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.

12 thoughts on “CrowdSpeak: NIMBYism in MS”

  1. When I had my lumbar puncture done, my level of discomfort during the procedure was greatly minimized by something quite simple–by merely having the nurse lay her hand on my shoulder during the procedure. Why not take that idea a step further and have a massage therapist available to give a very gentle head, neck, or shoulder rub during the procedure to offset the patient's discomfort? I don't know if there are any clinical or legal barriers to this idea, but I think that getting a free massage may entice more volunteers to put up with the dread of getting lumbar punctures.

    1. Re: "Could you set up a site were people can refer themselves."Our ethics approval does not allow for self-referral.

  2. I think there are a number of factors at play: (I) failure of earlier progressive MS trials; (II)a misunderstanding of what happens next ie if I'm on the trial and the results are good, can I keep on the drug; (lll) MSers awaiting the results of the Charcot Project, ocreluzimab trial, geneuron trial. You have to get yourself into the mindset of an MSer They are asking themselves "what's in it for me", "what's the best chance of slowing my progression". Your trial is one of many. I don't necessarily think its the fear of lumbar puncture's that is putting MSers off. It's the fear that they start the trial, get on the placebo arm and then miss out if another trial reports good results. To get the recruitment moving you need to convince MSers that it has a better than 50% chance of success and that trialists will be given the option of continuing on the drug if the trial shows good results. You have said before that there is a lot happening in the MS space – the slow recruitment use evidence of this. To get participants interested you need to get them hooked – what's the unique selling point / what's in it for them.

    1. Spot on.I would add to this an economic dimension: Many are to benefit (upstream and downstream) from drug discovery.How is it ethical not to pay patients who undertake procedures such as a lumbar puncture?Surely the hassle is worth a few hundred pounds…Patient recruitment should be a market-driven practice and a pricing equilibrium can be reached:a compensation enough to entice patients and within the budgets of clinical trials.

  3. I've had two lumbar punctures in my life and the headache I suffered for the following 10 days was so debilitating I had to remain in hospital. The actual procedure was fine and I didn't feel any discomfort. However, the nursing care that I received during these periods was appalling. I was put in a dementia ward where the poor patients were ranting the whole time. The pain was horrific. Before you call us NIMBYs, look at the eclusions. The other MSers I know have all had cancer, hypertension or some other co-morbidity. We can't help it that the medical profession has only just come up with a possible treatment, for most of us it is too late because e don't qualify. So spare a thought for those of us that are coping with some really horrible illnesses as well as MS.

    1. My brother had an LP for viral encephalitis. The medical professional doing the prodedure at the hospital didn't get it right and hit a nerve. He said it felt like a massive electric shock going down the whole of one leg. My dad said he's lucky not to be disabled by it. It's put me off having a LP for my MS.

  4. We've been let down so many times before with progressive trials. One friend was on the lamotrigine trial and another on CUPID. Lots of positive statements at the start and the results did not deliver. I'm not that bothered that you have spent 15 years on this – it's your job and you get paid. My interest is keeping the wheelchair at bay so I can make the most of my semi-retirement. Why is this trial likely to succeed when others have failed? I need something that works now. Trials come with the risk of placebo arm and failing. How are these risks being mitigated so that I might get benefit? While I'm happy to participate to help the next generation I also need to help myself / my family. The LPs aren't putting me off, it's the fear that I will invest hope and time for another experiment which will not deliver

    1. So the best way that you get a treatment that works now is to be on a trial because this trial could finish before any of the commercial trials deliver a treatment to the development of the general population.The lamotrigine trial had a problem that 50 percent of people were not taking the drug properly and analysis of the neurofilaments showed that those who did take the drug did better.

  5. According to the slide in Dr. G's presentation natalizumab normalizes nfl levels in the csf, a marker for neurodegeneration. Since this was a primary outcome in the study will the drug be approved for progressive disease or is this still pending the ASCEND trial?

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