Monday, 16 March 2015

CrowdSpeak: the rationale behind the PROXIMUS study

The scientific rationale behind the PROXIMUS trial. #CrowdSpeak #MSBlog #MSResearch

"I note my post on possible NIMBYism amongst progressive MSers generated a lot of negative comments; primarily directed at me. Let's hope it generates some grass roots activism. To try and make amends I would like to present to you some of the scientific rationale behind the PROXIMUS trial. Although we have posted on and discussed the paper below in detail it provides some very important insights that are relevant to the PROXIMUS trial."

"Lamotrigine is a sodium channel blocker that is used as an anticonvulsant medication in the treatment of epilepsy. Lamotrigine and belongs to the same class of drugs as oxcarbazepine that we are using in the PROXIMUS trial. We have good data showing that both Lamotrigine and Oxcarbazepine are neuroprotective in our animal model. Unfortunately, the lamotrigine in SPMS trial was negative; i.e. it did not show a positive effect on the primary outcome (brain atrophy) compared to placebo at 2-years. The problem with lamotrigine is that when you use it at high doses in SPMSers it is poorly tolerated due to excessive side effects. As a result of this a large number of subjects did not take the drug in the study. If, however, you limit the analysis to subjects who took lamotrigine in the study (those with detectable blood levels) you see a different result. MSers on lamotrigine were much more likely to have a reduction in the blood neurofilament levels compared to those who did not take the drug. This proves to me two things: (1) that lamotrigine is neuroprotective in MS and (2) neurofilament levels are a good proxy for neuronal loss in SPMS and using them will provide a read-out in other trials. The problem with this study is that too few MSers volunteered to undergo lumbar punctures hence we had to rely on analysing blood samples. The problem with blood samples is that too few MSers have detectable NF levels in their blood. The reason for this is that some MSers make antibodies against neurofilament that clears the protein from the blood very quickly; only about a third of SPMSers have detectable blood levels of neurofilament. Therefore, we had to design the PROXIMUS trial using spinal fluid and hence the need for lumbar punctures. All SPMSers, in fact all MSers, have detectable neurofilament levels in their spinal fluid."

"The other thing about the study below it showed that raised neurofilament levels predicted and correlated with multiple measure of disability; i.e. slowed walking times, the time it takes to do the 9-hole peg test (9-HPT), cognition (PASAT), psychological impact (MSIS-29, the EDSS and brain atrophy on MRI. In other words neurofilament looks like a potential biomarker of damage in MS."


 Survival curves of walking times and 9-hole peg test times (dominant and non-dominant hand) are plotted according to absent, below median or above median NfH levels.

Gnanapavan et al. Biomarker report from the phase II lamotrigine trial in secondary progressive MS - neurofilament as a surrogate of disease progression. PLoS One. 2013 Aug 1;8(8):e70019.

OBJECTIVE: Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.

METHODS: SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12-24 and 0-24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.

RESULTS: Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12-24 months p=0.043, Nfh 0-24 months p=0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.

CONCLUSIONS: The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.

"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 for clinical trials. We have moved to using atraumatic, or non-cutting needles, to reduce the incidence of post-LP headaches. 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 an 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."




"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. The following is the short YouTube video I made to explain the principles behind the PROXIMUS trial."




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.
CoI: this study was done by Barts-MS

8 comments:

  1. Prof G,

    Many thanks. This factual approach is likely to better received and trialists will start signing up.

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  2. Can you offer MSers incentives to do the trial? May get people to come forward. I see a lot of trials which compensate healthy people for their time / risk but not so much for MSers. Why is that?

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    Replies
    1. This is an ethical dilema. At the moment you are volunterring for the good of mankind, but in your scenario you are being paid to be in the trial so are you just doing it for money.

      In phase I the volunteers get paid not a lot, and I would say a derisory amount give the amount the companies doing the phase I trials actually charge the pharmaceutical company. However after the elephant head scare where the drug had a terrible reaction on the volunteers (they would have signed a consent form where death as a possible outcome would have been in the consent form I would bet). You would think people would run a mile but the opposite happened because people realise you get paid for this and so volunteered. I have no issues with people being on the trials getting rewarded for their bravery but it is an ethical issue that would need very good ethical safeguards

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  3. Does it matter what someone's motivation is for participating in a trial so long as they are compliant? And in respect of ethics I have to question the use of a placebo, particularly as people are being asked to give up considerable time and undergo what for many is an uncomfortable procedure. I'm all for the good of mankind but when it comes down to it our actions are often motivated by the hope of personal gain. I'm not trying to be negative here, I just find the ethics around research quite interesting.

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    Replies
    1. Interesting comment, but the question you're really asking is where does research meet the person? - am I correct? This is my take on it -
      1) harm can be done by licensing a drug in the long-run if it does not prove to be more efficacious than placebo; 2) to achieve neuroprotection, you must impact on neurodegeneration - the rationale for measuring neurofilaments in CSF. Can you do a drug trial for 10 or realistically speaking 50 years to see if a drug actually slows down neurodegeneration.
      These are mind boggling questions which ethics committee ponder over when studies involving lumbar punctures are authorised. In fact, I was exactly in such a situation when the Lamotrigine trial was reviewed by the ethics committee. The Lamotrigine trial was the first ever clinical trial in UK to have a lumbar puncture arm. The ethics committee decided to allow the lumbar puncture study to go ahead on a voluntary basis, and if the analysis had not been done we may have discarded sodium channel blockers as being useless in MS. Food for thought would you not say?

      Delete
  4. I have a question on the exclusion list for this trial, what the heck is malignancy?
    "Prior history of malignancy unless an exception is granted by the Chief Investigator."

    ReplyDelete

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