Thursday, 3 December 2015

Oestrogen and Glatiramer acetate when does failure mean success?

Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2015. pii: S1474-4422(15)00322-1. doi: 10.1016/S1474-4422(15)00322-1. [Epub ahead of print]

BACKGROUND: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.
METHODS: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.
FINDINGS: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 (1 relapse in 4 years) relapses per year (95% CI 0·17-0·37) in the estriol group versus 0·37 relapses (1 relapse in 3 years) per year (0·25-0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37-1·05; p=0·077)= NO DIFFERENCE. The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses (periods) were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.
INTERPRETATION: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.

So to do a 2 year trial involving 170 people took academia 7 years to achieve and reports that if you give oestrogen hormone supplementation on top of glaterimer acetate improved activity and they want to do a III trial to take this forward. 

However, hang on, when does failure become a success? In clinical trial land a trend is now beginning to say there was a difference but the statistics say this was all a failure and there was no difference between the groups P>0.08 = not different. But they say their aim was to get a significance of p=0.1 which is not significantly difference.  If this was the aim why start? Because the study is woefully underpowered.

A quick look on clinical trials.gov and I can see that the end point was relapse rate. Can someone show us where the significance level at 0.1 being a success was mentioned, besides in the write up. If it is there who were the ethics committee that allowed such guff as it is such a slipper slope to start on where you power your trials from failure.

The people doing the editorials are normally the people doing the reviews.   The editorial says "Sex hormones and multiple sclerosis:another informative failure".

What does it inform?. We need to get rid of "the trend" and put in real science and do proper trials that give definitive meaningful results...Yes this will probably come back to haunt me. 

So who is going to fund a phase III trial and the licencing for what appears to be a failure. If the relapse rate is 0.3-0.4 should we be aiming to use this or other drugs where the relapse rate may be 0.1-0.2.

I wonder how we can accept such drivel and make bad practise somehow good. I see "the trend" is leeching into the animal world as somehow being important. 

Be a mensch and say our study failed.

The peer review process sometimes make me despair and yes I am having a bad day because of this very process. 






26 comments:

  1. So to do a 2 year trial involving 170 people took academia 7 years - not that dissimilar to the Charcot Project! (A joke - my comment not the Charcot Project).

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    1. The Inspire Study took less than 7 years to complete. The study was negative in terms of the primary outcome. We will be presenting the results in a full at a scientific meeting next year.

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    2. Hold on....Charcot was negative???? Black swan dead?

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    3. My thoughts exactly. So why was Prof Gold hyping this up on the BBC? That is disgusting to falsely get hopes up.

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    4. Can you tell us more about Inspire failure?
      What does it means for virus in MS hypothesis?

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    5. So what was wrong? The hypothesis (it's not a virus after all) or just the drug which didn't get into the brain properly (so still a hope since there are many anti-virals to choose from)?

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    6. MouseDoc's CUPID trial was a similarly expensive and time-consuming study that failed epically. We don't give him a hard time about it.

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    7. The CUPID trial was nothing to do with the Mouse Docs. The study was based in Plymouth seeking to build on our experimental findings in mice in pwMS. Also to say it failed is not quite accurate as in a subset of pwMS there was evidence of a neuroprotective effect but the numbers weren't big enough to show significance.

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    8. Yes I agree with every thing that MD2 says, you are shooting the messenge. There was a significant benefit in people with and EDSS below 5.5 but who is going to do this trial again to test this? Nobody..... and so ten years of solid experimental work is flushed away.

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    9. Which is why we get frustrated with our clinical colleagues from time to time. This was hugely disappointing.

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    10. "Also to say it failed is not quite accurate as in a subset of pwMS there was evidence of a neuroprotective effect but the numbers weren't big enough to show significance."

      It sounds like Team G is looking for ways of P-hacking. If it was not significant it was a failure. You hypocrites can't bash others work while uplifting your own under the same circumstances

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    11. When one relies on the "anonymity" to criticize repeatedly because it is nothing but a coward ... If you have an idea, hypothesis better than can cause or leverage MS then mount a study, get funding and wait for the results, as these guys are doing rather more than many out there ...

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    12. I smelled a rat with the Charcot Project some time ago - hence my comment at the start of this thread. The lack of any updates over the last 6 months / lack of any transparency pointed to a negative result. It's the hope that kills you (as they say). Lot of excitement and enthusiasm at the research days I attended - I won't be attending another. Just makes me admire the contribution of Compston / Coles. No publicity / glitz - they ran with a good idea and patients like me and many others are experiencing the benefits. Would you put your money on the spasticity drug being a success? Sad day - this news should have been a proper post on its own.

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    13. "It sounds like Team G is looking for ways of P-hacking"

      Not at all correct the subgroup analysis was planned as part of the protocol.

      "If it was not significant it was a failure."

      The overall trial was a failure as we have said. This has nothing to do with us. As we said no one will do back to do the proper study. You sound like the narrow minded scientists that are two a penny.

      "You hypocrites can't bash others work while uplifting your own under the same circumstances".

      This is not our own work so you are talking rubbish!

      I won't be attending another research day....That is your choice it will save abit of cash! but if you spit the dummy when there is failure, then should we not try?. If you don't try you can't have success.

      However you need to understand the process, I suspect that with comments like yours you are more unlikely to get this explained and then you won't even know what to complain about

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    14. With all of the hype promoted on this blog about the Chorcot project you would have thought that a specific post would be generated to give notice of the failure.

      I remember G creating a post while he was vacationing on a beach in that he was equating himself to the innovators who created Google or some other amazing company.

      He probably still sees himself in this light as sociopaths cannot find fault within themselves and have the notion that they are leaders while reality says otherwise.

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    15. Maybe we just have to wait for publication of papers. Whilst the government want open access this does not mean dsiclosure before the paper is written and accepted and published

      May we should say that p=0.5 is success and then we can all be happy:-) So for trial we can flip coins

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    16. Try again, fail again. Fail better

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    17. at least we have the good news from prof schmeichel about cladribine

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    18. What News?

      He's got a job with Manchester United and Denmark:-) In goal., I guess I will have to wait until Prof Schmeichel spills the beans.

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  2. Re: "MouseDoc's CUPID trial was a similarly expensive and time-consuming study that failed epically. We don't give him a hard time about it."

    The amount of crap Team G has to endure is appalling. They must be tough-skinned.

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  3. hello
    I found this research into the pregnancy hormone interesting
    as I have read so many articles implying that during pregnancy
    MS stops. so can I ask as a man with MS will Estriol have the same effect in men
    as men don't get pregnant is there a male alternative to stop MS


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    1. If we give oestrogen to men they will be probaly get moobs.

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  4. Thank you all for your effort, I known that we patients are frustrated but there are no non patients as disappointed as this research team.

    Most of my life has been impacted by MS, from early memories I recall my mother being slowler than my gran and my own diagnosis last year. I do believe that we are getting closer to the cause every day. It will be something like:

    Genetic + EBV - Vit D + something = MS

    The below is interesting:

    http://www.medscape.com/viewarticle/854957

    Edison would say that we know one more way not to make a light bulb. Am convinced that some day soon we will see headlines that EBV is the most deadly virus in history.

    Nearly there.

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