“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.”
|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.|
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.
“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):
- A diagnosis of definite multiple sclerosis
- Treatment with DMDs for at least 6 months
- EDSS score between 3.5 and 6.0
- No history of relapses in the preceding 6 months
- A history of slow progression of disability, objective or subjective, over a period of at least 6 months
- Age 18-60 years
- Pregnant or breastfeeding or unwilling to use adequate contraception.
- Participants who do not take a DMDs for MS.
- A clinical relapse or pulsed intravenous or oral steroids in the 6 months preceding the baseline assessment.
- 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.
- Infection with hepatitis B or hepatitis C or human immunodeficiency virus.
- Participants receiving other sodium or calcium channel blockers in the previous 12 weeks
- Exposure to any other investigational drug within 30 days of enrolment in the study.
- 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).
- Prior history of malignancy unless an exception is granted by the Chief Investigator.
- History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
- Past untoward reactions to Oxcarbazepine or carbamazepine.