Condition category
Infections and Infestations
Date applied
20/03/2020
Date assigned
22/03/2020
Last edited
21/05/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
COVID-19 is a condition caused by a coronavirus (called SARS-CoV-2) that was first identified in late 2019. This virus can infect the respiratory (breathing) system. Some people do not have symptoms but can carry the virus and pass it on to others. People who have developed the condition may develop a fever and/or a continuous cough among other symptoms. This can develop into pneumonia. Pneumonia is a chest infection where the small air pockets of the lungs, called alveoli, fill with liquid and make it more difficult to breathe.
In 2020, the virus has spread to many countries around the world and neither a vaccine against the virus or specific treatment for COVID-19 has yet been developed. As of March 2020, it is advised that people minimize travel and social contact, and regularly wash their hands to reduce the spread of the virus.
COVID-19 disproportionately affects people aged over 50 years with other illnesses and those over 65 years old. The infection causes considerable illness and the risk of death in this population group in particular and is having a devastating effect on people's health and society internationally. So far, there are no proven COVID-19 specific treatments. Most cases are being managed in the community. It is essential to identify treatments that reduce the severity of the infection. An ideal treatment would one that is safe, with few side effects, helps prevent disease worsening, and can be given in the community using existing NHS processes and capability. This study will, in the first instance, evaluate a drug called hydroxychloroquine. This is a drug that is already available within the NHS but that has not been tested for this disease in Europe or in community healthcare settings with the aim of reducing the need for hospital assessment.

Who can participate?
Patients throughout the UK with symptoms of possible COVID-19 (continuous cough and/or high temperature) that started within the last 7 days, either aged 65 and over, or aged 50 and over with the following listed illnesses: known weakened immune system due to serious illness or infection (e.g. chemotherapy), known heart disease, known asthma or lung disease, known diabetes not treated with insulin, known mild hepatic impairment, or known stroke or neurological problem.
The study website https://www.phctrials.ox.ac.uk/principle-trial/how-to-join provides more information on how to take part.

What does the study involve?
Participants are randomly allocated to undergo standard care or hydroxychloroquine drug treatment plus standard care. The study drug is hydroxychloroquine sulphate 200 mg tablets. The tablets are for oral use, one tablet (200 mg) taken twice daily for 7 days by mouth (14 tablets in total). This is the standard dose for its normal use in adults. Each dose should be taken with a meal or glass of milk. Antacids may reduce the absorption of hydroxychloroquine so it is advised that a 4-hour interval be observed between taking hydroxychloroquine and an antacid.
The study website https://www.phctrials.ox.ac.uk/principle-trial provides more information, including participant information sheets in several languages.

What are the possible benefits and risks of participating?
By taking part in this study, participants will be contributing towards the understanding of how doctors can treat COVID-19 and how the symptoms progress. This may help to reduce the duration and severity of symptoms when people fall ill and reduce the burden on the NHS during this crisis. All participants will also receive a swab, and will be told if the swab is positive or not for COVID-19. With any medicine, including ones that are already used within the NHS, there is a risk of side effects. For the treatment in this study the common side effects include abdominal pain, decreased appetite, diarrhoea, headache, nausea, skin reactions, vision changes, and vomiting. Participants will be able to report whether they are experiencing any of these symptoms in the daily diary.

Where is the study run from?
All participating GP practices in England, managed by the University of Oxford Primary Care and Vaccines Clinical Trials Unit co-operative (UK)

When is the study starting and how long is it expected to run for?
March 2020 to March 2021

Who is funding the study?
Office of the Chief Medical Officer (UK)

Who is the main contact?
1. Prof. Christopher Butler
2. Dr Emma Ogburn
3. Ms Julie Allen
4. Dr Emily Bongard
5. Mrs Hannah Swayze
6. Dr Sharon Tonner
Please contact principle@phc.ox.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Christopher Butler

ORCID ID

http://orcid.org/0000-0002-0102-3453

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Type

Public

Additional contact

Dr Emma Ogburn

ORCID ID

http://orcid.org/0000-0001-7643-572X

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Type

Public

Additional contact

Ms Julie Allen

ORCID ID

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Type

Public

Additional contact

Dr Emily Bongard

ORCID ID

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Type

Public

Additional contact

Mrs Hannah Swayze

ORCID ID

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Type

Public

Additional contact

Dr Sharon Tonner

ORCID ID

Contact details

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom
+44 (0)800 138 0880
principle@phc.ox.ac.uk

Additional identifiers

EudraCT number

2020-001209-22

ClinicalTrials.gov number

Nil known

Protocol/serial number

IRAS 281958

Study information

Scientific title

Platform Randomised trial of INterventions against COVID-19 In older people (PRINCIPLE)

Acronym

PRINCIPLE

Study hypothesis

Trial treatments (hydroxychloroquine in the first instance) will be superior to standard care at reducing the need for hospital admission or death for patients aged ≥50 years with comorbidity, and aged ≥65 with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections.

Ethics approval

Approved 26/03/2020, NHS REC South Central - Berkshire (Health Research Authority, Skipton House, 80 London Road, London, SE1 6LH, UK; +44 (0)2071048046; berkshire.rec@hra.nhs.uk), ref: 20/SC/0158

Study design

Pragmatic open prospective individually randomised platform randomised controlled clinical trial in community care

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

GP practices

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

COVID-19 (SARS-CoV-2 infection)

Intervention

The trial will initially be two-arm, comparing usual care to usual care with hydroxychloroquine treatment.

The trial will be implemented in the first instance in practices that are already part of the RCGP RSC Network. Currently, over 500 practices are part of this network, with 100 already offering a sentinel viral swabbing service which is being scaled up and due to the pandemic, all practices in the UK have been asked to join the RCGP RSC Network.

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 interventions. New interventions will only be added after submission to the appropriate approval bodies.

The PRINCIPLE trial will begin as a 1:1 randomised trial of usual care plus study-specific medication (in the first instance hydroxychloroquine) versus usual care alone but the study design has the capability to add additional interventions over time. The evaluation of any new interventions will be governed by the master protocol, including adaptive and decision criteria. In addition, the inclusion of any new interventions will require supplementary appendices to the protocol and SAP.

The initial drug is hydroxychloroquine sulphate 200 mg tablets. The tablets are for oral administration. One tablet (200 mg) hydroxychloroquine to be taken twice daily for 7 days by mouth (14 tablets in total). This is the standard therapeutic dose for its normal indication in adults which is for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight. The Marketing Authorisation holder is Zentiva Pharma UK Limited, Guildford, Surrey, GU1 4YS, UK. Marketing authorisation number is PL 17780/0748.

Special instructions:
Each dose should be taken with a meal or glass of milk
Antacids may reduce the absorption of hydroxychloroquine so it is advised that a 4-hour interval be observed between taking hydroxychloroquine and an antacid

Comparator is usual care.

Intervention type

Drug

Phase

Phase III

Drug names

Hydroxychloroquine sulphate

Primary outcome measure

The need for 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 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 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

Overall trial start date

12/03/2020

Overall trial end date

24/03/2021

Reason abandoned (if study stopped)

Eligibility

Participant 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. 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

3000

Participant exclusion criteria

1. Pregnancy
2. Breastfeeding
3. Known severe hepatic impairment
4. Known severe renal impairment
5. Known porphyrias
6. Type 1 diabetes or insulin-dependent Type 2 diabetes mellitus
7. Known G6PD deficiency
8. Known myasthenia gravis
9. Known severe psoriasis
10. Known severe neurological disorders (especially those with a history of epilepsy — may lower seizure threshold)
11. Previous adverse reaction to, or currently taking, hydroxychloroquine
12. Known retinal disease
13. Judgement of the recruiting clinician deems ineligibility

Recruitment start date

25/03/2020

Recruitment end date

24/09/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

NIHR CRN: Thames Valley and South Midlands
OX3 9DU
United Kingdom

Trial participating centre

All participating GP practices in England
-
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

Clinical Trials and Research Governance Team (CTRG)
Joint Research Office
1st Floor
Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
United Kingdom
+44 (0)1865 289885
ctrg@admin.ox.ac.uk

Sponsor type

University/education

Website

https://researchsupport.admin.ox.ac.uk/ctrg

Funders

Funder type

Government

Funder name

Office of the Chief Medical Officer

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

IPD sharing statement
Not provided at time of registration

Intention to publish date

24/03/2022

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

21/05/2020: The following changes have been made: 1. The public title has been changed from "PRINCIPLE: A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre-existing conditions and those aged 65 years and above" to "PRINCIPLE: A trial evaluating treatments for suspected COVID-19 in people aged 50 years and above with pre-existing conditions and those aged 65 years and above". 2. The study websites have been added to the plain English summary. 09/04/2020: The ethics approval was added. 06/04/2020: The following changes were made to the trial record: 1. The trial participating centres were changed from 'Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) general practices' to 'All participating GP practices in England'. 2. The contact details were updated. 23/03/2020: Internal review.