In
March 2020, the UK-wide Platform
Randomised trial of INterventions against COVID-19 In older people (PRINCIPLE)
trial was established as a flexible, platform randomised clinical trial to test
a range of potential treatments for COVID-19 that might be suitable for use in
the community to help people recover more quickly and prevent the need for
hospital admission. The trial is one of three national platform trials for
COVID-19 treatments, and complements the RECOVERY and REMAP-CAP trials that
focus on hospitalised patients.
Azithromycin
and doxycycline are two commonly used antibiotics investigated as separate
treatments in the trial. Both drugs are being used by some doctors in the hope
of treating COVID-19 in the early stages of the illness.
After
reviewing interim analyses of both the azithromycin and doxycycline arms of the
PRINCIPLE trial, the independent Trial Steering Committee advised the trial
investigators, who concluded that there is no beneficial effect in patients
aged over 50 who are treated with either antibiotic at home in the early stages
of COVID-19. This is because interim data analyses show that neither treatment
reduces the time taken for people to first report that they feel recovered
sufficiently to achieve meaningful clinical benefit. The PRINCIPLE trial did
not look at the effects of these drugs in patients who were already admitted to
hospital with COVID-19.
No
further people are therefore being randomised to receive azithromycin or
doxycycline in the PRINCIPLE trial.
Summary
of the key clinical findings:
1. Azithromycin: A
total of 526 eligible participants were randomised to azithromycin (500 mg once
daily for 3 days) within the first 14-days of onset of COVID-19 and compared
with 862 participants randomised to usual care. Per protocol, randomisation into
the azithromycin arm was stopped for futility due to a small probability
(0.024) of clinically meaningful benefit compared to usual care at an interim
analysis with incomplete data. After 28-days of follow-up on the randomised
participants, the results showed the estimated median time to self-reported
recovery for azithromycin was 0.94 days shorter compared to usual care (95%
Bayesian credible interval -0.56 to 2.43 days), with a low probability (0.23)
of being a meaningful benefit. Also, there was no evidence that azithromycin
reduced hospitalisations or deaths compared with usual care (model-based
estimated increase in hospitalization rate of 0.3%, Bayesian credible interval:
-1.7% to 2.1%).
2. Doxycycline: A
total of 798 eligible participants were randomised to doxycycline (200 mg on
the first day followed by 100 mg a day for 6 days) within the first 14-days of
onset of COVID-19 and compared with 994 participants randomised to usual care.
Per protocol, randomisation into the doxycycline arm was stopped for futility
due to small probability (0.044) of a clinically meaningful benefit compared to
usual care at an interim analysis. Based on the interim incomplete data, both
the estimated clinical benefit in the time to recovery (less than 1 day
benefit) and hospitalisation rate (less than 2% benefit) is small for
doxycycline. Final results for the doxycycline arm of the PRINCIPLE trial will
be published after the full 28-day follow-up on all randomised participants are
available.
Additional
details and analyses on both the azithromycin and doxycycline arms of the
PRINCIPLE trial will be shared in the near future in peer-reviewed journals.
Recruitment
into the budesonide arm of the PRINCIPLE trial continues as planned.
Clinical
guidance in England currently recommends treatment with oral doxycycline for
suspected pneumonia in people with COVID-19 in the community if the cause is
bacterial, or if it is unclear whether the cause is bacterial or viral and the
symptoms are particularly concerning. The PRINCIPLE trial shows that
doxycycline is not effective as a treatment for suspected COVID-19 in the
absence of bacterial pneumonia, and should not be used in this way.
Professor
Chris Butler from the University of Oxford’s Nuffield Department of Primary
Care Health Sciences and Co-Lead of the PRINCIPLE trial, said: ‘Azithromycin and
doxycycline have anti-inflammatory, antibacterial and possibly antiviral
effects, and so were considered as potential treatments for COVID-19 in the
community. While we are completing the analysis of the full range of study
outcomes, and in different patient groups, our findings show that a three-day
course of azithromycin or a seven-day course of doxycycline has no important
clinical benefit in terms of the time taken to feeling recovered, and so will
not help most patients with COVID-19 in the early stages their illness. These
are two important findings, as both azithromycin and doxycycline have been used
for treating COVID-19 in the community even in the absence of suspected bacterial
pneumonia, so this practice should now be re-considered - particularly because
overuse of antibiotics in the community can fuel the emergence of antimicrobial
resistance. PRINCIPLE is one of the first trials to report about doxycycline
for COVID-19 worldwide, and as this drug is in common use for this condition,
this should help guide prescribing decisions for COVID-19.
‘The
PRINCIPLE trial has grown into a UK-wide community collaboration to find
effective treatments for COVID-19 that can be used in the community. Treatments
that can speed recovery and prevent hospitalisations are urgently needed
worldwide. The trial is ongoing and will continue to evaluate COVID-19
treatments suitable for use in the community that might speed-up recovery and
potentially reduce the need for hospital admission. Many more people are still
needed to join the study because there are several other treatments that need
to be tested.’
Professor
Richard Hobbs, Head of the University of Oxford’s Nuffield Department of
Primary Care Health Sciences and Co-Lead of the PRINCIPLE trial, said: ‘While it is
disappointing that neither azithromycin nor doxycycline speed-up recovery for
those with COVID-19 in the community, these are both important findings which
will reduce the use of ineffective antibiotics for this illness. This finding
shows the importance of doing rigorous clinical trials in real-world settings
before treatments are rolled out on a wide scale. Widespread use of treatment
should not be based on laboratory studies and opinion alone. We remain
incredibly grateful for the huge efforts from many patients, GP practices and
other organisations in delivering this national, flagship primary care study in
these challenging times.’
Azithromycin
and doxycycline are widely used in primary care to treat respiratory tract
infections. Data from the Oxford-Royal College of General Practitioners
Research (RCGP) and Surveillance Centre (RSC) shows that during the COVID-19
pandemic General Practitioners have been more likely to prescribe antibiotics
to people with lower respiratory infections, and the use of azithromycin has
increased compared with 2019, and doxycycline use has remained static despite a
reduction in new cases of respiratory disease.
Professor
Simon de Lusignan, Director of RCGP RSC and Co-Principal Investigator of the
PRINCIPLE trial,
said: ‘Whilst I fully understand why colleagues would want to do everything for
patients who might have COVID-19, PRINCIPLE usefully provides evidence that
prescribing these antibiotics for most people with possible COVID-19 is not
helpful.’
The
PRINCIPLE trial is primarily evaluating whether treatment prescribed in the
first 14 days of COVID-19 illness can speed up recovery and prevent the need
for hospital admission. It is open across the UK to people aged over 50 with
certain underlying health conditions, or anyone aged over 65. Those with
coronavirus symptoms, or a confirmed SARS-CoV-2 infection, can join easily from
home online, over the telephone or via their GP practice from anywhere in the
UK, without needing face-to-face visits with the trial team in Oxford. Any
health and social care professional is able to introduce potential participants
to PRINCIPLE and more than 3,700 people have joined to date.
Participants
are randomised to receive either usual care, or to be treated with the addition
of a trial treatment. Follow-up information is collected online or by
telephone, and from medical records.
PRINCIPLE
is funded by UK Research and Innovation and the Department of Health and Social
Care through the National Institute for Health Research as part of the UK
Government’s rapid research response fund.
