Tim Barrett update for Winter TreatWolfram newsletter
Dear friends and colleagues,
I hope everyone is keeping OK and managed to enjoy at least some good weather this Summer.
We are getting to the end of the TREATWOLFRAM trial, and the last participants will be having their last visits this October. We then hope to collect all outstanding data from study sites by the end of the year. The Clinical Trials Unit will then ‘lock’ the database so that our statistician can do the analysis. We expect to be told whether the treatment is effective or not, by the end of March or April 2025. As soon as I am told the results, I will write a report to our funder, the UK Medical Research Council; and I will of course share results through Wolfram Syndrome UK. Our trials unit team, Amy Lamb, Lewis James, Victoria Homer and Darren Barton, are working hard to make sure all the information that participants have kindly provided, will be ready to be analysed when the trial ends in October 2024.
Dr. Timothy Barrett’s Update | University of Birmingham, United Kingdom
Dear friends and colleagues,
I hope everyone is keeping OK. I have 3 items to update you on.
Firstly, the TREATWOLFRAM trial is continuing to progress well. We had an independent Data Monitoring Committee meeting in January. This is chaired by Professor Karen Morrison, an honorary consultant in adult neurology, who previously led the highly specialised service for adults with Wolfram syndrome. The Data Monitoring Committee reviewed the unblinded data. I am pleased to say that they had no safety concerns, and were happy for the trial to continue to completion. Following this meeting, our Trial Steering Committee met, chaired by Professor Marc Peschanski, Director of INSERM, a large research institute outside Paris. We discussed the trial progress so far, and plans for acting on the results at the end of the trial. The last participant will complete the trial at the end of October 2024. We will then have 2-3 months to collect any outstanding data from study sites. The Clinical Trials Unit… read in full here.
Tim Barrett update for Winter TreatWolfram newsletter
Dear friends and colleagues,
I hope everyone is keeping OK and are keeping warm enough in this cold weather. Our research teams have kept busy and I would like to use this letter to keep you updated on our progress.
The TREATWOLFRAM trial is now in its final year. It has been a long journey to get here, navigating medicine manufacture problems, BREXIT, Covid, and supply issues. Thank you to all the participants who have supported the trial with their involvement. Our trials unit team, Amy Lamb, Lewis James Victoria Homer and Darren Barton, are working hard to make sure all the information that participants have kindly supplied, will be ready to be analysed when the trial ends in October 2024. There has been an update from the UK Medicines Regulator (MHRA) to remind patients and the public about the safety precautions we all need to follow for people taking sodium valproate. Anyone female under 55 years who may be taking sodium valproate, needs to have a safety check with their doctor each year. It is important that sodium valproate should not be taken by women who may be pregnant, as there is a risk of significant harm to the baby. There is helpful information on this UK Government website: https://www.gov.uk/guidance/valproate-use-by-women-and-girls.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Paul Schlerethhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgPaul Schlereth2024-01-12 16:43:272024-10-12 16:51:23Clinical Trial Update by Dr. Barrett — January 2024
I hope everyone is keeping OK and have managed to have some time relaxing over the Summer. I wanted to provide some updates from our research teams here in Birmingham.
Firstly, the TREATWOLFRAM trial is continuing in the follow-up phase. Some participants have completed their involvement, and the remaining people are being seen every 6 months for an eye test, and every 12 months for more detailed assessments including MRI scans. Our trials unit team, Amy Lamb and Lewis James, are working hard to check all the information that participants have kindly supplied, ready to be analysed when the trial closes in October 2024. I am pleased to say that we have secure drug supplies to the end of the trial, and over 80% completion rates for the tests that we need to look at to see if the intervention works to slow down the progress of the condition. I’ll update further as we get nearer the end of the trial.
Secondly, our laboratory team, led by Dr Sovan Sarkar, has been very busy: Dr Malgosia Zatyka has been working on cell models of Wolfram, and her research has led to publication of a really interesting paper in the science journal “Stem Cell Reports”. The report is titled: “Depletion of WFS1 compromised mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome”. Essentially, mitochondria are the power houses of cells, generating the energy needed by cells to grow. Mitochondria operate closely with another part of the cell, the endoplasmic reticulum, to keep cells healthy. We’ve known for some time that the endoplasmic reticulum does not work properly in Wolfram syndrome. Malgosia has shown that in her Wolfram cell models, the mitochondria are also affected. This seems to relate to the way mitochondria interact with the endoplasmic reticulum. Her work implicates mitochondria in the disease processes that cause Wolfram, and suggests new targets for developing treatments for the condition.
Thirdly, my clinical consultant colleague Dr Renuka Dias has been investigating puberty and hormones in people affected by Wolfram syndrome. She has looked at a series of children and young people with Wolfram who have completed puberty. She and her team found that puberty was delayed or not completed in 40% of young men, and there were menstrual irregularities in 50% of young women. Testosterone supplements were effective in helping young men complete puberty, and there are treatments for young women to help make periods more regular. Dr Dias is presenting her findings at the European Society for Paediatric Endocrinology, so this study will reach a wide audience and help inform doctors to offer better treatments to people affected by Wolfram.
Finally, all our study team owes a big thank you to Wolfram syndrome UK as always for their generous support.
Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.
Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe, and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.
We now have really accurate and reproducible assessments in each site so that we can pool the results. Our independent data monitoring committee sees all the unmasked results and if there is a strong signal of effect, or signal of no effect, they will let us know without waiting for the end of the trial.
I am very grateful to everyone who is taking part or about to take part in this trial; and we are learning a lot about how to deliver clinical trials in Wolfram, for the future. Wolfram syndrome UK have been brilliant in supporting families to attend study visits; and we are very grateful to The Snow Foundation, Eye Hope Foundation, and Association Syndrome de Wolfram for support to collect research samples, which will be available to the whole Wolfram syndrome community.
Rebecca Storey and Shazia Ahmed, our senior and junior trials coordinators respectively, have been busy writing all the regulatory documents needed for the trial to go ahead. These were submitted to the Health Regulatory Authority in early January. The ethics committee met in early February. This was in Glasgow, but we were allowed to join by telephone conference. the committee was very sympathetic and had only minor requests. Rebecca and I are writing the response, which has to be back with them by Wed. We cannot get complete regulatory sign-off until we have evidence that the study medicine is stable outside it’s manufacturer’s packaging.
Regarding the study medicine, we have been in weekly contact with the pharmacy manufacturing unit at Guy’s and Thomas’s Hospital in London. They have outsourced the testing of the medicine to a commercial contract company, Butterworth’s. So, the problem is that the study medicine comes in foil blister packs. The manufacturer only guarantees the quality of the tablets while they are in their own packaging. For the clinical trial, Guy’s and Thomas’s Pharmacy have to take the tablets out of the manufacturer’s packaging and put them into white polypropylene containers, so that they can be masked (blinded) with the placebo tablets. Unfortunately, these study tablets absorb moisture from the atmosphere when taken out of their foil packaging, which in theory may affect the stability of the active component. Guy’s and Thomas’s hospital have been trying to test some tablets that they have kept in typical study bottles; but without success. They then outsourced this job to Butterworth’s, who found a non-standard method to measure drug stability. However, when they tried to convert this to an approved method, they could not get the measurements to work. This is turning into a major headache, and is the reason the study has been held up. We are having a telephone conference on Monday with the pharmacy team to get an update and plan what we do next.
We have appointed a new study team member, Heather Rose, who will look after the MRI scans for the trial, and do the measurements to see if the study drug is slowing down the brain changes. She is getting the scanners set up in Birmingham for both children and adults to take part.
Rebecca has been in touch with the international sites, in Almeria, Montpellier, Paris and Lodz, to start getting them set up.
Finally, I have been asked to speak with the French families in Paris on March 17th to explain to them where the trial is at.
One of the global health priorities of the International Rare Diseases Research Consortium (IRDiRC, www.irdirc.com) is on to find new treatments for the 80% of rare diseases that currently have no cure or means to treat. We know of over 8,000 rare diseases, so this is a really big challenge. As everyone knows, it is a huge task to come up with a treatment, then get it approved so that patients can have it in the clinic. Once you have come up with a treatment, people ask: ‘how do you know it will work?’.
The best example I can think of is anaemia. You may be feeling tired and pale with a lack of energy, and go to your doctor – she takes a blood test, tells you that you are anaemic, and prescribes you some iron medicine. You take the medicine, and after a few weeks you feel better so your doctor invites you back for another blood test, says your blood count has come up, and you can stop the medicine. That blood count is what we call a ‘biomarker’ – something that we can measure to see if a treatment has worked. The doctor needs it to decide when to tell you to stop taking your medicine. Without it, she doesn’t know whether you feel better because the medicine worked, or because you are eating better, or just because the sun has come out!
A biomarker is anything that we can measure, to see if a treatment is working. If the treatment is to help you lose weight, the biomarker is your weight. If you have a metabolic problem where a toxin builds up in your blood, then the biomarker is the level of toxin in your blood. It can even be a change seen on X-ray or brain imaging scan.
Biomarkers become especially important when you are treating a disease that takes months or years to progress- if you start taking a treatment, you want to know it is helping you, without waiting for years to find out if you are going to develop any complications of the disease.
When we study a medicine to see if it will treat a disease like Wolfram, it may take at least two years, or probably longer, to tell if the medicine has stopped the disease getting worse. If after 2 years, the person’s disease is still getting worse, then the medicine has not worked, and he/she has to start the process from the beginning with another treatment.
You might ask – why not try several different treatments at once? That’s a good question but there are two problems: firstly, the treatments may not work; or only one of them may work and the others are unnecessary; and then every treatment has side effects, which may get worse when you mix them with other medicines.
So why might biomarkers help? Well, to use the example of anaemia again: if you have something that you can measure, like a blood count in anaemia, you can quickly find out if the treatment is working, even before the person who was anaemic feels any better.
In Wolfram, if we ask people to take a treatment for the disease, we want something we can measure that will tell us quickly whether the treatment is working or not, without having to wait 2 or more years to tell if the disease has stabilised.
Biomarkers become really useful in clinical trials of a treatment: we really need a biomarker that will tell us whether the treatment is working within 6 months; so that if it is not, we can stop the trial, and switch to another treatment.
This is why we will be asking people to donate blood samples during our upcoming clinical trial. We want to make the samples available for the wider research community, and support the international effort to find biomarkers to measure the effectiveness of treatments in Wolfram.
Tim Barrett
The consortium Left : prof. Timothy Barrett, Right, 1st line: prof. Melanie Calvert, Dr Kristian Brock, Dr Zsuzsanna Nagy Right, 2nd line : prof. Richard Sinnott, Dr Anita Slade, Dr Ben Wright
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Tim Barretthttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgTim Barrett2018-02-06 09:45:532020-09-07 20:03:09What are biomarkers and why are they important?
Three British and one Australian research teams, coordinated by Professor Timothy Barrett, have been awarded the funding of 200,000 € by the Association syndrome de Wolfram, the Eye Hope Foundation and the Snow Foundation. Their project aims at “developing biomarkers that will show early evidence of benefit of a treatment; and patient self-report outcome measures that will help with regulatory approval. These two initiatives will speed up the delivery of treatments to patients in the clinic”.
They organized a call for proposals, which was a great success. Six research teams, located in six different countries (USA, Belgium, France, United-Kingdom, Spain and Israel), have sent a proposal. These proposals were then evaluated by a pool of independent world-renowned experts in the field of Wolfram syndrome and drug development. Based on their recommendations, the Presidents of the three organizations have elected the most promising project.
The project coordinated by Professor Timothy Barrett is entitled “Accelerating clinical trials in Wolfram syndrome: development of efficacy biomarkers and patient relevant outcome measures”. It will start on October 1st 2017 and will terminate by September 2019. It is funded through equal contributions from the Association syndrome de Wolfram (France), the Eye Hope Foundation (Belgium) and the Snow Foundation (USA).
A note from Dr. Timothy Barrett
“The international Wolfram community stands out from other rare disease communities in that it is highly collaborative: research scientists and patient groups work closely together across academic institution and national boundaries. The initiative by Association Syndrome de Wolfram, Eye Hope Foundation, and The Snow Foundation, is an outstanding example of this. Our teams are highly honored to be awarded the first joint funding, and we will work hard to ensure our research leads to benefits for patients. We will address one of the blocks to treatments, by finding ways to measure their effects on outcomes important for patients. At the end of our studies, we will have a toolbox of markers to show when treatments work, and to help convince health regulators to license treatments for patients to use in the clinic.”
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00Tim Barretthttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgTim Barrett2017-10-02 11:00:252020-09-07 20:03:30A British Consortium wins the joint call for proposals
I would like to give you an update as to progress with our clinical trial of a treatment for Wolfram syndrome.
We had the final confirmation of funding from the UK Medical Research Council on December 16th 2016, so were able to start work on the study protocol early in the New Year. We were fortunate to have Ms Rebecca Storey appointed as Senior Trials Coordinator in January. She has lots of experience in running clinical trials, and is based in the Clinical Trials Unit, University of Birmingham. She hopes to attend the family conference in October, so I hope some of you will meet her.
We then appointed local lead investigators for the UK: this will be Dr Renuka Dias for the children’s hospital clinic, and Dr Ben Wright for the Queen Elizabeth Hospital adult clinic. Also in January, Tracy kindly met with me at my parents’ house near Gatwick Airport, where we discussed what the clinical trial would look like, and what to include in the participant information sheets. The main point was that families would prefer partipants to have an increased chance of receiving the study medicine rather than the placebo. I took this back to our trial statistician Kristian Brock, who has been able to include this request. Participants will now have a 2:1 chance of being given the study medicine rather than the placebo. Kristian Brock is an expert in statistics and trial design, and will also try to attend the family conference.
In February we started discussions with Guy’s and Thomas’s Pharmacy manufacturing unit to prepare the medicine and placebo. We also prepared the ethics application form, and had a telephone conference with our international partners in Spain, France and Poland.
In March I went to our local Young Persons’ Advisory Group. This is a group of 11-23 year olds, who kindly volunteer to read study information and critically appraise it so that it is readable and easily understood. I took them the participant information sheets I had prepared, and I am sorry to say they looked them over very critically! They pointed out that the layout could be improved; that there was some repetition; and that a glossary of medical terms would help. I am very grateful to them and the information sheets are now shorter and clearer to read.
In April I attended the European Medicines Agency in London with Julie Warner, from Boyd Consultants, who provide regulatory advice. They agreed that we must check if the treatment slows the rate of deterioration of vision; however they would like a second outcome measure that is important for families. We are now working with experts on patient reported outcome measures, and would like to propose some ideas to you – things to measure which are important for a treatment to improve.
I also visited the French Wolfram association in Paris, just before Easter, and attempted to present the clinical trial in French. The audience was very polite and tolerated my schoolboy French! In May I gave a similar presentation to Spanish families in Almeria, hosted by Dr Gema Esteban, our Spanish collaborator. There is a lot of enthusiasm to take part, and there were many questions. Some of these related to randomisation, and I had to explain that the European Medicines Agency insist that some people receive the medicine and some the placebo. This is in order to provide the strongest evidence that our medicine works.
We are now hoping to sign the contract with the pharmacy manufacturers; submit the ethics application package in September; and recruit the first participants in the UK at the end of November. The timescale has been extended as we have to show that the medicine is stable outside the manufacturer’s packaging, when we put it in airtight plastic containers. This stability testing started last week, and takes 3 months.
Later this month, we have a local investigator meeting, where we will sort out the practical aspects of what tests we will be asking participants to have. I would like to write another update at the beginning of July when I can feed back on this meeting.
Please don’t hesitate to get in contact if I can help at all with any questions. Meantime, thankyou all for your kind interest and support!
Dear friends and colleagues,
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