Earlier this year, Cancer Research UK announced it was taking part in a clinical trial to investigate whether a drug, typically used to treat pancreatitis in Japan and South Korea, could be used as an antiviral to treat Covid-19.
Covid-19
The Spike1 clinical trial is sponsored by Cancer Research UK Centre for Drug Development (CDD) and is being funded through the medical research charity LifeArc, whilst being run in collaboration with the University of Edinburgh and biotech company Latus Therapeutics. The trial, which enrolled and treated its first patient last month, is an example of the collaborative efforts of charity, academia and industry, and also speaks to the way players in life sciences have had to adapt to Covid-19.
Here we speak to Dr Sarah Halford, head of Medical Sciences, Cancer Research UK Centre for Drug Development about the trial and its Covid-19 efforts.
First of all, could you briefly introduce the SPIKE1 trial?
SPIKE1 is recruiting participants who have symptoms of Covid-19 and test positive, at their initial presentation in the community setting. Participants are assessed daily by telephone and self-report their temperature, pulse and blood oxygen levels. The primary outcome will be to evaluate the efficacy of camostat in preventing respiratory deterioration in participants with SARS CoV-2 infection. Hospital admission requiring supplemental oxygen is the primary endpoint. Participants will be randomised to either the camostat arm or to standard of care.
Cancer Research UK was approached by Latus Therapeutics regarding the potential of camostat. What made the charity so keen to work with the pharma company on the drug?
Latus Therapeutics are the originators of this study and approached us because Cancer Research UK had indicated that the CDD was willing to use their expertise in drug development and early clinical trials to help develop treatments for Covid-19. The Covid-19 pandemic has had a profound effect on all facets of public and private life and on cancer patients in particular, with initial disruption to the delivery of all cancer services (screening, diagnosis, ongoing treatments and clinical trials). The development of effective antivirals will help to minimise further disruption to cancer services, which is particularly important as we enter the second wave.
How does camostat work?
The hypothesis is that camostat blocks TPMRSS2-dependent entry of the SARS-CoV-2 virus into cells, thereby reducing viral load and the length of time Covid-19 patients are infectious, as well as the severity of their disease.
*Editor’s note - TPMRSS2 is an enzyme which is thought to play an important role in enabling SARS-CoV-2 to infect healthy cells.
The trial was set up in a matter of weeks. What were some of the biggest factors in helping expedite the quick turnaround.
Having an engaged chief investigator, professor Kev Dhaliwal, with an experienced team based in Edinburgh was a major factor, enabling us to set up the trial quickly. Bringing together skilled and knowledgeable people internally to support the trial and ensuring the key objectives and goals were clear was also important. It was an opportunity to look at our internal processes and see where we could creatively adapt them, whilst still maintaining the high standards mandated from a clinical, safety and regulatory perspective when setting up new trials. For example, we were able to build the clinical database in four weeks by making use of libraries of existing forms, keeping edit checks to a minimum, and putting extra resources onto the project. In addition, we set up the randomisation element of the study in parallel with the database build.
What were some of the logistical challenges of importing camostat into the UK?
The rapidly evolving trial design made it quite challenging to define the number of tablets needed for the trial and, of course, this is the most important thing to decide when importing the drug. Once that had been agreed we needed to ensure that all the regulatory documentation required for both Clinical Trial Authorisation (CTA) submission and Qualified Person release of the drug for the trial was available, and also that all the necessary legal and technical agreements were in place with the parties concerned. Both Ono Pharmaceutical and the CDD teams worked very efficiently and collaboratively in ensuring timely shipment of camostat from Japan into the UK despite the challenges brought by the ongoing pandemic.
How did you identify which primary care practices to work with on the trial and how many participants will be involved?
The trial aims to treat up to 400 participants. When approaching feasibility activities, we initially focused on our lead site in Edinburgh and Oxford, where our other key clinical collaborators are located. Discussions with both sites were important in establishing the critical areas to discuss with other potential sites. Infection rates are a rapidly changing situation across the UK so we are targeting areas where infection rates are rising or where local outbreaks are anticipated. We have approached the Clinical Research Networks across the UK, The Royal College of GPs and other Trusts, providing them with information to assess if our trial is something they can support. Discussions have been informative, and we have had a lot of interest in the trial from both GPs and hospital sites. The lead site in Edinburgh was opened in early August and will aim to recruit participants from across the Lothian region, and at the time of publication had enrolled the first four patients onto the trial. We also continue discussions to link to the Track and Trace systems in each region to further boost our ability to reach as many potential participants as possible.
How difficult was it to stay up to date with the emerging Covid-19 data and how did this affect the endpoints for the SPIKE1 trial?
We are very aware that this is a rapidly changing landscape and new data are emerging all the time. To overcome this our trial has an adaptive design that allows us to respond to emerging knowledge and data from both our trial and external sources. As we obtain a greater understanding of both the disease and the drug’s impact on the disease, we can adapt the trial accordingly.
An important part of Spike1 is that it is being run virtually, outside of healthcare settings. What are the benefits for patients in doing this?
Covid-19 requires people to isolate at home. The SPIKE1 trial does not require participants to visit their GP or a hospital once they are enrolled, so this lowers the risk of spreading the infection. We ask all participants to record their daily temperature, pulse and oxygen levels (we provide all participants with a tympanic thermometer and pulse oximeter). Daily calls from the research team will enable real time data collection of patient-reported outcomes allowing efficient adaptation of the trial and timely identification of symptoms that might require hospitalisation. In due course we may introduce an app that will help with gathering some of this information making the process even more convenient to participants.
If patients are being remotely monitored from their own homes, how will you ensure patient safety and how will the appropriate data be collated?
During the development of the protocol much thought went into reducing the burden on both NHS resources and the participants. We established the key questions that will allow adequate and safe monitoring of the participants and deliver the endpoints of the trial. Having daily calls with the research team is key. Participants will be called daily on days 1-14 (regardless of which arm they are randomised to) and then two further follow up calls on Days 21 and 28. The team has a series of questions to go through with each participant, which provides consistency in the data recorded. The use of a questionnaire and the checking of vital signs recorded by the participant will be part of these calls as well as any Covid-19 symptoms and, if they are randomised to camostat, any side effects of the drug. The questions can be adapted as more people take part, it is not just a script, it is a dialogue between caller and participant who is encouraged to give as much detail as possible. The data will be recorded in real time to allow continuous monitoring by the sponsor and the clinical investigator. If participants feel unwell at any time, they are asked to contact NHS 111, their GP or the NHS 999 service.
Do you think virtual trials will become part of routine practice due to the restrictions Covid-19 has placed on clinical trial operations?
Yes, I think virtual trials will be a positive legacy from running clinical trials during the pandemic, and aspects will be applied to all our oncology trials going forwards. Minimising patients’ visits to hospital in the early stages of the pandemic led to more creative follow-up of patients on existing clinical trials, including video conference and telephone calls, supplying drugs directly to patients at home, reducing the number of blood tests or other investigations and taking a risk-based approach to these. The most intensive period for a patient on an early phase clinical trial is usually the first cycle of treatment and if the patient continues to later cycles there may be more scope to manage the patient remotely. Allowing people enrolled into trials to take more control of their own data, empowering them to record it and having more patient reported outcomes goes hand in hand with this. The tools are out there and using them will allow for more efficient real time data collection. SPIKE1 is currently assessing an online tool, which should allow participants to self-report their data and have the functionality to set reminders e.g. to take their drug and capture other key data throughout the day. This tool is under development and if implemented, will hopefully further improve the participant experience.
What other lessons can you take from the SPIKE1 trial into future trials?
The regulatory authority MHRA, research ethics committee (REC) and Health Research Authority (HRA) all provided a streamlined CTA application process because of the urgency in finding treatments to manage the Covid-19 pandemic. Following the expedited review process established by the MHRA we were able to achieve CTA approval within two weeks of submission and in less than two months from initiating work on the project, which is a fraction of the time required in normal circumstances.
Virtual meetings, including the REC meeting and the site initiation visit, worked extremely well. It is certainly something we would like to see happen more often. I think the use of online applications for patients wishing to be considered for trial participation is something we haven’t yet taken full advantage of in our oncology trials, but the ambition to use an app for collection of data in SPIKE1 is an approach we want to use. Use of video conferencing with patients and clinicians during the pandemic has proven very effective and it is something that we would like to explore and take advantage of in future clinical trials.
Given the impact on cancer care due to Covid-19, why did CRUK choose to use some of their resources on a drug focused on helping to ease the impact of COVID-19?
Cancer Research UK is not funding this trial. This trial is fully funded by LifeArc and uses the CDD’s drug development expertise. Very early on in the pandemic the vast majority of cancer trials were put on hold. We quickly realised the huge impact of Covid-19 on all cancer services and the importance of mitigating these effects by developing antiviral treatments and vaccines. Delivering cancer clinical trials remains our priority and our involvement in SPIKE1 hasn’t impacted cancer patients on the CDD’s phase 1 clinical trials. Given the disruption to cancer services we felt that we should use our considerable expertise in clinical trials and drug development to help beat Covid-19 so we can get back to beating cancer sooner. The lessons learned by the CDD can now be applied to speeding up early phase cancer clinical trials, which is hugely important. Cancer Research UK remains committed to our vision to bring forward the day when all cancers are cured.