PRINCIPLE: A clinical trial evaluating treatments for suspected and confirmed COVID-19 for recovery at home

• Register: ISRCTN
• Last refreshed on: 18 March 2024
• Main ID: ISRCTN86534580
• Date of registration: 22/03/2020
• Prospective Registration: Yes
• Primary sponsor: University of Oxford
• Public title: PRINCIPLE: A clinical trial evaluating treatments for suspected and confirmed COVID-19 for recovery at home
• Scientific title: Platform Randomised trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE)
• Date of first enrolment: 25/03/2020
• Target sample size: 12000
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN86534580
• Study type: Interventional
• Study design: Pragmatic platform randomized controlled trial of interventions for COVID-19 in primary care (Treatment)
• Phase: Phase III

Countries of recruitment

England, United Kingdom

Contacts

• Name: Jared Robinson

• Name: Johanna Cook

Key inclusion & exclusion criteria

Inclusion criteria: Current participant inclusion criteria as of 27/01/2022:
1. Participant or their legal representative, is willing and able to give informed consent for participation in the study, and is willing to comply with all trial procedures
2. A positive test for SARS-CoV-2 infection within the past 14 days (patient reported PCR test or lateral flow test result), with symptoms consistent with COVID-19*
3. Symptoms must have started within the past 14 days and be ongoing
4. Participant is aged 18 or over

*These symptoms may include, but are not limited to: a high temperature; a new, continuous cough; loss or change to your sense of smell or taste; sore throat; shortness of breath; general feeling of being unwell; muscle pain; diarrhoea and vomiting.


Previous participant inclusion criteria as of 26/04/2021:
1. Participant is willing and able to give informed consent for participation in the study
2. Participant is willing to comply with all trial procedures
3. Suspected COVID-19 using the NHS syndromic definition, or symptoms consistent with COVID-19 (including, but are not limited to, shortness of breath, general feeling of being unwell, muscle pain, diarrhoea and vomiting) and with a positive test for SARS-CoV-2 infection within the past 14 days
4. Aged 65 years or over, aged 18-64 and is experiencing shortness of breath as part of COVID-19 illnesses, or aged 18-64 and has any of the following underlying health conditions:
4.1. Known weakened immune system due to a serious illness or medication (e.g. chemotherapy);
4.2. Known heart disease and/or a diagnosis of high blood pressure
4.3. Known chronic lung disease (e.g. asthma)
4.4. Known diabetes
4.5. Known mild hepatic impairment;
4.6. Known stroke or neurological problem;
4.7. Self-report obesity or body mass index =35 kg/m²


Previous participant inclusion criteria as of 08/06/2020:

1. Participant is willing and able to give informed consent for participation in the study
2. Participant is willing to comply with all trial procedures
3. Onset of symptoms of possible COVID-19 in the community (continuous cough and/or high temperature) should be within 14 days of inclusion OR a positive test for SARS-Co-V2 infection which was taken fewer than 15 days ago, AND the participant is unwell with symptoms of COVID-19. These symptoms may include, but are not limited to, shortness of breath, general feeling of being unwell, muscle pain, diarrhoea, vomiting,fever and cough, and they must have had them for fewer than 15 days.
4. Patients aged =50-64 years with any of the following listed comorbidities OR patients aged =65 years with or without comorbidity:
4.1. Known weakened immune system due to serious illness or medication (e.g. chemotherapy)
4.2. Known heart disease and/or hypertension
4.3. Known asthma or lung disease
4.4. Known diabetes not treated with insulin
4.5. Known mild hepatic impairment
4.6. Known stroke or neurological problem

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Previous inclusion criteria:

1. Participant is willing and able to give informed consent for participation in the study
2. Participant is willing to comply with all trial procedures
3. Onset of symptoms of possible COVID-19 in the community (continuous cough and/or high temperature) should be within 7 days of inclusion
4. Patients aged =65 with or without comorbidity, and patients aged =50 years with the following listed comorbidities:
4.1. Known weakened immune system due to serious illness or infection (e.g. chemotherapy)
4.2. Known heart disease
4.3. K
Exclusion criteria: Current participant exclusion criteria as of 27/01/2022:
1. Patient currently admitted in hospital
2. Almost recovered (generally much improved and symptoms now mild or almost absent)
3. Judgement of the recruiting clinician deems ineligible.
4. Previous randomisation to an arm of the PRINCIPLE trial
5. Known or suspected pregnancy
6. Breastfeeding
7. Women of childbearing potential (premenopausal female that is anatomically and physiologically capable of becoming pregnant*), or male with a partner of childbearing potential, not willing to use highly effective contraceptive** for the 28-day duration of the trial.

* As recorded by the participant on the screening form and confirmed on Day 1 by a call between clinician and participant
** Highly effective methods have typical-use failure rates of less than 1% and include male or female sterilisation and long-acting reversible contraceptive (LARC) methods (intrauterine devices and implants) OR if a couple is using another method of contraception, such as a combined hormonal method, progestogen-only pill or injection, they are only eligible if they are willing to use an additional barrier method (e.g. male condom) for the 28-day duration of follow-up in the trial. Note: a barrier method on its own is not sufficient.


Previous participant exclusion criteria as of 26/04/2021:
1. Patient currently admitted in hospital
2. Almost recovered (generally much improved and symptoms now mild or almost absent)
3. Judgement of the recruiting clinician deems ineligible
4. Previous randomisation to an arm of the PRINCIPLE trial

Additional exclusion criteria specific to each intervention arm are listed in the Protocol. For participation, participants must be eligible to be randomised to at least one intervention arm as well as the Usual Care arm.


Previous participant exclusion criteria as of 16/06/2020:

1. Patient currently admitted in hospital
2. Almost recovered (generally much improved and symptoms now mild or almost absent)
3. Judgement of the recruiting clinician deems ineligible
4. Patient already taking an intervention arm medication (hydroxychloroquine or azithromycin) or other macrolides or ketolides

5. Exclusion criteria related to azithromycin:
5.1. Pregnancy
5.2. Breastfeeding
5.3. Known severe hepatic impairment
5.4. Known severe renal impairment
5.5. Known myasthenia gravis
5.6. Previous adverse reaction to, or currently taking, azithromycin or other macrolides or ketolides
5.7. Patients taking the following drugs: hydroxychloroquine or chloroquine, sotalol, amiodarone, ciclosporin, digoxin, bromocriptine, cabergoline, ergotamine, ergometrine, methysergide or any ergot derivatives
5.8. Already taking antibiotics for an acute condition Known congenital or documented QT prolongation
5.9. Known allergy to soya or peanut due to the risk of hypersensitivity reactions

_____

Previous exclusion criteria as of 08/06/2020:

1. Patient currently admitted in hospital
2. Almost recovered (generally much improved and symptoms now mild or almost absent)
3. Judgement of the recruiting clinician deems ineligible
4. Patient already taking an intervention arm medication (hydroxychloroquine or azithromycin) or other macrolides or ketolides

Additional exclusions specific to each intervention arm are listed below. Participants can take part in the study if they are eligible to be randomised to at least one intervention arm as well as the control arm.

5. Exclusion criteria related to hydroxychloroquine:


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

COVID-19 (SARS-CoV-2 infection)
Infections and Infestations
Coronavirus infection, unspecified site

Intervention(s)

Current intervention as of 23/03/2022:
The study treatment of Favipiravir is 9 x 400 mg tablets (1800 mg) to be taken on day 1 (5 tablets AM, 4 tablets PM) and then 2 x 400 mg tablets (800 mg) twice daily for four days (maintenance dose) - a total of 25 tablets, over 5 days. The study treatment of Ivermectin will be 3 mg tablets once daily (300 µg/kg body weight) for 3 days.

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Previous interventions as of 27/01/2022:
The study treatment of Favipiravir is 9 x 200mg tablets (1800mg) to be taken twice a day on day 1 (loading dose) and then 4 x tablets (800mg) twice daily for four days (maintenance dose) - a total of 50 tablets, over 5 days. The study treatment of Ivermectin will be 3mg tablets once daily (300µg/kg body weight) for 3 days.

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Previous interventions as of 12/05/2021:
The study treatment of Favipiravir is 9 x 200mg tablets (1800mg) to be taken twice a day on day 1 (loading dose) and then 4 x tablets (800mg) twice daily for four days (maintenance dose) - a total of 50 tablets, over 5 days. The study treatment of Colchicine is 500mg tablet once daily for
14 days. The study treatment of Ivermectin will be 3mg tablets once daily (300µg/kg body weight) for 3 days.

_____

Previous interventions as of 26/04/2021:
The PRINCIPLE trial platform is currently evaluating usual care alone vs usual care plus Colchicine vs usual care plus Favipiravir.

A platform trial, in contrast to say a traditional two-arm design, allows multiple arms to be considered simultaneously, and interventions can be dropped and replaced as evidence emerges for effectiveness or lack of it. The intent is to establish an on-going trial infrastructure within a master protocol that uses all the data already accumulated for the assessment of current and subsequently introduced interventio

Primary Outcome(s)

Current primary outcome measure as of 18/01/2021:

The main objective of the trial is to assess the effectiveness of the interventions in reducing time to recovery and in reducing the incidence of hospitalisation and/or death.The trial has co-primary endpoints:
1. Time taken to self-reported recovery, defined as the first instance that a participant reports feeling recovered from possible COVID-19
2. Hospitalisation and/or death

Both collected within 28 days of randomisation from patient report, study partner report, medical records, daily online symptom scores .
_____

Previous primary outcome measure as of 10/06/2020:

Hospital admission or mortality related to suspected COVID-19 infection assessed using reports of patients’ medical records, from enrolment up to 28 days after completing treatment

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Previous primary outcome measure as of 08/06/2020:

Hospital admission or mortality related to suspected COVID-19 infection.

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Previous primary outcome measure:

Hospital admission or death, for patients aged =50 years with comorbidity, and aged =65 years with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections, measured by hospital admission or mortality related to suspected COVID-19 within 28 days

Secondary Outcome(s)

Current secondary outcome measures as of 27/01/2022:

1. All cause of death or non-elective/urgent hospitalisation
2. Patient-reported illness severity
3. Duration of severe symptoms and symptom recurrence, measured by patient report on day recovered
4. Contacts with the health services, reported by patients and captured by reports of patients' medical records where the practice is a member of the RCGP RSC network
5. Consumption of antibiotics, measured using bi-weekly reports from participants' primary care medical records
6. Hospital assessment without admission, measured using patient report/carer report/medical record in primary care and hospital care
7. Oxygen administration, measured using patient report/carer report/medical record in primary care and hospital care
8. Intensive Care Unit admission, measured using patient report/carer report/medical record in primary care and hospital care
9. Mechanical ventilation, measured using patient report/carer report/medical record in primary care and hospital care
10. Duration of hospital admission
11. Negative effects on well being
12. New infections in household
13. To investigate the safety of treatments that are not licensed in the UK


Previous secondary outcome measures as of 26/04/2021:

1. Patient-reported illness severity
2. Duration of severe symptoms and symptom recurrence, measured by patient report on day recovered
3. Contacts with the health services, reported by patients and captured by reports of patients' medical records where the practice is a member of the RCGP RSC network
4. Consumption of antibiotics, measured using bi-weekly reports from participants' primary care medical records
5. Hospital assessment without admission, measured using patient report/carer report/medical record in primary care and hospital care
6. Oxygen administration, measured using patient report/carer report/medical record in primary care and hospital care
7. Intensive Care Unit admission, measured using patient report/carer report/medical record in primary care and hospital care
8. Mechanical ventilation, measured using patient report/carer report/medical record in primary care and hospital care
9. Duration of hospital admission
10. Negative effects on well being
11. New infections in household
12. To determine if effects are specific to those with a positive test for SARS-CoV-2
13. To investigate the safety of treatments that are not licensed in the UK

Measured using the following methods/timepoints:
1. Daily online symptoms score and diary
2. Telephone call or text on days 7, 14, and 28 if data not being received online
3. GP notes review where available through RSC network after 28 days
4. HES/ONS data linkage after 28 days where patients have been assessed in hospital
5. Swab result available once processed from GP record and from the supporting PHE laboratory
6. Evaluation of overall safety of drugs by the monitoring of pre-defined Adverse Events

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Previous secondary outcome measures as of 18/01/2021:

1. Patient-reported illness severity
2. Duration of severe symptoms and symptom recurrence, measured by patient report on day recovered
3. Contacts with the health services, reported by patients and captured by reports of patients' medical records where the practice is a member of the RCGP RSC network
4. Consumption of antibiotics, measured using bi-weekly reports from participants' primary care medical records
5. Hospital assessment without admission, measured using patient report/carer report/medical record in primary care and hospital care
6. Oxygen administration, measured using patient report/carer report/medical record in primary care and hospital care
7. Intensive Care Unit admission, measured using patient report/carer report/medical record in primary care and hospital care
8. Mechanical ventilation, measured using patient report/carer report/medical record in primary care and hospital care
9. Duration of hospital admission
10. Negative effects on well being
11. New infections in household
12. To determine if effects are specific to those with a positive test for SARS-CoV-2

Measured using the following methods/timepoints:
1. Daily online symptoms score and diary
2. Telephone call or text on days 7, 14 and 28 if data not being received online
3. GP notes review where available through RSC network after 28 days
4. HES/ONS data linkage after 28 days where patients have been assessed in hospital
5. Swab result available once processed from GP record and from the supporting PHE laboratory

_____

Previous secondary outcome measures as of 08/06/2020:

1. Duration of severe symptoms, measured by patient report on day recovered
2. Time taken to self-report recovery, measured by patient report on day recovered
3. Contacts with the health services, reported by patients and captured by reports of patients' medical records where the practice is a member of the RCGP RSC network
4. Consumption of antibiotics, measured using bi-weekly reports from participants' primary care medical records
5. Hospital assessment without admission, measured using patient report/carer report/medical record in primary care and hospital care
6. Oxygen administration, measured using patient report/carer report/medical record in primary care and hospital care
7. Intensive Care Unit admission, measured using patient report/carer report/medical record in primary care and hospital care
8. Mechanical ventilation, measured using patient report/carer report/medical record in primary care and hospital care
9. Swab results either at baseline or day 5 for SARS-CoV-2 will indicate an 'Intention to Treat Infected' group within the overall cohort for sub-analysis. Blood test on recovery (optional) for evidence of historic COVID-19.
10. Follow up swab at day 5 (if available) will indicate ongoing viral shedding, allowingcomparison between groups
11. Negative effects on well-being measured using WHO-5 Well-Being Index

Measured using the following methods/timepoints:
1. Daily online symptoms score and diary
2. Telephone call or text on days 7, 14 and 28 if data not being received online
3. GP notes review where available through RSC network after 28 days
4. HES/ONS data linkage after 28 days where patients have been assessed in hospital
5. Swab result available once processed from GP record and from the supporting PHE laboratory

_____

Previous secondary outcome measures:

1. Duration of severe symptoms, measured by patient report on day recovered
2. Time taken to full recovery of illness, measured by patient report on day recovered
3. Contacts with the health services, reported by patients and captured by reports of patients' medical records where the practice is a member of RSC
4. Consumption of antibiotics, measured using bi-weekly reports from participants' primary care medical records
5. Hospital assessment without admission, measured using patient report/carer report/medical record in primary care and hospital care
6. Oxygen administration, measured using patient report/carer report/medical record in primary care and hospital care
7. Intensive Care Unit admission, measured using patient report/carer report/medical record in primary care and hospital care
8. Mechanical ventilation, measured using patient report/carer report/medical record in primary care and hospital care
9. Swab results for COVID-19 will indicate an “Intention to Treat Infected” group within the overall cohort for sub-analysis, to determine if effects are specific to those with the infection's syndrome but who test positive for COVID-19

Measured using the following methods/timepoints:
1. Daily online symptoms score and diary
2. Telephone call or text on day

Secondary ID(s)

IRAS 281958

Nil known

2020-001209-22

Source(s) of Monetary Support

Office of the Chief Medical Officer

Ethics review

Status: Approved
Approval date: 26/03/2020
Contact:

[e-mail]

NHS REC South Central - Berkshire; ref: 20/SC/0158

[phone]

[e-mail]

Results

• Results available: Yes
• Date Completed: 11/07/2023