable, measured at day 1-28, after 3 and 6 months
8. Complications (i.e. hospitalisation, death) measured using weekly diary at day 7, 14, 21 and 28 or Serious Adverse Event reporting during the entire duration of study participation
9. Healthcare utilisation for COVID-19 or COVID-like-illness (GP and hospital visits) measured using participant diary at day 1-28, months 3 and 6
10. Long-term consequences of COVID-19 or COVID-like-illness (e.g. cough, shortness of breath and/or difficulty breathing, fast heart rate, fatigue, tiredness and/or loss of energy, sleep alterations, loss of smell and/or taste, emotional sensitivity, depression and/or anxiety, concentration problems and/or difficulty thinking, muscle aches and or generalised body pains, diarrhoea and/or stomach pain, other) measured using a follow-up call or electronic questionnaire after 3 and 6 months
11. The incidence of COVID-19 and COVID-like-illness in other members of the household, measured using participants' diaries and/or swabbing the symptomatic household member(s) at daily day 0 - 28, if this will be measured using swabs in household members then timepoint(s) will be specified in the intervention specific appendix

Exploratory parameters:
1. Emergence of mutations in causative pathogens in index cases and potentially in household members measured using combined pharyngeal/nasal swabs for participants swabs that are taken at Day 0, 4, 7 and 14 can be used, if this will be measured in household members then timepoint(s) will be specified in the intervention specific appendix
2. Experiences of researchers and network coordinators of setting up the trial in multiple countries, including views on optimising trial delivery, recruitment, and implementation (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with researchers and network coordinators will take place throughout the period of ECRAID-Prime prior to trial set up through to completion of recruitment and follow-up of patients. We will aim to include longitudinal interviews, interviewing the same participant at multiple timepoints, where possible, to gain insights into how researchers apply learning to improve trial processes throughout the study
3. Healthcare professionals’ views and experience of taking part in the trial (in the context of a pandemic), the novel trial design, recruiting patients and views on the intervention(s) (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with healthcare professionals will take place throughout the trial and will focus on key timepoints such as start of recruitment and introduction of a new intervention arm.
4. Patient views and experiences of taking part in the trial and trial interventions, including how they conceptualise their illness and recovery (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with patients participating in the trial will take place at a suitable timepoint after their initial consultation (depending on their diagnosis, likely recovery time and the regimen of any trial intervention), likely around 2 weeks, to understand their experience of being recruited to the trial, trial processes, their views of the intervention and intervention adherence (where relevant).


Previous secondary outcome measures:
Secondary study parameters/endpoints include:
1. Time to first self-report of return to usual daily activity (days), measured using self-report until the end of the study
2. Presence and severity of COVID-19 or COVID-like-illness symptoms (runny/congested nose, sore throat, cough, fever shortness of breath, fatigue/tiredness, sweats/chills, headache, muscle, joint and/or body aches, loss of taste/smell, diarrhoea, other) as: absent, mild, moderate, severe, measured using a daily diary at day 0-28.
3. Participant-reported overall wellbeing, reported by rating of how well participant feels (scale 0-10) at day 0-28, and after 3 months and 6 months
4. Possible side effects of the IP measured using a daily diary at day 1-28
5. Evaluation of overall safety of the IP by monitoring of AEs for the duration of IP administration and a defined period after the IP administration finishes. The duration of investigational product administration is dependent on the investigational product and will be specified in the intervention specific appendix, for the selected IPs only side effects will be measured, as safety data are already available.
6. Impact on usual daily activities (work/education, caring for (grand-) children, household activities, sports, social life), as: no, slight, moderate, severe, not applicable, measured at day 1-28, after 3 and 6 months
7. Complications (i.e. hospitalisation, death) measured using weekly diary at day 7, 14, 21 and 28 or Serious Adverse Event reporting during the entire duration of study participation
8. Healthcare utilisation for COVID-19 or COVID-like-illness (GP and hospital visits) measured using participant diary at day 1-28, months 3 and 6
9. Long-term consequences of COVID-19 or COVID-like-illness (e.g. cough, shortness of breath and/or difficulty breathing, fast heart rate, fatigue, tiredness and/or loss of energy, sleep alterations, loss of smell and/or taste, emotional sensitivity, depression and/or anxiety, concentration problems and/or difficulty thinking, muscle aches and or generalised body pains, diarrhoea and/or stomach pain, other) measured using a follow-up call or electronic questionnaire after 3 and 6 months
10. The incidence of COVID-19 and COVID-like-illness in other members of the household, measured using participants' diaries and/or swabbing the symptomatic household member(s) at daily day 0 - 28, if this will be measured using swabs in household members then timepoint(s) will be specified in the intervention specific appendix

Exploratory parameters:
1. Emergence of mutations in causative pathogens in index cases and potentially in household members measured using combined pharyngeal/nasal swabs for participants swabs that are taken at Day 0, 4, 7 and 14 can be used, if this will be measured in household members then timepoint(s) will be specified in the intervention specific appendix
2. Experiences of researchers and network coordinators of setting up the trial in multiple countries, including views on optimising trial delivery, recruitment, and implementation (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with researchers and network coordinators will take place throughout the period of ECRAID-Prime prior to trial set up through to completion of recruitment and follow-up of patients. We will aim to include longitudinal interviews, interviewing the same participant at multiple timepoints, where possible, to gain insights into how researchers apply learning to improve trial processes throughout the study
3. Healthcare professionals’ views and experience of taking part in the trial (in the context of a pandemic), the novel trial design, recruiting patients and views on the intervention(s) (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with healthcare professionals will take place throughout the trial and will focus on key timepoints such as start of recruitment and introduction of a new intervention arm.
4. Patient views and experiences of taking part in the trial and trial interventions, including how they conceptualise their illness and recovery (qualitative study) measured using interviews either remotely (by telephone or online or in person as appropriate). Interviews with patients participating in the trial will take place at a suitable timepoint after their initial consultation (depending on their diagnosis, likely recovery time and the regimen of any trial intervention), likely around 2 weeks, to understand their experience of being recruited to the trial, trial processes, their views of the intervention and intervention adherence (where relevant).