Skip to main content

New drug treatment regimen shows promise for patients with lupus

Written by Louise Stanley on . Posted in Clinical trials, Inflammation and chronic disease.

The results of a randomised controlled trial, published in Annals of Internal Medicine, found that a new drug treatment regimen – using belimumab soon after rituximab – reduced a disease-related autoantibody and severe disease flares in lupus patients.

Systemic lupus erythematosus (SLE or lupus) is a long-term autoimmune condition, causing a variety of problems including joint pain, skin rashes, kidney disease and tiredness. While there is no known cure for this debilitating disease, the BEAT-Lupus clinical trial found that the combination of belimumab and rituximab shows promising results; reducing severe lupus flares by 3-fold for patients who had persistent, severe lupus disease requiring rituximab therapy at the beginning of the study.

Senior author Professor Caroline Gordon, Emeritus Professor of Rheumatology and member of the Institute of Inflammation and Ageing’s Rheumatology Research Group, together with colleagues from University College London conducted a phase 2 randomised trial involving 52 patients with SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy. Patients were treated with rituximab and then randomly assigned four to eight weeks later to receive intravenous belimumab or placebo for 52 weeks.

The researchers found that IgG anti-dsDNA antibody levels were lower in belimumab-treated patients at 52 weeks compared with placebo-treated patients (geometric mean, 47 versus 103 IU/mL; 70% greater reduction from baseline). The risk for severe flare was reduced significantly with belimumab versus placebo (hazard ratio, 0.27), with three and 10 severe flares in the belimumab and placebo groups, respectively. There was no increase seen in the incidence of serious adverse events in the belimumab group.

Professor Michael Ehrenstein, Chief Investigator of the BEAT-Lupus trial, said: “Thanks to the dedication of the lupus teams at participating hospitals we are delighted to not only have completed recruitment, but also to provide preliminary evidence for a clinical benefit of the combination of rituximab and belimumab, compared to patients treated with rituximab alone.”

“These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE, at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages,” the authors write.

Professor Gordon previously pioneered the methodology for assessing lupus disease activity and flares using the BILAG-2004 index. The main secondary clinical outcome of reduction of severe lupus flare in the BEAT-Lupus trial was based on this work, and flare was defined using this index.

She explained: “We were delighted to find that this treatment regimen not only reduced disease causing autoantibodies but also reduced severe flares which cause very distressing symptoms and disruption to patients’ lives. This study offers the hope that this combination of drugs will be useful in the future if the results are confirmed in a larger trial.”

The study was funded primarily by Versus Arthritis; GlaxoSmithKline provided belimumab free of charge, as well as some additional funding.

Triple-drug combo could prove key weapon in fight against cancer

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials, Experimental medicine.

Combining three existing drugs – a commonly-used anti-epileptic, a contraceptive steroid and a cholesterol-lowering agent – could form an effective and non-toxic treatment for a range of aggressive blood cancers, a new study reveals.

The discovery by University of Birmingham scientists has led to a £1 million funding award from Blood Cancer UK to run a randomised clinical trial to test the new drug combo against another experimental agent (Danazol) in patients living with Myelodysplastic Syndromes (MDS).

Over 7,000 people in the UK have MDS and many patients die because their disease transforms into acute myeloid leukaemia (AML) – an even more aggressive blood cancer. The general outlook for AML is poor, but when AML arises from MDS it is worse.

Left untreated, AML kills patients quickly by crippling production of normal blood cells. AML is most prevalent in elderly people – many of whom cannot tolerate ‘traditional’ treatment of intensive chemotherapy because of their age and frailty.

Scientists at the University of Birmingham had already discovered that mixing bezafibrate (BEZ – cholesterol-lowering) with medroxyprogesterone acetate (MPA – contraceptive steroid) eased a range of blood cancers including AML, chronic lymphocytic leukaemia (CLL) and non-Hodgkins lymphoma.

Now clinical trials show that adding valproic acid to a low-dose combination of the other two drugs offers enhanced killing of AML cells – giving the low-dose triple-drug combo (VBaP) a cancer-busting impact similar to a high dose of BEZ and MPA (BaP).

Researchers from the University of Birmingham have published their findings in British Journal of Cancer.

Co-author Professor Chris Bunce, commented: Using existing drugs to treat conditions outside of their approved indications is a proven approach to generate effective low-toxicity therapies. We believe that treating patients earlier with low toxicity therapies is the most effective clinical strategy for improving patient outcomes.”

Earlier clinical trials had shown that low-doses of BaP given to patients who could not have chemotherapy produced no toxic side effects and helped patients to boost their production of blood cells.

However high doses of the dual combo were not well tolerated, due to the frail nature of the patients caused by their age, poor kidney function, disease and, in some cases, prior chemotherapy treatments.

Co-author Dr Farhat Khanim commented: “A major challenge in our previous BaP trials has been the focus on elderly patients for whom more intensive therapies were not option.

“For many of these patients there are very few treatment options other than regular transfusions to combat life-threatening deficits in red cells and platelets and antibiotic control of frequent life threatening infections.

“It is therefore an attractive option to consider testing VBaP in MDS patients. As the drug combination may have profound impact on quality of life and survival of these patients.”

community group meeting - people gathered around a table on sofas

SPIRIT-PRO extension: guidelines for inclusion of patient-reported outcomes in protocols of clinical trials

Written by Louise Stanley on . Posted in Clinical trials, Health inequalities.

Patient Reported Outcomes (PROs) can provide valuable evidence on the impact of disease and treatment on patients’ symptoms, function and quality of life. High-quality PRO data from trials can inform clinical care, regulatory decisions and health policy. However, problems such as poor data collection, analysis, reporting and interpretation often reduce or negate their value. This paper attempts to raise standards by enhancing the international SPIRIT-PRO guidelines that were created to optimise the design of clinical trials and encourage the consistent, high-quality reporting of PROs and ultimately to inform patient-centred care. This case study originally appeared on the HDR UK website – visit to read further health data case studies.

Challenge

The PRO content of past trial protocols has often been incomplete or unclear leading to research waste. An appraisal of the PRO content of >350 past trial protocols showed that many lacked the specific information needed for high-quality PRO data collection and evidence generation. As a result this may lead to poor quality or non-reporting of PRO trial results, which may hinder the potential for PRO evidence to be used in regulatory decision-making, health policy and clinical care

The SPIRIT-PRO guidance and the subsequent SPIRIT-PRO Extension (a 16-item checklist intended to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection) were created to establish standards to improve the content and quality of trial protocols. However, further work is required to support uptake and implementation.

Solution

A team led by Melanie Calvert, NIHR Senior Investigator, Professor of Outcomes Methodology at the University of Birmingham and Director of Centre for Patient Reported Outcomes Research and Professor Madeleine King, University of Sydney, have developed tools to support the use of SPIRIT-PRO by researchers to generate high quality PRO data to inform patient care. This includes a protocol template, detailed descriptions and examples of good practice.

Impact and outcomes

While trial protocols are the foundation for study planning, conduct, reporting and appraisal, they vary greatly in content and quality. By providing specific recommendations about PRO endpoints it is possible to improve the situation – providing valuable information for clinicians and patients about the risks, benefits and tolerability of an intervention.

The work carried out by Prof. Calvert, Prof. King, Dr Olalekan Aiyegbusi with international collaborators (supported by UCB Pharma, Macmillan Cancer Support, the NIHR and HDR UK) has the potential to dramatically improve the quality and value of PRO data gathering and reporting in clinical trials. This in turn has far-reaching implications for care – allowing patients and their care teams to understand how an intervention will affect someone, whether it is appropriate or if an alternative should be considered.

Patient and Public Involvement and Engagement

Patient partners were involved in the design, conduct, reporting and dissemination plans of the research. This included the development of the SPIRIT-PRO Extension, the paper, protocol template, tools to support implementation by patient partners. Patient partners are included as co-authors.

Insights from the HDR UK Impact Committee

The HDR UK Impact Committee serves to raise the profile of both ours and our contributors’ outputs. The Impact Committee are keen to celebrate significant impacts which clearly demonstrate the value of of our mission to unite the UK’s health data to enable discoveries that improve people’s lives.

Contact

Prof. Calvert: m.calvert@bham.ac.uk

New Birmingham-Roche collaboration targets new treatments for inflammatory bowel disease

Written by Louise Stanley on . Posted in Clinical trials, Inflammation and chronic disease.

A new £850k collaboration between Birmingham Health Partners (BHP) and global biotechnology leaders Roche is set to improve both diagnosis and care of patients with inflammatory bowel disease (IBD) by investigating promising biomarkers and inflammatory mechanisms in the search for new treatment targets.

IBD affects around 250,000 people in the UK in the form of ulcerative colitis and Crohn’s disease, and is characterised by an imbalance in gut bacteria which causes debilitating damage to the intestines.

Current treatments, which target the body’s immune response, are ineffective for the majority (around two-thirds) of patients, meaning many of them eventually have to undergo invasive surgery. These diseases affect mainly younger people of working age, and as the precise cause is not yet fully understood, there is a pressing need to identify non-surgical therapies which can improve quality of life.

As host to the largest IBD clinic in Europe, BHP founder-member University Hospitals Birmingham NHS Foundation Trust (UHB) will lead the new active translational research collaboration with Roche scientists, alongside BHP colleagues at the University of Birmingham’s Institute of Cardiovascular Sciences (ICVS) and Microbiome Treatment Centre. Newly-diagnosed IBD patients will be seen weekly at new clinics across sister UHB sites Queen Elizabeth Hospital Birmingham and Heartlands Hospital.

This unique patient cohort will provide invaluable biological samples taken before they begin treatment – allowing researchers to investigate biomarkers identified by Dr Asif Iqbal of ICVS. Dr Iqbal’s team will study disease pathology including the role of immune cells, the microbiome and metabolome in driving the various inflammatory mechanisms associated with IBD.

Professor Tariq Iqbal, Consultant Gastroenterologist at UHB and Director of the Microbiome Treatment Centre at the University of Birmingham explained: “IBD is an underfunded disease area and the potential benefits to patients which will arise as a result of this collaboration are likely to be lifechanging for many. Those participating in the trial will help build the first clinical resource of its kind from which we aim to promote earlier diagnosis and more effective treatments.

“Cross-discipline collaboration, facilitated by BHP, will be crucial in unlocking these advances as we tap in to expertise in specialties such as genomic sequencing as well as the University’s Microbiome Treatment Centre.”

Dr Asif Iqbal commented: “This project will demonstrate the power of combining basic science with translational clinical research for patient benefit. Through identifying targets in immune cells which drive this chronic inflammatory disease, we hope to develop a range of novel therapeutics.”

The collaborative research award of £844,163 from Roche funds two combined IBD projects from March 2021 to January 2023. UHB is aiming to recruit 60 patients to the study.

World-first trial to assess ‘life-extending’ cannabis-based drug for thousands with aggressive brain tumours

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials, Experimental medicine.

BHP founder member the University of Birmingham will co-ordinate a major UK trial to analyse the efficacy of cannabis-based drug Sativex in treating the most aggressive form of brain tumours.

The new phase II trial, to be funded by The Brain Tumour Charity, is to launch at 15 NHS hospitals and follows promising results from a phase I study in 27 patients. The phase II trial will assess whether adding Sativex (an oral spray containing cannabinoids THC and CBD) to chemotherapy could extend life for thousands diagnosed with a recurrent glioblastoma, which currently has an average survival of less than 10 months*.

In a phase I trial in glioblastomas earlier this year**, the drug — already used in treating multiple sclerosis — was found to be tolerable in combination with chemotherapy, with the potential to extend survival.

While the phase I study observed that more patients were alive after one year in the Sativex arm compared to the placebo arm, the study was not sufficiently powered to show survival impact.

The new three-year phase II trial (called ARISTOCRAT), led by Professor Susan Short at the University of Leeds and co-ordinated by the Cancer Research UK Clinical Trials Unit at the University of Birmingham, is due to begin recruiting over 230 patients across all UK nations in early 2022, subject to sufficient funds being raised.

Having seen its income drop by over 25% last year due to the pandemic and been forced to pause its regular research grant funding programme, The Brain Tumour Charity has today launched an appeal to raise the £450,000 needed to open the trial as soon as possible.

Experts hope that, should the trial prove successful, Sativex could represent one of the first additions to NHS treatment for glioblastoma patients since temozolomide chemotherapy in 2007.

Glioblastomas are the most common and most aggressive form of brain cancer, with around 2,200 people diagnosed each year in England alone***. They are usually fast-growing and diffuse, with poorly-defined boundaries and thread-like tendrils that extend into other parts of the brain.

Almost all glioblastomas recur even after intensive treatment including surgery, radiotherapy and chemotherapy, and average survival is just 12-18 months from first diagnosis****.

Over the last decade, there has been significant global interest within both patient and scientific communities about the activity of cannabinoids in brain tumours, with the view that cannabinoid-based products may not only help relieve symptoms but could also have a positive impact on survival.

Several pre-clinical laboratory studies***** have suggested that cannabinoids THC and CBD may reduce brain tumour cell growth and could disrupt the blood supply to tumours – however, to date, clinical evidence that they could treat brain tumours has been limited.

In this new phase II trial, researchers will assess whether adding Sativex to the current standard chemotherapy treatment (temozolomide) could offer extra time to live for adults diagnosed with a recurrence of their glioblastoma after initial treatment.

The trial plans to recruit 232 participants across a minimum of 15 hospitals******: two thirds of the participants will be given temozolomide plus Sativex, while one third will be given temozolomide plus placebo*******.

Sativex, manufactured by GW Pharma, is an oromucosal spray containing 1:1 THC (Delta-9-tetrahydrocannabinol) and CBD (cannabidiol), with the active ingredients being absorbed in the lining of the mouth, either under the tongue or inside the cheek.

Participants will be asked to administer up to 12 sprays per day (or to the maximum dose they can tolerate if fewer than 12) of Sativex or placebo oral sprays. Participants will then undergo regular follow-up including clinical assessment (every four weeks), blood tests, MRI scans (every eight weeks), and they will complete quality of life questionnaires. This will also be one of the first trials to integrate with The Brain Tumour Charity’s app BRIAN.

The trial will measure whether adding Sativex to chemotherapy extends the overall length of patients’ lives (overall survival), delays the progression of their disease (progression-free survival) or improves quality of life.

Professor Pam Kearns, Director of the Cancer Research UK Clinical Trials Unit (CRCTU) at the University of Birmingham, which is co-ordinating the trial, said: “Our mission at the CRCTU is to translate cutting-edge science and research into improved patient care by identifying novel therapies that will save lives. It is vital that trials like this, investigating the role cannabis or the chemicals in it can play treat cancer, are carried out.”

Principal Investigator, Professor Susan Short, Professor of Clinical Oncology and Neuro-Oncology at the University of Leeds, said: “The treatment of glioblastomas remains extremely challenging. Even with surgery, radiotherapy and chemotherapy, nearly all of these brain tumours re-grow within a year, and unfortunately there are very few options for patients once this occurs.

“Cannabinoids have well-described effects in the brain and there has been a lot of interest in their use across different cancers for a long time now. Glioblastoma brain tumours have been shown to have receptors to cannabinoids on their cell surfaces, and laboratory studies on glioblastoma cells have shown these drugs may slow tumour growth and work particularly well when used with temozolomide.

“It’s really exciting that we’re now at the point where we can run a definitive, well-designed study that will tell us the answer to whether these agents could help treat the most aggressive form of brain tumour. Having recently shown that a specific cannabinoid combination given by oral spray could be safely added to temozolomide chemotherapy, we’re really excited to build on these findings to assess whether this drug could help glioblastoma patients live longer in a major randomised trial.”

Dr David Jenkinson, Interim CEO at The Brain Tumour Charity, which is funding the trial, said: “We hope this trial could pave the way for a long-awaited new lifeline that could help offer glioblastoma patients precious extra months to live and make memories with their loved ones.

“With so few treatments available and average survival still so heartbreakingly short, thousands affected by a glioblastoma in the UK each year are in urgent need of new options and new hope.

“We know there is significant interest among our community about the potential activity of cannabinoids in treating glioblastomas, and we’re really excited that this world-first trial here in the UK could help accelerate these answers. The recent early-stage findings were really promising and we now look forward to understanding whether adding Sativex to chemotherapy could help offer life-extension and improved quality of life, which would be a major step forward in our ability to treat this devastating disease.

“But we also know that for many, this trial won’t come soon enough. In the meantime, while other cannabis-based products may help alleviate symptoms, there is insufficient evidence to recommend their use to help treat brain tumours. For anyone considering using cannabis-based products or other complementary therapies, it’s vital that you discuss these with your medical team first, as they could interact with other treatments such as anti-epileptic medicines or steroids.”

Stephen Lee, 62 from Leyland in Lancashire, took part in the phase I trial of Sativex in 2015 after his glioblastoma returned following initial treatment. Stephen was first diagnosed in 2010, just a few months after he had very sadly lost his older brother to the same disease. Stephen said: “My diagnosis was very sudden and was one of those days you never forget. Having had to leave work early with a severe headache and a stabbing pain in my right eye, my wife insisted that we go straight to hospital after what my brother had experienced.

“I was admitted that same day, had a scan and that’s when they identified it was a brain tumour. I had the operation the following week, and beforehand my wife and I agreed that we wanted to stay positive, to keep living our lives and to enjoy however much time we had together.

“I joined the early trial of Sativex in the hope that it could improve my quality of life, but I also thought it was important to do so as the chemotherapy and radiotherapy I was having had all been trialled by other people before it could be used safely. I thought it only right and proper that I followed in their footsteps and joined a trial to help prove a new drug which could benefit so many people in the future with a recurring glioblastoma.

“I took the oral spray 10 times a day, and it was easy as I could take it wherever we were going, even while out for dinner. While I don’t know whether I had Sativex or the placebo, since the trial finished in 2016, all my MRI scans have been clear.

“This new trial is so important as it will give people hope that there could be life beyond a glioblastoma diagnosis and that there are other treatments being trialled to support them to live their lives.”
Anyone affected by a glioblastoma can speak to The Brain Tumour Charity on 0808 800 0004.

References:

*Twelves et al. A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma. Br J Cancer 124, 1379–1387 (2021).

**The initial phase 1b trial, led by the same authors, was published in the British Journal of Cancer in February 2021. The study assessed the safety and potential effectiveness of adding Sativex to temozolomide for patients with a newly recurrent glioblastoma (GBM) – finding it could be tolerated, did not appear to interfere with temozolomide treatment and had the potential to improve survival. In the first part of the study, 6 patients received a personalised regime of Sativex of up to 12 sprays per day, alongside their temozolomide therapy – and the side-effects were recorded and reviewed. In the second part of the study, 21 patients were randomised to receive either Sativex with temozolomide (12 patients) or placebo with temozolomide (9 patients) for a total duration of 12 months. 10 out of 12 (83.3%) patients receiving Sativex were still alive after one year, compared to 4 out of 9 (44.4%) patients in the placebo arm.

***Greenberg et al. Incidence and outcomes for cerebral glioblastoma in England, Public Health England; Brodbelt, A., Greenberg, D., Winters, T., Williams, M., Vernon, S. and Collins, V.P. Glioblastoma in England: 2007–2011. Eur. J. Cancer 2015, 51, 533–542.

****The prior figure (‘less than 10 months’) is the average survival from the point of tumour recurrence following initial treatment, whereas the ‘12-18 months’ figure is the average survival from first diagnosis.

****Rocha et al. Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol, 2014. 116(1): p. 11-24; Dumitru, C.A., I.E. Sandalcioglu, and M. Karsak, Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs. Front Mol Neurosci, 2018. 11: p. 159; Torres, S., et al., A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther, 2011. 10(1): p. 90-103.

******The recruiting centres include: Leeds General Infirmary; Guy’s and St Thomas’, London; Queen Elizabeth Hospital, Birmingham; Addenbrooke’s Hospital, Cambridge; Western General Hospital, Edinburgh; The Beatson, Glasgow; The Clatterbridge Cancer Centre, Liverpool; The Christie, Manchester; Queen’s Medical Centre, Nottingham; John Radcliffe Hospital, Oxford; Southampton General Hospital; Southmead Hospital, Bristol; Charing Cross Hospital, London; Velindre Cancer Centre, Cardiff, and the Royal Victoria Hospital, Belfast.

*******Both Sativex and the placebo are being provided free-of-charge for the duration of the trial by GW Pharma.

blood cancer cells

Blood cancer trial sponsored by the University of Birmingham opens for recruitment

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials.

A new Cancer Research UK-funded clinical trial being sponsored by BHP founder-member the University of Birmingham has opened for recruitment – aiming to investigate the efficacy of a novel treatment for patients affected by a specific type of blood cancer.

PROMise, which is being co-ordinated via the Cure Leukaemia-funded Trials Acceleration Programme (TAP) hub at the University of Birmingham’s Cancer Research UK Clinical Trials Unit (CRCTU), will recruit patients aged over 16 who suffer with myelofibrosis (MF).

Over the next two years, 15 NHS centres will recruit MF patients who will be given a novel agent called PLX2853 in addition to the existing standard treatment of ruxolitinib.

Each year in the UK over 300 patients are diagnosed with MF, which is a blood cancer associated with debilitating symptoms including extreme fatigue, pain, weakness and shortness of breath. Around 10-20% of MF patients go on to develop acute myeloid leukaemia (AML) and consequently, a diagnosis of MF has a huge impact on both length and quality of life, with median survival from the time of diagnosis being just two years for patients with high-risk disease.

The only curative therapy for MF is stem cell transplant; however, this is only suitable for a small minority of younger patients who don’t present with comorbidities (the effect of all other conditions an individual patient might have – physiological or psychological).

The current NHS standard of care for those unsuitable for stem cell transplant is treatment with ruxolitinib, approved for use in 2011 and currently the only therapy approved with an indication for MF.

Professor Pam Kearns, Director of the University of Birmingham’s CRCTU, said: “Whilst ruxolitinib is already in widespread clinical use, many patients do not achieve an adequate response. Significant residual symptoms remain in most patients thus there is a major unmet clinical need and the PROMise trial is addressing an urgent need for improved therapeutic approaches for MF patients.”

Chief Investigator, Professor of Haematology at University of Oxford, Adam Mead, said: “The PROMise study is a really exciting study that has just opened in the UK and will be opening across 15 centres. This is introducing a new treatment called PLX2853, in combination with ruxolitinib, for patients with MF. The impact on patients for this combination of treatments, I hope, will be improvement of their symptoms, improvement of their quality of life, without causing them side effects.”