CrowdSpeak: NIMBYism in MS

Are you an MS NIMBY? #CrowdSpeak #MSBlog #MSReserch #NIMBY

"If you live in the UK you will know all about being a NIMBY (not in my backyard) and NIMBYism (the behaviour to describe people who resists unwanted development, such as manufacturing plants, prisons, power companies, or chemical companies in his or her own neighborhood or town)."

"An example of NIMBYism in medicine is the emerging resistance to vaccination. 'Yes, I want all the other children in the country to be vaccinated so that my children will benefit from herd immunity, but I don't want my children to be vaccinated as I am concerned about them developing rare by serious adverse events from vaccines'. This attitude, which we can all identify with, has resulted in the re-emergence of measles epidemics in many developed countries and is a very sad indictment of modern human behaviour."

"So it really saddens me to have to write that NIMBYism has spread to the field of MS. We have desperately being trying to improve the lot of progressive MSers, by developing new biomarkers of disease progression with the hope of using them as an outcome measure in clinical trials. Our PROXIMUS trial which is testing a putative neuroprotective agent oxcarbazepine as an add-on therapy in early SPMS is recruiting very very slowly. Why? MSers don't want to have lumbar punctures; this is despite us getting an affirmative response from you on the scientific principles underpinning the need for doing lumbar punctures as part of a clinical trial."

"The PROXIMUS trial is the culmination of over 15 years of my life; we simply have to make it work. We have very good data from animal models, and from a subgroup analysis of the lamotrigine trial in SPMS, that sodium channel blockers are effective neuroprotective agents in MS. In our animal model of MS sodium channel blockers, in particular carbamazepine and oxcarbazepine, are very effective at preventing damaged axons from dying. Therefore we think we have the right class of drug for the PROXIMUS trial. I am also hopeful that the results of our phenytoin in acute optic neuritis trial will also support the scientific principle of using add-on sodium channel blockers in MS. Phenytoin is the original sodium channel blocker that was initially licensed as an anticonvulsant for epilepsy."

"The primary outcome in the PROXIMUS trial is a reduction in the spinal fluid levels of neurofilament. Neurofilaments are the proteins that form the scaffold in neurons and axons. If you damage axons and nerves the neurofilament levels are released and can be measured in the spinal fluid. The higher the levels of neurofilament in the spinal fluid the more damage that has occurred. We and others have shown that spinal fluid neurofilament levels are a good marker of ongoing neuroaxonal damage in MS. If you have raised levels in your spinal fluid you are more likely to progress over the next 3-14 years than if your spinal fluid neurofilament levels are normal. This is why we are only including MSers with raised levels of spinal neurofilament levels in the PROXIMUS trial."

"We have actively be promoting the therapeutic concept that to tackle progressive MS we need a stepwise, pyramidal approach, i.e. to add-on neuroprotective drugs to anti-inflammatory drugs. The recent failure of fingolimod in PPMS highlights this need for combination therapies; one agent is simply not enough to stop, or slow down progressive MS. We need to move into the era of combination therapies. This is why in the PROXIMUS trial we are adding-on a neuroprotective drug to an existing anti-inflammatory drug."

"Speed of drug development has been and still is a big problem in progressive MS. A current phase 2 trial of a neuroprotective drug in progressive MS takes at least 2 years to run with literally hundreds of SP or PP MSers per arm. This takes time and money. The PROXIMUS trial has been designed to be small and rapid; i.e. 30 subjects per arm and 12 months. We estimate that if the PROXIMUS trial works it could speed up drug development for progressive MS 10-fold."

"A problem in the past has been complications associated with doing lumbar punctures. Therefore we have gone to extraordinary lengths to de-risk the procedure. We have moved to using atraumatic, or non-cutting needles, to reduce the incidence of post-LP headaches. We have actually shown this in our own hospital. Getting neurologists and other clinicians to change their LP habits is not easy, but we are getting there with a large initiative to nudge them to change their behaviour. We have also purchased a ultrasound machine to help with doing lumbar punctures; this is particularly useful when we can't find the interspace between the vertebra to inset the lumbar puncture needle. Doing LPs when necessary under ultrasound guidance reduces complications. We have also designed and produced a very neat little online APP to educate potential study subjects about LPs at our hospital. This APP is part of a suite of APPS we are developing for MSers."

"As you can see we have gone to extraordinary lengths to get all these things in place to make the PROXIMUS trial a success. However, when my colleagues approach MSers to participate in  the PROXIMUS trial they say thanks, but no thanks. With this attitude the PROXIMUS trial will fail and progressive MSers will be no better off than than they were in 2005 before the PROMISE 2010 programme started. I have now asked all our PIC (patient identification) sites not to tell potential subjects for the PROXIMUS trial about the need for lumbar punctures, but to refer them to us so that we can explain the rationale of the study before informing them about the need for multiple lumbar punctures. We have found from the MSers that we have already enrolled in the study that once they understand what we are trying to achieve in the PROXIMUS trial that they are more willing to have multiple lumbar punctures. I hoping that the observed NIMBYism can be counteracted by education. The following is the short YouTube video I made to explain the principles behind the PROXIMUS trial."

"For the sake of progressive MSers we need to stamp out MS NIMBYism before it takes hold. We are all in this together and we will only be able to crack progressive MS if we work together. I will be doing several posts on this topic over the next few weeks and months to keep you informed on how we are doing with regard to the PROXIMUS trial. We need your help so any suggestions will be very welcome."

Disclaimer: please note Barts-MS can't recruit subjects for clinical trials via this blog. If you are interested in participating in the PROXIMUS trial you need to be referred to Barts-MS via your GP or treating neurologist.

The following are the inclusion and exclusion criteria for the PROXIMUS Trial (NCT02104661):
Inclusion Criteria:

  1. A diagnosis of definite multiple sclerosis
  2. Treatment with DMDs for at least 6 months
  3. EDSS score between 3.5 and 6.0
  4. No history of relapses in the preceding 6 months
  5. A history of slow progression of disability, objective or subjective, over a period of at least 6 months
  6. Age 18-60 years

Exclusion Criteria:

  1. Pregnant or breastfeeding or unwilling to use adequate contraception.
  2. Participants who do not take a DMDs for MS.
  3. A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
  4. Participants presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil count <1.5 or platelet count <100, or thrombocytopenia <1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the participant.
  5. Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
  6. Participants receiving other sodium or calcium channel blockers in the previous 12 weeks
  7. Exposure to any other investigational drug within 30 days of enrolment in the study.
  8. Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (CSSRS).
  9. Prior history of malignancy unless an exception is granted by the Chief Investigator.
  10. History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
  11. Past untoward reactions to Oxcarbazepine or carbamazepine.

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