Saturday, 30 November 2013

Beta-interferon in CIS 8-year follow-up

Early treatment delays cognitive progression. #MSBlog #MSResearch

"What do long-term extension studies tell us? They give us insights that are not necessarily obvious in the short 2-year pivotal trial. The one that stands out in this 8-year open-label extension study is that CISers treated immediately with IFNbeta had better cognitive outcomes at 8 years compared to MSers who had a delayed start on treatment. This is a very strong argument for early treatment. Treat early to delay the progression of cognitive impairment in MS. I have made the point in the past that in early MS cognitive impairment is the main driver of early disability in MSers; long before physical disability. If IFNbeta, which on average is only moderately effective, can have an impact on cognition if used early what impact will the more effective therapies have? Unfortunately, we don't have this data to hand, but all the efficacy data suggests they would have a major impact."
"Have you aligned all your ducks? 


Epub: Edan et al. Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry. 2013 Nov 11. doi: 10.1136/jnnp-2013-306222.

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in CISers with a first event suggestive of MS.

METHODS: In the original placebo-controlled phase of BENEFIT, CISers were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all CISers/MSers were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, CISers/MSers were enrolled in an observational extension study for up to 8.7 years.

RESULTS: Of the initial 468 CISers, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% were receiving IFNB1b. CISers originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated CISers. EDSS remained low over time with a median of 1.5 in both arms.

CONCLUSIONS: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in CISers with a first event suggestive of MS.

CoI: multiple


  1. What about the people who have delayed their treatment to participate in your trial? Will a 6 to12 month delay have an effect on their cognitive health?

    1. Re: What about the people who have delayed their treatment to participate in your trial?

      Not sure as we don't have data on what a 6 month delay in treatment will do. Some of those volunteering for our trial can't access DMTs as they are not eligible under current guidelines, some don't want to go onto injectables due to needle phobias and some are simply being altruistic in helping test a new strategy. The important thing is informed consent and a get out clause if their disease becomes clinically active (relapses). We took one trial participant out of the study to go onto a DMT after having a relapse. Trial participants are informed about the possibility of them being eligible for DMTs under the NHS and that they can withdraw from the study at any time. The latter is a standard ethical requirement for trials of this nature.
      Yes, in principle being in placebo-controlled trials or in proof-of-concept studies comes at a risk to the individual. This is the dilemma we face and is not unique to MS. This occurs in almost all disease areas; e.g. cancer patients are often asked to participate in a new trial comparing and unknown drug with a standard treatment with known benefits. Placebo-controlled trials are still being imposed on us by the FDA and EMA, although I suspect the regulatory authorities will be forced to abandon their stance with regard to phase 3 trials.
      At a population level a 6 month delay in starting treatment is nothing compared to what our current NHS England treatment guidelines are doing to MSers. We can only start DMTs in a minority of CISers (those who actually have MS under the McDonald guidelines) and we can only escalate treatment to more effective based on severe relapses and not MRI activity. In my opinion the smouldering MS problem is the elephant in the room.
      At the end of the day we rely on MSers volunteering for innovative clinical trials; without their participation the field will stagnate. We would not have the current DMTs without 1000s of MSers having volunteering for trials in the past. We should pause to thank them for getting us to this point.

  2. Thank you for the response. I am on the Charcot trial and I will see it through to the end if I can. Everyone I have come into contact with during the previous couple of months on the trial have been helpful and transparent and I also understand the decision to participate is mine alone. However, as a sensible adult I also need to weigh up the facts. When I read posts like this one, it worries me that my altruistic intentions will be detrimental to my health.
    I have not relapsed but as you know, in order to participate I need to have active lesions. Just because they are in less eloquent areas of my brain does not mean that damage is not occurring. That damn elephant again...

  3. One interesting element of this paper is that the median EDSS was just 1.5 in both arms, 8 years on. 1.5 is pretty minor on the spectrum of things - no walking difficulties etc. Technically "no disability - minor signs in more than 1 FS". That's not to under-estimate the impact of cognivite disability etc or to be complacent about MS but it should be somewhat comforting to newly diagnosed people. That's almost 500 new MS'ers with no disability on average, 8 years into their disease. This supports the notion that the natural history of MS is changing due to wider diagnosis and more mild cases being picked up, as well as DMTs - even older ones such as IFN - having a positive impact as well. Go back 20 years and it is unlikely the median EDSS of 500 people 8 years post-diagnosis would be so low.

    1. "This supports the notion that the natural history of MS is changing..."

      This study does not support a change in natural history as these MSers all ended up on treatment; one could argue it is the impact of the DMT. I would add the impact of early treatment with a DMT.

  4. I was diagnosed with a CIS in January. I’ve had two further MRI’s since with no progress thankfully and I’ve been fortunate to make a full recovery. I’ve fought for DMD’s since being diagnosed which has lead to changing neuro’s three times. I’ve finally been given the go ahead to start Rebif which is brilliant news but I don’t understand why I’ve had to fight tooth and nail when there is clear evidence it helps. I’m thankful I’m of stubborn character and strong enough to self advocate. Not everyone is and that worries me greatly.

  5. I couldn't agree more with this comment. It is a tragedy that all but the most fervent self-advocates will end up on inferior or no treatment and end up far more impacted by their MS than they need be. I noted one of Prof G's recent slide shows visually showing the population impact of widespread early, effective induction therapy. It changes MS from a disabling disease in the main to a disabling disease for just an unfortunate minority. I don't know how much of the stats in those slides showing a certain number of well people, certain number of mildly disabled and a certain number of more seriously disabled is based on actual data versus a gut feel for the kind of impact that could be made but it was striking. There are highly effective treatments now available for MS, that used early - ideally before the EDSS has moved far off 0 - would make a huge difference but they won't because of the problem identified above. I don't see NICE approving Alemtuzumab for NHS patients first-line at their request, given they require 2 'disabling' relapses just to start Rebif... It's such a shame - I honestly believe if everyone was given access to something like Alemtuzumab as a front line treatment, wheelchair use in MSers in 20-30 years time would be a rarity and the disease we're dealing with would look very different to today's.


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