Sunday, 18 May 2014

Pegylated Interferon another placebo trial in RRMSers

Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A; for the ADVANCE Study Investigators.Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 . pii: S1474-4422(14)70068-7. doi: 10.1016/S1474-4422(14)70068-7. [Epub ahead of print]

BACKGROUND:Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis.
METHODS:We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399.
FINDINGS:We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common.
INTERPRETATION:After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments.
 
Adding PEG (a type of anti-freeze) onto the  interferon beta can make it hang around longer and so you don't need to inject it as often but it still works and side effects are there. ProfG has reported on this study in the past and on the licencing

I wonder if a non-inferiority trial against standard interferon would have been more ethical than a trial against placebo. 

Surely this would have told the company, if their new drug was as good as its own beta interferon product it was hoping to replace. Obiviously they were not willing to risk this on the off cahnce its worse. Without a head to head how do we know?

This would not have destined 500 people (on placebo) to accumulate some damage because of the attacks they would invariably have. 

Surely it is time for the regulators and ethics committees to get some spine and say time to stop the placebo for RRMS. Maybe neuros need to take some affirmative action and question whether it is unethical to recruit in their neck of the woods, because it is not so much ADVANCE as BACKWARDS as far are MSers are concerned. Some may say this allows some who would slip through the current treatment net due to restrictions say from NICE, to access drug. Many of the study participants however may not have such an easy fall back position.

Whilst it is clear it is easier to see an effect against nothing, surely this situation cannot continue.....What do you think?

16 comments:

  1. Do a network meta-analysis

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  2. This is the same drug with PEG attached to increase half-life. Optimal drug levels and relapse rate with standard interferons should already be known. This seems to be simply a question of finding the appropriate dosing schedule. Placebo comparator? Why? Does pegylation effect interferon activity?Pegylated interferons are/have been in use for HCV infection.

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  3. In reality, finding any significant difference between the pegylated interferon and the normal interferon in a two year trial is not likely to present itself. Likewise this small difference is not going to have any implications for longterm success.

    If it was me and I had the choice to be in this trial and had no other options, I would jump at the chance to get on the new drug knowing that I would have a 50% chance to be in the placebo arm.

    In an ideal world, everyone would be diagnosed quickly and have access to effective drugs. But this is the real world and not everyone has this privilege. The question is would the drug manufacturer conduct this study with the two different interferon formulations in a country that has poor access to ms medications? If the answer is yes than a placebo should not be used as a comparator. Unfortunately, the answer is probably no in all cases.

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    1. So enticing the have nots....nice one...maybe more reason for the regulators to get some spine and do something for the have nots in Society. As Steve S says it should be a no brainer what the result would be. You can't really blame pharma here for preferring to do the easy route...so state sponsored guinea pigs..

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    2. Why not cut all superilous EAE research and shift that money to give the have nots the best drugs. It would be money much better spent. You're not the only one who can live in a fantasy world.

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    3. They have already However whilst it may be science fiction it is the future.

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    4. To have everyone on the planet access to equal healthcare is a noble goal, but I don't think it is going to happen anytime soon.

      If a drug is available to a person only through a placebo controlled trial it maybe their only option. The odds are those on placebo will be switched over to the active drug after two years and remain on it for the longterm extension studies. If you ban placebo controlled trials, this option will go away.

      Time to keep it real.

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    5. Good point...however tell that to the people who get disability because of this.

      Yes you should do trials but we now have 9-10 drugs known to work some better than others. This is saying you can't assess whether a drug is working if there is no placebo group. In the age of highly effective DMT you don't need a placebo to know if they are working or do you? If your drug is not inferior to a drug you know works then surely it works and you don't need placebo.

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    6. Well, if all of these other highly effective treatments are available to the patients who wish to participate in a placebo controlled trial, why on earth would they enroll? It seems like the drug makers are looking for locations where ms medication is non existent. I don't think anyone in a country with adequate healthcare is going to enroll for a chance to be on an interferon.

      So, yes people on the placebo arm are likely to sustain damage but if there is no alternative it is better than nothing.

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    7. Belgium:
      Bulgaria:
      France:
      Netherlands:
      Romania:
      Spain:
      Serbia:
      Mexico:
      Ukraine:
      Greece:
      Colombia:
      Estonia:
      New Zealand:
      Czech Republic:
      Peru:
      Poland:
      Russia:
      Czech Republic:
      Peru:
      Germany:s
      Croatia:
      Georgia:
      Canada:
      United Kingdom:
      Latvia:
      United States:
      Chile:
      India:
      Romania:

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    8. Interferon must be better that what you have been proclaiming. What a turnout.

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    9. Trial sites so what is acess to DMT like in them.

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    10. Better than nothing. Still iz this ethical a non inferiority would show no difference and so drug should be considered active.

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    11. Well, if they are doing it in all of those countries I would say it is unethical if the patient has other options. I have to wonder why someone would sign up for the trial?

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    12. In some countries mentioned above no DMTs available via the healthcare system, in some only interferon biosimilars of very bad, awful quality (cinnovex, ronbetal, etc), so the only possibility to get DMT for people there is to get into the trial, and even Rebif would be great for them and definitely better then nothing.

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  4. The FDA's position on alemtuzumab with the FDA criticising the use of an active comparator won't do much to encourage this in future trials.

    Are placebo controlled trials accepted in heavily DMT prescribing countries (eg Australia)?

    As you suggest, this may be seen as acceptable by some in the UK.... and a 50% rate of receiving a DMT is higher than what I remember the prescribing rate being in various parts of the UK (think it was an avg of 40%, down to only 30% in Wales). I think we'll have sunk pretty low if we allow the horrendous UK prescribing rates as a justification for anything (other than complaint).

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