Wednesday, 28 March 2012

Meta-analysis of randomised controlled MS trials

Epub ahead of printZintzaras et al.  Network Analysis of Randomized Controlled Trials in Multiple Sclerosis. Clin Ther. 2012 Mar 21. 

BACKGROUND: The optimal treatment of MS is not yet well-defined.



OBJECTIVE: To estimate the relative effectiveness of treatments in MS, we performed a network of multiple-treatments meta-analysis of randomized controlled trials (RCTs) for relapsing MS using three main efficacy outcomes: relapse-free patients, patients without disease progression, and patients without magnetic resonance imaging progression.

METHODS: We systematically searched PubMed and the Cochrane Central Register of Controlled Trials to identify English-language articles with RCTs that compared pharmaceutical treatments using the terms multiple sclerosis and randomized controlled trial. All RCTs that involved patients with definite relapsing MS and provided data for calculating the odds ratios for the main outcomes were considered. First, comparative effectiveness relative to placebo was assessed using direct analysis. Then, each therapy was compared with interferon beta-1b (250μg) in direct and indirect analyses. Effect sizes were estimated by applying a random-effects model.

RESULTS: We identified 4165 titles; after screening, 109 articles were eligible for inclusion. In total, 26,828 patients were included. The network consisted of 145 treatments involving 59 direct comparisons with placebo and 8 direct comparisons with interferon beta-1b (250μg). Two treatments showed better response compared with placebo (direct analysis) for all three efficacy outcomes: natalizumab (300mg) and fingolimod (0.5mg). In comparing treatments with interferon beta-1b (250μg), the network analysis revealed that no therapy shows better response for all 3 efficacy outcomes and alemtuzumab, 12 and 24 mg, have better response for 2 of the outcomes (relapse-free patients and patients without disease progression).

CONCLUSIONS: Although some treatments seem to have better efficacy, the results should be interpreted with caution because the network was dominated by indirect comparisons. Data from the selected studies included in the network cannot be extrapolated beyond them. Large RCTs that make head-to-head comparisons between treatments are needed to draw safe conclusions for the optimal treatment of MS.

"Did we need a meta-analysis to tell us that Natalizumab, Fingolimod and Alemtuzumab are more efficacious than interferon beta-1b and that glatiramer acetate and interferon beta-1a are similar in efficacy to interferon beta-1b? Almost certainly not!"

"The good news is that we are entering an era were will have access to therapies which are on average more effective than interferon beta and glatiramer acetate. I am sure that these treatments will make it easier for us to assess the impact on suppressing relapses on disease course. I have little doubt that MSers on these therapies will do better in the long-term."

16 comments:

  1. Correct me if I am wrong here, but Alemtuzamab is not currently available on prescription in any country for MS. It has side effects that are of major concern, it may not even become a prescribed drug for MS. Seems a little disingenuous to give the big tick to a drug that does not have a life outside of clinical trial. Even if it appears to be the "poster drug" for the Brits!

    I thought the trend was starting to move away from 'autoimmune' to viral causation in MS.

    And you really wonder why CCSVI seems attractive ( although not for me) when there is this persistence to embrace immunosuppressive medications.

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  2. I’m sure I’m misunderstanding this, (I haven’t access to the full text), but…

    ‘Two treatments showed better response compared with placebo (direct analysis) for all three efficacy outcomes: natalizumab (300mg) and fingolimod (0.5mg).’

    Does this mean that these are the only two treatments that were shown to be better than placebo across the three outcome measures?

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  3. Re: "Seems a little disingenuous to give the big tick to a drug that does not have a life outside of clinical trial."

    Alemtuzumab is available outside trials.

    A lot of clinicians have been using this drug off license, for many years, and across the world. I am aware of off-license use on several continents.

    The phase 3 clinical trials are important for safety; we already know the drug is very effective. It is all about benefits and risks; a lot of MSers and their neurologists have decided the benefits outweigh the risks without waiting for the FDA and EMA to rule.

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  4. Re: "Does this mean that these are the only two treatments that were shown to be better than placebo across the three outcome measures?"

    No the relative reduction to placebo was better than that which occurs with IFNbeta-1b.

    In other words:

    IFNbeta-1b (Betaferon/Betaseron)= IFNbeta-1a (Rebif & Avonex) = glatiramer acetate (Copaxone)

    Nalatizumab > IFNbeta-1b (Betaferon/Betaseron)

    Fingolimod > IFNbeta-1b (Betaferon/Betaseron

    Alemtuzumab relative to IFNbeta-1a (Rebif) > IFNbeta-1b (Betaferon/Betaseron)

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  5. For MSers who have to pay for their own treatment (in developing countries) it might be a good idea to take Alemtuzumab now. After FDA approval it will be too expensive. At the moment it's probably cheaper than other DMDs.

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  6. Re: "For MSers who have to pay for their own treatment (in developing countries) it might be a good idea to take Alemtuzumab now. After FDA approval it will be too expensive. At the moment it's probably cheaper than other DMDs."

    I would not advise this. The reasons for doing clinical trials is equipoise; is the drug safe enough and whom should we use the drug. Until all the data from the trials is in the public domain and/or the regulatory authorities have made a judgement it is difficult to assess this. In addition the MSers who have been treated with alemtuzumab need to be monitored very carefully. Any deaths outside of clinical trials may make the regulatory authorities worried that if the drug is licensed it won't be used properly with adequate monitoring outside of clinical trials. It also puts your neurologist in an awkward situation; they have to be able to justify their decision of using a drug off-license if something goes wrong. With licensed therapies available this is difficult. An MSer dying from complications due to alemtuzumab therapy is potentially a medico-legal nightmare.

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  7. Re: "I thought the trend was starting to move away from 'autoimmune' to viral causation in MS."

    The answer to this question depends on who you ask. The majority of KOLs (key opinion leaders) still back the autoimmune hypothesis. Me personally am a viral man; the reason for this is ours and others work on EBV and MS. However, if you ask me how EBV causes MS I don't have a clue. But I plan to spend the rest of my productive research career trying to find out. I hope the funders of medical research allow me to follow this path.

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  8. Prof G, thanks for the clarification. I do not know any one being prescribed Alemtuzimab, in Australia ( not that I know every MS er, all 20,000 of us - but you may know a neurologist who does). I am certainly aware of it in current clinical trial in my own State. Alemtuzimab was only added to prescribing list here in 2006, and then for CCL, as far as I understand it the Cambridge studies into it's application to MS were commenced circa 2008. Maybe UK neurologists are more proactive? Is it the 'last case' option?

    On a another issue, I had a consult some months ago with one of the two MS researcher/specialists in this State to see if I was eligible for Tysabri - however because my MRI's continue to show no further progression over an eight year period - I was not be given a script for it - I did not actually want it - was just testing the waters and seeking an opinion from an MS expert. Although I would prefer to not to personalise the question - the point I wish to make is a bit about 'gatekeeping' and the differences in prescribing between neurologists around countries. If I was keen to get Tysabri I would be forced to 'doctor shop'. Something, I have issues with. I read this meta analysis and am wondering whether I should revisit the issue. In the end, I want it to be my choice what treatment I am prepared to take risks with - but where there is gatekeeping this is not possible. Your thoughts on neurological gatekeeping? Proactivity in the prescribing process?

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  9. As far as I'm aware, alemtuzumab was developed in the 1980's as a treatment for CLL(chronic lymphocytic leukaemia).Between 1991 and 2002 58 patients with MS were treated with alemtuzumab in Cambridge. The clinical trials developed from there. Althoug it has only finished phase 3 trials recently numerous patients have been treated with it in the US in particular, but also in the UK. Maybe it depend upon the legailities of your health system. In the Uk it is a licensed drug for CLL thus it can be prescribed by a physician as he sees fit, even for MS, either paid for by a PCT or privately.

    I've no idea about neurological gatekeeping

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  10. Re I would not advise (alemtuzumab):

    When would you advise off-license use? As you said, it is already being used for MS. I believe it is prescribed quite often.

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  11. Re: "When would you advise off-license use? As you said, it is already being used for MS. I believe it is prescribed quite often."

    Only under exceptional circumstances; i.e. lack of access to Natalizumab or anti-natalizumab antibody positive. Now that we have fingolimod available this is another option that needs to considered before using Alemtuzumab off-license. Mitoxantrone is another option.

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  12. Re: "In the Uk it is a licensed drug for CLL thus it can be prescribed by a physician as he sees fit, even for MS, either paid for by a PCT or privately."

    That is correct; but we in the UK are cautious.

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  13. Re: "Your thoughts on neurological gatekeeping? Proactivity in the prescribing process?"

    This is a problem, but is not surprising considering the cost of the DMTs. Healthcare budgets are not limitless; by setting national guidelines and licensing drugs for limited indications helps keep the lid on widespread prescribing of more effective treatments. On the other hand these treatments come with increased risks.

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  14. Re off label use: thank you for the reply.

    Lack of access to other treatments (because of expense) is why I suggested off-label alemtuzumab.

    Of course, you need a competent and careful neurologist in a good hospital who is willing to prescribe it.

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  15. I realise that alemtuzumab hasn't been approved yet by the various regulatory committees, but it has completed phase 3 trials, and those with aggressive RRMS will still have to wait 12-18 months for the paperwork to be done, when early aggressive treatment may be the best way to combat the disease. I don't believe you think that it will not be approved by the regulatory committees for aggressive RRMS, and its price as Lemtrada may be the only stumbling block with NICE.
    You suggest using Tysabri- with its known risk of PML, or Gilenya- with its unevaluated cardio risks, or mitoxantrone- with its cardiotoxicity and acute myloid leukaemia risks.
    All the more aggressive treatments have risk factors attached, and alemtuzumab's don't seem to be the worst of those already currently licensed for MS.

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  16. Beverley
    "All the more aggressive treatments have risk factors attached, and alemtuzumab's don't seem to be the worst of those already currently licensed for MS."

    This may well be that a lot less MSers have been treated with alemtuzumab so far than Tysabri or Gilenya. We'll have to see when more have been treated with alemtuzumab how its safety profile stacks up against the other two.

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