Understanding the PRINCIPLE Trial: A Guide for Patients and the Public
The COVID-19 pandemic presented an unprecedented challenge to healthcare systems worldwide. As researchers raced to find effective treatments, the Platform Randomised Trial of Interventions against COVID-19 in Older People (PRINCIPLE) trial played a crucial role in evaluating potential therapies for COVID-19 in community settings.
This page aims to provide a comprehensive, fact-based, and easy-to-understand explanation of the PRINCIPLE trial, its methods, and its findings. Our goal is to make the complex science behind this important study accessible to patients, their families, and the general public.
By demystifying the trial's design, procedures, and analyses, we hope to foster a better understanding of the rigorous process undertaken to evaluate potential COVID-19 treatments. This guide will cover various aspects of the trial, including its adaptive platform design, participant eligibility criteria, outcome measures, and the specific treatments investigated.
Additionally, we will address frequently asked questions, clarify key terms, and provide insights into the ongoing conversation surrounding the trial's findings, particularly those related to ivermectin, an at times divisive medication in relation to COVID-19.
Whether you are a patient, a caregiver, or simply someone interested in learning more about this research, we hope this guide will serve as a valuable resource. We may, from time to time, update this article to better clarify or expand the information within it.
Contents
Click the links to move to that section:
- The PRINCIPLE Trial
- Adaptive Platform Trial Design
- Pre-specified criteria and decision-making
- Eligibility and randomisation – who could take part and how did we decide who was given what?
- Outcome Measures – what PRINCIPLE was looking for
- What treatments did PRINCIPLE look at and what did it find?
- FAQs
- Why wasn't a placebo used in this trial?
- What was 'usual NHS care'?
- If usual care changes over time, how do you account for that?
- What's a 'hazard ratio' and why did you use it?
- Who funded this work? Was it independent?
- How did you make sure that the trial was fair / unbiased?
- Why did PRINCIPLE still recruit people who had been ill for up to 14 days? Isn't that too long?
The PRINCIPLE trial
The Platform Randomised trial of treatmeNts in the Community for epIdemic and Pandemic iLlnEsses (PRINCIPLE) study was a ‘large, adaptive platform trial’ designed to evaluate potential treatments for COVID-19 in the community setting. The study aimed to identify existing, available medicines that could help people recover faster and reduce the need for hospitalisation, thereby reducing suffering and the burden on healthcare systems.
PRINCIPLE was commissioned and funded by the UK Department of Health and Social Care during the height of COVID-19 pandemic in the UK (March 2020) and funded through its rapid research response fund. It was a UK wide trial with input and recruitment in all four devolved administrations (England, Wales, Scotland, and Northern Ireland).
This was a time of great uncertainty about the course and impact of the pandemic, and there was considerable concern about the ability of the UK health and care system to cope with the rising number of hospitalisation due to covid.
At this time there were no proven effective anti-covid medications and PRINCIPLE’s aim was to identify existing drugs which could be repurposed to treat COVID-19 patients in community settings, with the main aim of preventing them becoming so ill they needed hospital treatment.
Patients and the public consulted at the time also indicated that ‘time to recovery’ – how quickly people felt well again – was important to them so this was added as an additional ‘primary outcome’ to the trial.
By the close of the trial over 11,700 participants had taken part. The COVID-19 vaccination programme in the UK began on December 8, 2020.
Adaptive Platform Trial Design:
PRINCIPLE used an ‘adaptive platform trial design’, which allows for flexibility in testing multiple treatments simultaneously. This differs from more traditional clinical trial types which are usually set up to only test one or two pre-specified medication types.
This design meant that the trial could evolve as new evidence emerged, with the ability to add, modify, or remove treatment arms based on pre-specified criteria. The adaptive nature of the trial ensures that resources are efficiently allocated to the most promising treatments, while quickly identifying and discontinuing ineffective or harmful medications.
For a more detailed explanation of how platform trials work, see here: www.phctrials.ox.ac.uk/platform-trials-an-explainer
Pre-specified criteria and decision-making:
To maintain scientific integrity and ensure that decisions were made objectively, before the trial began PRINCIPLE established and published criteria for adding, modifying, or removing treatments – the trial ‘protocol’. You can view this online here: www.principletrial.org/files/trial-documents/principle-protocol-v14.0
These criteria were based on statistical thresholds, and some assumptions that had to be made at the time – such as how long a typical course of infection lasts – and were designed to guide decision-making throughout the trial.
For example, a treatment may be dropped for ‘futility’ if it fails to show a meaningful benefit compared to the usual care arm. On the other hand, a treatment may be declared ‘superior’ if it demonstrates a significant improvement in outcomes compared to usual care.
These pre-specified criteria help to minimise bias and ensure that decisions are made based on robust statistical evidence. The reasoning behind these criteria is to maintain the scientific rigour of the trial while still allowing for flexibility in response to evolving evidence.
Eligibility and randomisation – who could take part and how did we decide who was given what? :
The PRINCIPLE trial had clear inclusion and exclusion criteria to ensure participant safety and data reliability.
Participants were eligible for the trial if they were aged 18 or above, had confirmed COVID-19 , and were experiencing symptoms. For some of the treatments studied, additional exclusion and inclusion criteria were specified based on known risks of the medication itself.
During the course of the trial, it became possible for the trial team to get the legal permission to develop the systems for people with COVID-19 to safely participate in the trial from their own homes, since much of PRINCIPLE was carried out during lockdown or when people with some conditions were still advised to be ‘shielding’ – avoiding unnecessary contact with others to avoid contracting covid.
Once enrolled, participants were randomly assigned (by a computer algorithm) to receive either usual care or a trial treatment in addition to usual care. The randomisation process helps to minimise bias and ensure that any differences in outcomes between the treatment arms can be attributed to the different medications being tested.
Outcome Measures – what PRINCIPLE was looking for:
The primary outcomes measured in the PRINCIPLE trial were:
- Time to self-reported recovery from randomisation.
- Participants were asked to rate their symptoms daily using an online or telephone-based symptom diary.
- Recovery was defined as the first instance that a participant reported feeling recovered from their illness.
- Hospitalisation and/or death due to possible COVID within 28 days from randomisation.
- Hospitalisation was defined as an overnight stay in a hospital due to possible SARS-CoV-2 infection or a complication related to the infection.
- Death was defined as any death that occurs within 28 days of randomisation, regardless of the cause.
- The criteria for assessing hospitalisation and death ensure that only events directly related to COVID infection are included in the analysis.
These pre-specified criteria for assessing the primary outcomes ensure that the data collected is consistent, reliable, and comparable across treatment arms. The use of standardised definitions and timeframes helps to minimise bias and provides a clear framework for evaluating the effectiveness of the medications being tested.
There were also ‘secondary outcomes’ measured. These included things like measures of symptom severity, healthcare system use, and participant well-being, as well as longer term follow-ups up to 12 months after the last patient was randomised for each medication. Taken together, these outcomes provided a more comprehensive picture of the effectiveness and impact of the treatments being investigated.
What treatments did PRINCIPLE look at and what did it find?
In total there were six medications examined in PRINCIPLE. These were:
Hydroxychloroquine
Hydroxychloroquine is a prescription medication that is primarily used to treat and prevent malaria. It is also used to treat certain autoimmune diseases such as lupus and rheumatoid arthritis.
Added on: 02 April 2020
Recruitment ended: 23 May 2020
Summary of findings:
- Removed from the trial early on instruction from the UK regulator, the MHRA.
Inhaled budesonide
Budesonide is a corticosteroid or steroid medication that is used to prevent and reduce inflammation in the lungs. Typically used to treat asthma.
Added on: 27 Nov 2020
Recruitment ended: 31 Mar 2021
Summary of findings:
- Early treatment with inhaled budesonide shortens recovery time by a median of three days in high-risk COVID-19 patients treated in the community.
- Budesonide was the first widely available, inexpensive drug found to shorten recovery times in COVID-19 patients aged over 50 treated at home and in community settings.
- Treatment with budesonide had a high probability of reducing the need for hospital admission
- Analysis included 1073 people in the budesonide group and 1,988 in the usual care group who were COVID-19 positive.
Azithromycin
Azithromycin is an antibiotic used to treat a variety of bacterial infections affecting the lungs, skin, ears, eyes, and sexually transmitted diseases.
Added on: 23 May 2020
Recruitment ended: 31 Nov 2020
Summary of findings:
- Azithromycin was not effective in reducing time to recovery or risk of hospital admission for people with suspected COVID-19 in the community.
- Analysis included 500 patients receiving azithromycin plus usual NHS care, compared with 823 patients receiving usual NHS care alone.
Doxycycline
An antibiotic used to treat a variety of bacterial infections including respiratory tract infections, urinary tract infections, dental infections, acne, rosacea, and sexually transmitted diseases. It also is known to have some anti-inflammatory effects.
Added on: 22 Jul 2020
Recruitment ended: 14 Dec 2020
Summary of findings:
- Doxycycline was not effective in reducing time to recovery or risk of hospital admission in COVID-19 patients.
- Interim analysis included 798 patients receiving doxycycline with usual NHS care, compared with 994 patients receiving usual NHS care only.
Colchicine
An anti-inflammatory medication that commonly used to treat gout and familial Mediterranean fever.
Added on: 03 Mar 2021
Recruitment ended: 26 May 2021
Summary findings:
- Colchicine did not improve time to recovery for high-risk COVID-19 patients in the community.
- Analysis included 156 patients receiving colchicine plus usual NHS care, compared with 1,145 patients receiving usual NHS care only and 1,454 patients receiving other treatments.
Ivermectin
A medication commonly used to treat parasitic worms and other parasitic infections that also has some anti-inflammatory effects.
Added on: 23 Jun 2021
Recruitment ended: 01 Jul 2022
Summary findings:
- In this largely vaccinated population, there was no differences in hospital admission, a modest reduction in first-reported time to recovery (from 16 to 14 days) , and no impact work or studies at three, six and 12 months,
- analysis included 2,157 participants receiving ivermectin plus usual NHS care, compared with 3,256 participants receiving usual NHS care alone, with a total of 8,811 confirmed COVID-19 cases in the whole trial.
Favipiravir
Favipiravir is an antiviral medication that is licensed in Japan for treating influenza and is also being studied to treat other viral infections, including COVID-19.
Added on: 8 April 2021
Recruitment ended: 1 July 2022
Summary of findings:
- Favipiravir reduced the time to feeling recovered from COVID-19 by about 3 days (from a median of 16 days to 12 days).
- However, favipiravir did not reduce the risk of hospitalisation or death from COVID-19.
- At 6 months, there was a small increase in the proportion of participants feeling fully recovered in the favipiravir group (74.9% vs 71.3% in usual care).
- The effects were modest overall.
You can find out more about each of these are the trial findings and publications here: www.principletrial.org/results
FAQs
Why wasn’t a placebo used in this trial?
A placebo is a dummy treatment that looks like the real treatment but has no active ingredients. In a placebo-controlled trial, participants are randomly assigned to receive either the active treatment or the placebo, and neither the participants nor the researchers know who is receiving which treatment. This helps to minimise bias and ensure that any observed effects are due to the treatment itself rather than other factors, like people just expecting to feel better.
At the time the trial began, the most important question was whether the medications tested improved patient outcomes compared to not prescribing it. This is what is called a ‘pragmatic, real-world evaluation’, in that it reflects what would happen in routine day-to-day clinical practice, where placebos are not used. So, in PRINCIPLE medications in the trial were compared against ‘usual NHS care’.
While the researchers acknowledge that this trial design does not allow them to estimate the extent to which any beneficial effects or harms from a medication are due to placebo or nocebo effects (where patients experience negative effects due to their expectations), they believe that this design provides the best estimate of what would happen if the medication was used in real-world clinical practice.
In summary, while the lack of a placebo control group is a limitation of the PRINCIPLE trial, the researchers argue that their pragmatic, real-world trial design is appropriate for answering the most pressing clinical question at hand and that any potential bias from the lack of placebo would likely favour ivermectin.
What was ‘usual NHS care’?
This is the care people received from the NHS during the course of the trial. This was not mandated as people needed to be free to follow the advice of their doctors, which changed over time as we learnt more about treating COVID-19. The question the trial aimed to answer was whether adding in a treatment, over and above what was already being done, benefitted patients.
If usual care changes over time, how do you account for that?
The PRINCIPLE trial was designed as a flexible, adaptive trial that allowed adding or removing treatments over time. This means that the trial could evolve as new evidence emerged during the pandemic, ensuring that the most promising treatments were prioritised for investigation. Changes in the average duration of the illness and the treatment effects were taken into account in the complex statistical analyses used in the trial.
When analysing the effectiveness of a specific medication, the researchers used a statistical approach called ‘Bayesian analysis’. This approach allowed them to use data from all COVID-positive participants enrolled in the trial up to the point of analysis, regardless of when they joined the trial.
This method acknowledges that there may be changes in recovery and hospitalisation rates over time due to factors such as the emergence of new COVID-19 variants or increasing vaccination rates. However, PRINCIPLE’s pre-specified analysis plan was developed to account for these changes using statistical methods.
To double-check their findings, the researchers performed a ‘sensitivity analysis’. They compared the results of participants who received a specific medication to those who received usual care at the same time.
In summary, while the trial included participants from different time periods receiving different types of care with different vaccination status, the researchers used appropriate statistical methods to account for these differences and ensure that the results remained reliable and unbiased.
What’s a ‘hazard ratio’ and why did you use it?
When looking at how quickly people recover from COVID-19, a straightforward figure like "recovering two days faster on average" might suggest a clear benefit. However, the reality is more complex, especially when considering health systems working with large populations.
People naturally recover from COVID-19 at different rates, regardless of treatment. For some, getting better two days faster could mean a 50% reduction in illness duration if they would have only been ill for four days. But for others who might have been ill for 16 days, two days represent only a 13% change. Additionally, the last two days of the illness are likely to be the mildest, symptom-wise.
To account for these variations, researchers use a statistical tool called a "hazard ratio." Imagine two groups of people in a race – one taking the regular path and the other trying a shortcut. The hazard ratio compares the chances of someone in the shortcut group finishing at any given time to someone on the regular path, whilst also taking into account that some people are naturally faster or slower.
In PRINCIPLE, the hazard ratio allowed us to evaluate if a medication genuinely increased the chances of recovering from COVID-19 at any given moment, rather than just comparing median recovery times. It provided a more reliable way to assess the treatment's impact using all of the recovery data while accounting for individual differences in recovery rates.
At the start of the trial most people in usual care were expected to recover in about nine days. The trail pre-specified that a hazard ratio of 1.2 would be needed to be ‘clinically meaningful’, i.e. enough of a difference to make it worth prescribing through health care systems. This would mean people receiving the medication would need to get better about 1.5 days faster or more if the duration of illness without treatment was nine days.
However, the trial found that most people took closer to 16 days to feel better. With a hazard ratio of 1.2, this would mean people would need to feel better 2.7 days faster, or more, for the treatment to be considered clinically meaningful.
In summary, by using a hazard ratio we get a more comprehensive and reliable assessment of a treatment's effect than simply comparing average recovery times, as it accounts for the natural variation in how quickly people recover from COVID-19.
Who funded this work? Was it independent?
Yes, this was independent scientific research.
The PRINCIPLE trial was commissioned and funded after an open competition and peer review by UK Research and Innovation (UKRI) and the Department of Health and Social Care (DHSC) through the National Institute for Health and Care Research (NIHR), . These are public funding bodies in the United Kingdom that support research across various fields, including healthcare.
PRINCIPLE was supported by the NIHR and its Clinical Research Network, NHS DigiTrials, Public Health England, Health and Care Research Wales, NHS Research Scotland, the Health and Social Care Board in Northern Ireland, and the DHSC Therapeutics Task Force.
The trial was led and sponsored by the University of Oxford, a globally respected academic institution known for its rigorous research standards. The University of Oxford has a long-standing reputation for conducting independent, high-quality research.
While the PRINCIPLE trial receives government funding, the researchers maintain academic independence in designing, conducting, and interpreting the trial results. This independence is crucial to ensure that the findings are unbiased and based solely on the evidence gathered during the trial. See ‘How did you make sure that the trial was fair / unbiased?’ below.
Moreover, the trial's protocol, methods, and results are transparently available for public scrutiny, including the pre-specified criteria used for analysis of the primary and secondary outcomes, with all findings were made public as soon as possible.
For example, The Journal of Infection put the submitted form – also called a pre-print –of the paper describing the ivermectin findings on its website for public scrutiny, as soon as it was accepted, while the full peer-review and publishing processes took place.
In summary, the PRINCIPLE trial was funded by UK public research bodies in open competition and after rigorous review of its application to the DHSC, but is independently conducted by researchers at the University of Oxford. The trial's design, execution, and reporting adhere to rigorous scientific standards, ensuring that the findings are reliable and unbiased.
How did you make sure that the trial was fair / unbiased?
To ensure that the trial was fair and unbiased, the researchers took several steps:
- Blinding: The trial team was not allowed to see the data until all the information for each medication tested had been collected. This is called "blinding," and it helps prevent the researchers from accidentally influencing the results based on their expectations or hopes.
- Independent oversight: The trial had to be approved by the Ethics Committee of the Health Research Authority – an independent group that makes sure the trial is conducted ethically and safely. The trial was also monitored by two other independent committees: the Data Monitoring and Safety Committee, which kept an eye on the safety of the participants, and the Trial Steering Committee, which made sure the trial was running smoothly and fairly.
- Pre-published protocol: The plan for how the trial would be conducted (called the protocol) was approved and published before the trial started. This allows other researchers to check that the trial was done the way it was supposed to be.
- Pre-specifying what success would have to look like: The researchers decided ahead of time what would count as success or failure for ivermectin as a COVID treatment. These "thresholds" were written down in the trial protocol and in a separate "statistical analysis plan" before any data was analysed. This helps prevent the researchers from moving the goalposts or changing their definition of success based on what the data shows.
Why did PRINCIPLE still recruit people who had been ill for up to 14 days? Isn’t that too long?
In the PRINCIPLE trial, researchers allowed people to be ill for up to 14 days before enrolling in the trial. They included participants with a range of illness durations, as long as they were still experiencing COVID-19 symptoms. The goal was to find out if the treatments being tested could help those who were still suffering from acute COVID-19.
Different treatments might work through various mechanisms, such as antiviral or anti-inflammatory properties, and could potentially benefit people at different stages of the illness. One question the researchers wanted to answer was whether someone should take the treatments being tested if they have prolonged symptoms of COVID-19.
To answer this question, the trial needed to include people who remained sick for longer periods. The researchers didn't want to deny people a potentially beneficial treatment just because they had been ill for more than five days, especially since many people who are admitted to the hospital have been sick for at least that long.
The trial specifically excluded people who were starting to feel recovered from the illness, as the goal was to find treatments for those who remained ill and were of particular concern. The median (average) duration of symptoms before people joined the trial was four days in the treatment groups.
The researchers used statistical models to estimate the time to recovery, taking into account the duration of symptoms before joining the trial. They found no difference between the treatment and control groups. They also compared the effect of the treatments in people with symptom duration of less than seven days to those with symptom duration of more than seven days and found no evidence that the effects on hospitalisation, death, or time to recovery were different between the two symptom duration groups.
By including participants with a range of illness durations, the PRINCIPLE trial aimed to provide a comprehensive understanding of the potential benefits of the treatments being tested for people at different stages of COVID-19.
Other resources in this section
- Glossary – key terms breifly explained.
- Examining the Evidence: Ivermectin – A more detailed look at the results of the ivermectin arm of PRINCIPLE.