CaPPtain's Blog

  • Captain's Blog: John Burn, January 2017

    posted on Thursday, 9th February 2017

    Not tagged.

    Captain's Blog: John Burn, January 2017

    A lot has happened since my last message. On the positive side, we are getting close to the magic 1000 recruits and after long negotiations; we are finally open in Finland. Negotiations are almost complete in Tel Aviv (site visit photo above) and Melbourne to allow recruitment to start there too. Our target is to recruit another thousand people with Lynch syndrome by the end of 2018. Our earliest recruits are now finishing their first two years of randomised aspirin and are about to be seen in clinic to transition to the open phase of the study. After much debate, we have changed our plan for the next phase. Instead of asking everyone to take a cardio aspirin, we are asking that people stay on the dose they have been taking for the previous two years. The reason for this is two-fold; first, we are forced to go "open label" because putting the aspirin in packets where no-one knows their dose is great for the science but very, very expensive. By switching to open label after two years we can keep the costs down but continue to keep in touch, while we wait to see what effect the aspirin is having on the risk of cancer. The second part is the decision to ask people to stay on the same dose. This is all about POWER - not the sort Mr Trump is after, but statistical power. Basically, the more people who try a treatment and the longer they do it, the more chance there is of getting a reliable result. We worked out the size of the study based on the results of CAPP2. Over the last few years we have collected more information and we have read about the results of other aspirin research. We are now convinced that we will be better able, to decide the best dose if people can stay on the same dose for longer. We don't expect it to make much difference in terms of side effects, but it will be important if the people on the bigger dose have fewer cancers. If they do, then we can recommend the bigger dose to everyone for the years to come. If the number of cancers is the same in all three groups, then we can opt safely for the smallest dose, which will have the fewest side effects over a lifetime.

    This begs the question, why did we need the "blind phase"? There are two main reasons; the first is that people are more convinced by trials where the people taking part are blinded to the dose they are taking. This mainly affects side effect reporting. We need to know if there is a difference in side effects, like indigestion. We are very suggestible, so if we know we are on the bigger dose we might experience more discomfort. The second reason is about doctors. For years, doctors have been told that aspirin causes many side effects. This was mainly in older people and often involved doses much higher than the ones used in CaPP3, but the effect has been that doctors are not keen to prescribe aspirin, especially in doses higher than the cardio aspirin. We have helped with a study of GP opinions, which confirms that many are unwilling to prescribe doses above 100mg. We need to be absolutely sure we are making a difference if we are going to change their minds. A disadvantage of everyone knowing the dose is that we can't rely on the polyp counts so much in case knowing the dose influenced the decision to report a polyp. The good news is that we are not relying on polyp counts, as we are focussing on cancers as a clear endpoint. Knowing how much aspirin someone is taking will not affect a decision to diagnose a cancer.

    Getting these changes through all the bureaucracy around clinical trials has taken several months. The next step is to clear with the hospitals that it's OK to give people their second phase "open label" aspirin as a routine prescription. Meanwhile, the packs of blister packed aspirin are coming to the end of their shelf life in April 2018, so we have asked Bayer for some more tablets and Cancer Research UK for an extra grant to allow us to pack another 4000 boxes. That will see us through to the end of the last recruits "blind phase" in 2020.

    We are happy to come and talk to you about the CaPP3 amendment and give you a study update. Some visits have already been organised.

  • Captain's Blog: John Burn, June 2016

    posted on Thursday, 30th June 2016

    Not tagged.

    Halfway to the end of the beginning


    Last week we posted a picture of our research nurse Jackie, celebrating the recruitment of the 750th CaPP3 participant (@CaPP3 & www.capp3.org). Thanks again to all for this great support. We calculated we could get a useful answer from 1500 recruits followed for five years but that the result would be even more valuable if we could include centres in other countries as we did in CAPP2.

    It's topical that this has been made almost impossible by the 2004 EU Clinical Trials Directive, a failed attempt to enhance clinical trials by harmonising regulations across the EU. By demanding a single sponsor, academic led trials were almost wiped out as it meant that NHS hospitals and universities would be legally liable for treating people in other countries. Pleas to exclude academic trials were ignored until 2014, but the reform will not take effect for some time yet. The creation of the European Clinical Research Infrastructure Network (ECRIN) to help overcome the problem has not found support in the UK. We thought to sidestep the problem by encouraging other centres to set up an identical "parallel" trial on the understanding we would pool data for a single analysis. Great effort by international members of the CaPP consortium has made some progress. Fin Macrae in Melbourne, Nadir Arber in Tel Aviv and J-P Mecklin in Jyväskylä, Finland are almost good to go, although the insurance people are still ruminating on how to insure our University as being responsible for the protocol. Sometimes you don't know whether to laugh or cry. Saying "it's only aspirin" wears thin after the first few years. Meanwhile the insistence on a procurement system which allows no negotiation and treats all interventional agents equally meant that almost half of our entire grant funding had to be spent on packaging the aspirin.

    On the positive side, several trials have now started to test the beneficial effects of aspirin as an adjuvant, being included in the treatment of people with a range of common cancers, most notably the Cancer Research UK & NIHR HTA sponsored Add-Aspirin trial. It seems that there is growing evidence of a short term therapeutic benefit as well as the long established preventive effects.

    Combining these developments, it has been decided to adjust the design of CaPP3 such that when participants reach the end of the blinded treatment phase they will be re-consented to continue to take the dose to which they have been allocated rather than switch everyone to the very low 100mg dose at 2 years. This will boost the power of the trial by avoiding the possibility that having everyone on the same dose for the last three years might obscure a potential difference in cancer rate. Funds will not permit the ideal option of keeping everyone on the blinded dose in the very expensive blister packs. With open label treatment there will be no need for dummy tablets and we can pack in bottles rather than blistering. The Trial Steering and Data Monitoring Committees are content that having cancer as a "hard" endpoint means this open label phase will not compromise the outcome.

    So now we have to sort out the approvals, ethics, MHRA and Cancer Research UK, for this substantial amendment and organise the open label phase aspirin in time for the first recruit reaching the end of the blinded phase in October of this year. Looks like we will be too busy to help with the Brexit negotiations.

    In the meantime, keep calm and carry on recruiting, only 750 to go!

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  • Review of the role of aspirin in preventing colorectal cancer

    posted on Tuesday, 24th October 2017

    Review of the role of aspirin in preventing colorectal cancer written by John Burn and his postdoctoral research assistant Harsh Sheth

  • Lynch Syndrome UK

    posted on Thursday, 5th March 2015

    Lynch Syndrome UK is a registered charity stemming from a long running support group on Facebook.  Our many members are passionate about our cause to educate and empower people living with this genetic condition and offering support to both them and their families when they need it most.