#MSBlog: Are you interested in an MS stem cell trial? This one may be for you.
We invited Dr Muraro to answer a few questions:
Prof G: "What is this trial aiming to show?"
PM: "We are using autologous (a patient’s own) mesenchymal stem cells (MSCs) normally found in the bone marrow to see if giving them back intravenously after growing them in the laboratory can prevent inflammation and perhaps even help repair the nervous system. The patients will be monitored both clinically and radiologically (MRI) after enrolment throughout the duration of the trial. All patients will receive their MSCs but whilst some will receive them at the outset, others will receive theirs 6 months later. The sequence of treatment is “double blinded” – neither patients nor doctors will know in which order the active stem cell product or the dummy product are infused. Although this trial is small, only aiming to recruit 13-15 patients over the next 12 months, we will be contributing to an international effort in which results from about 15 centres are combined to give, what should be, statistically meaningful outcomes."
Prof G: "Which patients are you trying to recruit?"
PM: "Although the trial will look at all 3 types of MS to include relapsing-remitting, secondary progressive and primary progressive, the inclusion criteria are very restrictive and the key one requires the presence of an active inflammatory lesion on a MRI scan. This scan needs to be very recent and actually within 3 months of any planned bone marrow harvest. As you can imagine, this means that the majority of patients we will be able to recruit will have either relapsing-remitting or early secondary progressive MS. These patients will also require a moderate-severe relapse in the last 18 months. Other relevant criteria include being between 18-50 years old (inclusive), having had a formal diagnosis – not symptoms - of MS of between 2-10 years from entering the study and an EDSS score of between 3.0 - 6.5. Although we are not limiting the trial to London residents and it is open to MS patients within the UK who are registered with the NHS, patients will have to think quite carefully if they live a significant distance from London – the travel expenses allowed will not cover such costs."
Prof G: "Why has it taken so long for this trial to start from when it was initially announced by the MS Society?"
PM: "As with any clinical trial there are many regulatory bodies to satisfy before the trial gets the go-ahead. In the case of our trial involving mesenchymal stem cells, there were additional requirements. We had to obtain ethics approval from the Gene Therapy Advisory Committee (GTAC), and from the Medicines and Healthcare Regulatory Agency (MHRA) as an Advanced Medicinal Therapeutic Product, and each required extensive documentation, before finally being approved by our local NHS Trust. It’s certainly been a long process but it should be reassuring for patients to know that the trial has gone through some very rigorous assessments. In addition to the regulation, the practical experience is also reassuring: MSCs have been given before for a number of different disorders and seem very safe."
Prof G: "It was initially reported that you had identified enough participants – can patients still contact you if interested in this trial?"
PM: "When the research funding was first announced and major media including the BBC reported about our study, there was such high interest that we were inundated and nearly overwhelmed by the many enquiries and referrals received. Yet at that stage, we could only register interested people. After all required permissions for the trial were received, we contacted everyone who had confirmed their interest in the trial and found, unfortunately, most were ineligible as they did not fulfil (or no longer fulfilled) all the criteria. We have therefore opened up the trial to any new interested participants who may fulfil these criteria. The study will aim to recruit the participants over the next 12 months."
Prof G: "What is the process that a MSer needs to go through to get recruited?"
PM: "The first step would be to email email@example.com – a member of the research team will then contact the patient requesting more information. If the basic criteria appear to be met, we will invite the patient to our NHS clinic initially to discuss the situation and the trials available to them – for this though, we would need a referral from the patient’s GP or Neurologist. If suitable for STREAMS, we would then invite the patient to a screening visit – this is when the trial starts for the patient. The full schedule of visits over the course of the next 12 months is detailed in the patient information sheet."
The following is the latest patient information sheet for the STREAMS study.
Patients with clinically and radiologically active multiple sclerosis as defined by:
1. Diagnosis of MS:
a. Relapsing remitting MS (RRMS)
≥1 moderate-severe relapse and ≥1 gadolinium enhancing lesion (GEL) in past 18 months
≥1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months.
b. Secondary progressive MS (SPMS)
With an increase of ≥1 EDSS point (if baseline EDSS ≤ 5.0) or 0.5 EDSS point (if baseline EDSS ≥5.5), in the previous 18 months and ≥1 GEL in past 18 months
≥1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months.
c. Primary progressive MS (PPMS) patients with positive oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF)
Require both an increase of ≥1 EDSS point (if base-line EDSS ≤ 5.0) or 0.5 EDSS point (if baseline EDSS ≥5.5), or quantifiable, objective evidence of equivalent progression in the previous 18 months
≥1 GEL in past 18 months or ≥1 new T2 lesion in past 18 months.
2. Age 18 to 50 years.
3. Disease duration 2 to 10 years from diagnosis (inclusive).
4. EDSS 3.0 to 6.5 at screening evaluation.
5. ≥1 GEL on MRI within 3 months prior to harvesting.
1. RRMS without at least one severe relapse in the previous 18 months or without at least one GEL or one new T2 in the previous 18 months.
2. SPMS without relapses and without new lesions (GEL or T2 positive) on MRI in the last 18 months.
3. PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 months.
4. No gadolinium enhancing lesion(s) in the 3 months prior to bone marrow harvesting.
5. A previously ineligible patient who failed to meet the MRI requirements of the inclusion criteria will not be reviewed again even if further imaging, revealing ≥1 GEL, becomes available.
6. Failure of BM sample to generate MSCs suitable for clinical use within a specified time frame.
7. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the last 3 months.
8. Treatment with interferon-beta or glatiramer acetate within the last 1 month.
9. Treatment with alemtuzumab (campath-1H) within the last 2 years.
10. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation.
11. Participation in clinical trials of any experimental drugs in the 6 months before study entry.
12. Corticosteroid treatment in the previous 30 days.
13. Presence of any active or chronic infection.
14. Previous history of a malignancy other than basal cell carcinoma of the skin and carcinoma in situ that has been in remission for more than one year.
15. Severely limited life expectancy by any other co-morbid illness.
16. Abnormal blood counts, a history of myelodysplasia or other cytopenia.
17. Known pregnancy, positive urine pregnancy test at screening or risk or pregnancy (this includes patients who are unwilling to practice active contraception for the duration of the study).
18. Any breastfeeding woman.
19. Contraindication to MRI including but not limited to intracranial aneurysm clips (except Sugita), history of intra-orbital metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray), pacemaker and non-MR compatible devices (e.g. heart valves, inner ear implants), history of claustrophobia or the inability of the subject to lie still on their back for a period of 1.5 hours in the MRI scanner.
20. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or history or presence of renal impairment (e.g. serum creatinine clearance less than 30ml/min).
21. Inability to give written informed consent/comply with study procedures.
22. Any significant organ dysfunction or co-morbidity that the Investigators consider would put the subject at unacceptable risk by participating in the study or that would interfere with the functional assessments.
Information about the Principal Investigator for the STREAMS trial:
Paolo A. Muraro, MD, PhD is Clinical Reader and Head of the Clinical Neuroimmunology Group at Imperial College London.
Dr Muraro's research is aimed at improving the biological understanding and developing effective therapies for inflammatory neurological diseases, with focus on multiple sclerosis (MS). His programme is funded by the Medical Research Council, the UK Multiple Sclerosis Society, the UK Stem Cell Foundation, the Wellcome Trust and the Italian Multiple Sclerosis Society.
He is Chair of the Autoimmune Disease Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR; the largest organization of hematopoietic cell transplantation and cellular therapy research worldwide), University of Wisconsin, USA; is a Member of the UK Multiple Sclerosis Society Research Strategy Working Group and of the Scientific Committee of the Italian Multiple Sclerosis Foundation (FISM).
His proposal for a randomised, double-blind crossover trial of mesenchymal stem cells in Multiple Sclerosis (STREAMS) was awarded £525K in 2011 by the UK MS Society and the UK Stem Cell Foundation. For this trial, he leads a team of distinguished co-investigators and collaborators that include Dr Richard Nicholas (Consultant Neurologist, Imperial College Healthcare NHS Trust), Professor Francesco Dazzi (Professor of Stem Cell Biology, Imperial College), Professor David Miller (Professor of Clinical Neurology at the Institute of Neurology, UCL and a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, London), Professor Siddharthan Chandran (Professor of Neurology, University of Edinburgh) and Dr Omar Malik (Consultant Neurologist, Imperial College Healthcare NHS Trust).