Frequently Asked Questions for the MILI Trial

Eligibility and trial participation

  • My whole-body MRI scan is more than 3 months old, can I still be enrolled into the trial?
    • No, however if may be possible to enrol onto the trial following your next WB-MRI scan. It’s important that everyone enrolled in the trial has a similar aged scan so we can measure the impact of the drug being tested in the trial (metformin).
  • Why are only over 16-year-olds invited?
    • The trial is only recruiting adults, of which the trial definition of an adult is 16 years of age and over.
  • I was not sure the first time I was approached about the study, but have changed my mind, can I still be recruited?
    • Yes, please contact your local genetics team who will discuss the trial further with you.
  • What happens if I move away from my recruiting centre, can I transfer my care to another centre?
    • This depends on where you are moving to. If your new local centre is also a participating site then you will need to contact your new genetics team to inform them that you are on the trial.
  • If I decide to have risk-reducing mastectomies whilst on the trial, will I still be able to participate?
    • Yes, you will still be able to participate in the trial. Just ensure that the doctor who is responsible for your care is aware of your participation in the trial as you may need to temporarily stop taking metformin around the time of the procedure. Please also inform your local site team to ensure they can assist you in re-starting on the metformin.
  • I am about to get a tattoo; will this affect my trial participation?
    • No, getting a tattoo will not affect your trial participation if you are eligible. If you end up taking any medications as part of the recovery/healing process, make sure you let your local site team know.
  • I enjoy my nights out with my friends and we drink a fair amount of alcohol, can I still take part?
    • Drinking alcohol does not limit you from taking part in the trial but it’s important to understand the risks of excessive alcohol consumption and taking metformin. Please ensure you discuss your alcohol intake with the doctor during the screening process as regular heavy alcohol use may make you ineligible.
  • I don’t smoke anymore but vape, can I participate in the trial?
    • Yes, smoking or vaping does not limit you from taking part in the trial if you meet the other eligibility criteria.
  • I am on maintenance chemotherapy or hormone treatment for cancer, would this affect my eligibility?
    • Certain therapies are acceptable whilst others are prohibited. Please speak with your doctor and local site team who will be able to discuss this further with you.
  • I take herbal supplements, including berberine, would this affect my eligibility?
    • No, it will not affect your eligibility. Supplements are fine to take before and during the trial. Please let the trial team know what supplements you are taking so these can be recorded, along with any other medications.
  • Why am I being asked to complete quality of life questionnaires?
    • The questionnaires you are asked to complete are important in determining the impact of metformin and screening (whole-body MRI) on your quality of life. The data collected will help answer some important questions for the trial, but also gather information that can help future research.

Randomisation queries

  • What reasons do only half the participants get metformin?
    • In order to determine what difference metformin makes to cancer risk, we must compare it to a group who isn’t taking it. To prevent bias, we have to randomise participants so they are evenly distributed between the metformin and non-metformin groups. This is discussed in more detail here: https://www.tp53.co.uk/2024/08/13/why-is-mili-randomised/
  • My brother was recruited and takes metformin, will that mean I will NOT be given metformin if I participate?
    • The trial allocates individuals to either the metformin and screening group or screening-only group randomly (using randomisation software). Therefore, there is a 50:50 chance that you will end up taking metformin, which is the exact same chance as any other individual, family or not, who is recruited onto the trial. The software does not take into account if other family members are already taking part in the trial and what they have been randomised to.

Pregnancy and fertility

  • What happens if I fall pregnant on the trial or are planning starting a family?
    • If you become pregnant during the trial you can still continue to participate in the trial and receive 6 monthly telemed calls, but you will not be required to attend study visits during your pregnancy. If you are allocated to take metformin, you can decide if you wish to continue taking the metformin or not. Metformin is considered safe during pregnancy and is often prescribed to treat gestational diabetes. If you are on the screening-only arm and are prescribed metformin for diabetes please inform the local site team.
  • Does taking metformin affect fertility?
    • There is no evidence that metformin affects the fertility of women or men taking it.

Metformin queries

  • What are the risks of taking metformin?
    • Metformin is most commonly used for the treatment of Type 2 diabetes and Polycystic Ovary Syndrome (PCOS) and is taken regularly by an estimated 3 million people in the UK. The majority of people who take metformin tolerate it well but about 30% experience side effects such as mild diarrhoea, nausea or vomiting. These tend to occur soon after starting treatment and are less likely to occur if metformin is started at its lowest dose and gradually increased (as we will be doing in this trial). Other side effects resolve spontaneously or if the dose is reduced.
  • Do you know if metformin will prevent cancer?
    • We don’t know yet. Previous studies have shown an association between metformin and reduced cancer risk. For example, an analysis of data from over 10 million diabetic patients showed those taking metformin were at a significantly lower risk of developing cancer. However, this association has not yet been proven in a non-diabetic population. In addition, studies conducting in ‘LFS mice’ have shown that metformin significantly delays any cancers arising in them – so it is possible that metformin is especially protective in LFS. Hence, the MILI trial is measuring the impact of metformin on preventing or delaying cancer in people with LFS.
  • If I don’t get metformin, what are the benefits of being on the trial?
    • Firstly, it will be impossible to demonstrate the benefits of metformin without a control group for comparison. To get metformin licenced for people with LFS in the future we will have to present a compelling case to the government regulators. The study is designed to present this evidence and, to meet regulatory requirements, has to be a randomised study with a control arm for comparison. If metformin is demonstrated to improve outcomes, we can make a case for everyone with LFS to get metformin in the future, regardless of the arm they drew while in this study.
    • But the study is not just about showing whether metformin has any preventive activity, it is also to understand why and how cancers start in LFS as we still don’t have a definitive answer to this question. Blood samples are being collected from participants in both arms of the study and we will be conducting a detailed analysis on them as well as developing biomarkers that can be used to provide an early warning sign of cancer for people with LFS. We also want to develop a more specific preventive than metformin in the future. This again can come from the samples we collect during the MILI study. Being on a trial means you get closer surveillance, and will be helping answer essential questions about LFS that can benefit you and future generations.
    • Being on the trial also means that all patients, whether in the metformin arm or not, will receive regular screening, including whole-body MRI. In this way all patients in the trial will be receiving the best level of care.
  • I have just been diagnosed with polycystic ovary syndrome (PCOS) and my doctor wants to prescribe metformin for me, can I still continue on the control arm?
    • No, if you began to take metformin you would need to withdraw from the trial. If you are already on the metformin arm, please inform the local site team of your PCOS diagnosis.
  • I am about to have a minor operation; do I still continue taking Metformin?
    • Please discuss this with the team conducting the surgery. In general, for minor procedures performed under local anaesthesia, metformin may not need to be stopped. But for moderate or major surgeries performed under general anaesthesia or using IV contrast, metformin is typically stopped on the day of surgery (or a couple of days before) and restarted 24-48 after surgery.
  • Do I need to stop metformin before scans with contrast?
    • Please discuss this with both your local trial team and also the doctor/team performing the scans. Metformin may need to be temporarily stopped if you are having a scan with IV contrast (like a CT scan or angiography) and then can be started 24-48 hours afterwards. For scans without contrast (e.g. MRI, ultrasound, X-rays) metformin does not usually need to be stopped.
  • I am having a colonoscopy, when should I stop and restart metformin?
    • Please discuss this with your local genetics team and also the doctor/team performing the colonoscopy. We would advise you to stop metformin on the day before the procedure and restart once you are drinking fluids normally again.
  • What will happen if I experience side effects from metformin?
    • For the first couple of months of taking metformin, you will have fortnightly calls with a nurse from the central telemed team who will discuss your side effects and, if required, reduce your dose of metformin. If after a few months of taking metformin, you experience any new or persisting side effects, you can contact your local genetics team who will discuss the options of adjusting the dose. If at any time you feel the side effects are intolerable, then the nurse/genetics team may suggest you take a lower dose or stop taking the metformin altogether.
  • Could you be on metformin for life is this works?
    • Currently, metformin is not licenced or approved for LFS which means it can’t be prescribed by your GP as a cancer preventive. If the study results show that metformin is effective at preventing cancer, the findings will be discussed with the regulatory bodies MHRA/NICE. If metformin is then licenced your GP will be able to prescribe this for you.
  • I forgot to take my metformin, what should I do?
    • We understand that on some days you may forget to take the tablets. If you miss a morning or an evening dose of metformin, you should take it as soon as possible after that time. However, if there has been a delay of more than 6 hours since the missed dose, the dose should be skipped and the next dose of metformin taken at its regular time. Please keep note of any days you’ve missed your doses as the telephone nursing team will be collecting this information from you every 6 months.
  • How will I receive the metformin medication packs?
    • Your hospital pharmacy will likely post the metformin to you via Royal Mail, in packages that can fit through a letterbox. Please check with your genetics team for confirmation of this.
  • Does taking metformin bring on the menopause?
    • There is no evidence that metformin brings on the menopause. In fact, metformin can be a very effective treatment for menopausal women because it helps to manage insulin resistance, and there is some research evidence it may help women with type 2 diabetes living with obesity who have, or are at risk of, breast cancer. Some women notice changes to their menstrual cycle on metformin (e.g. becoming more regular) but this is related to improved hormone balance rather than a direct effect of metformin.
  • Does taking metformin lead to weight loss?
    • Yes, some people notice metformin can lead to minor weight loss of on average 5-10 pounds. This can be through improved insulin sensitivity resulting in less fat storage and also because metformin can lower appetite.
  • Does metformin lead to liver impairment?
    • No, although a very rare side effect of metformin is abnormalities in liver function tests or hepatitis (less than 1 in 10,000 people). We check the liver tests of all participants entering the study and this is rechecked every year throughout the study.
  • Does metformin lead to renal impairment?
    • Metformin is excreted from the body via the kidneys so it is important that people taking it have good renal (kidney) function to prevent levels of metformin from accumulating. We check the renal function of all participants entering the study and this is rechecked throughout the study.
  • If this tablet slows my metabolism down, would you put on weight?
    • Metformin doesn’t slow your metabolism; but it changes it so that the body uses sugar to create energy and prevents the liver from releasing sugar into the blood stream. This actually improves the burn rate of calories and may actually lead to slight weight loss.
  • If I have indigestion whilst on metformin, could I take Rennies or other antacids for it without it being a problem?
    • Indigestion medication such as Rennie or over the counter antacids are safe to take if you are also taking metformin.

End of trial and results

  • What happens at the end of 5 years?
    • Once you have completed 5 years on the trial and had your final annual visit, you will return to the normal care of your local team. No further trial activities will take place, and individuals on metformin will be asked to take any remaining tablets to their local pharmacy in order to be destroyed.
  • Will the trial continue?
    • The trial will continue until we have enough data to show whether metformin works as a cancer prevention drug. Once you have been randomised into the trial, you are expected to remain on the trial for 5 years.
  • Will the trial continue to collect data after 5 years is completed e.g. cancer incidence 10 years on from recruitment? We know in CAPP2 trial for Lynch Syndrome that some of the benefits were only really realised many years after the intervention had been discontinued
    • The trial will not be collecting further data once the last participant has completed their year 5 trial visit.
  • Are there any early results of the trial?
    • The trial is not planning to release any early results. The results will be made available when all of the data from the UK trial has been analysed.
  • Are there other worldwide studies looking at similar patients? Could the results be combined?
    • Yes, the MILI trial is part of an international LFS Consortium with similar studies taking place in USA, Germany and Canada. Results from all studies will be pooled in a meta-analysis to definitively determine the benefit of metformin at preventing cancer in LFS patients.

Travel expenses and trial payments

  • Do you get paid for being on the trial?
    • No, there is no payment for taking part in the trial.
  • Do you get travel expenses for being the trial?
    • Yes, reasonable travel expenses can be claimed from your trial site for the screening visit and each subsequent annual visits.

Travel insurance

  • Do I have to declare I am on a clinical trial for travel insurance purposes?
    • When individuals apply for travel insurance, insurers will typically ask questions about an individual’s health in order to make an accurate risk assessment. This risk assessment takes into consideration the health of the individual and the insurer will typically ask questions about any pre-existing health conditions and medical treatments for those conditions. Travel insurers do not typically ask about clinical research trials. In the instance where an insurer does ask an individual about their participation in clinical research trials, the insurer must ensure the question is clear and the individual should answer it accurately and honestly.  (Source: Academy statement: Clinical trials and travel insurance (2024 update) – AOMRC  )