Wednesday, 24 April 2013

Nutriceutical activity in MS trial?

Would you take omega 3 and omega 6 fatty acids? #MSBlog #MSResearch

Pantzaris et al. A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial. BMJ Open. 2013 Apr; 3(4).

OBJECTIVE: To assess whether three novel interventions, formulated based on a systems medicine therapeutic concept, reduces disease activity in RRMSers who were either treated or not with disease-modifying treatment.


DESIGN: A 30-month randomised, double-blind, placebo-controlled, parallel design, phase II proof-of-concept clinical study.

PARTICIPANTS: 80 participants were randomised into four groups of 20 each. A total of 41 (51%) MSers completed the 30-month trial. The eligibility criteria were an age of 18-65; a diagnosis of relapsing-remitting MS according to the McDonald criteria; a score of 0.0-5.5 on the EDSS; MRI showing lesions consistent with MS; at least one documented clinical relapse and either receiving or not a disease-modifying treatment within the 24-month period before enrolment in the study. MSers were excluded because of a recent (<30 days) relapse, prior immunosuppressant or monoclonal antibody therapy, pregnancy or nursing, other severe disease compromising organ function, progressive MS, history of recent drug or alcohol abuse, use of any additional food supplements, vitamins or any form of polyunsaturated fatty acids, and a history of severe allergic or anaphylactic reactions or known specific nutritional hypersensitivity.

INTERVENTIONS: The first intervention (A) was composed of Ω-3 and Ω-6 polyunsaturated fatty acids at 1:1 wt/wt. Specifically, the Ω-3 fatty acids were docosahexaenoic acid and eicosapentaenoic acid at 3:1 wt/wt, and the Ω-6 fatty acids were linoleic acid and γ-linolenic acid at 2:1 wt/wt. This intervention also included minor quantities of other specific polyunsaturated, monounsaturated and saturated fatty acids as well as vitamin A and vitamin E (α-tocopherol). The second intervention (B, PLP10) was a combination of A and γ-tocopherol. The third intervention (C) was γ-tocopherol alone. The fourth group of 20 participants received placebo. The interventions were administered per os (by mouth) once daily, 30 min before dinner for 30 months.

MAIN OUTCOME MEASURES: The primary endpoint was the annualised relapse rate (ARR) of the three interventions versus the placebo at 2 years. The secondary endpoint was the time to confirmed disability progression at 2 years.

RESULTS: A total of 41 (51%) MSers completed the 30-month trial. Overall, for the per-protocol analysis of the 2-year primary end point, eight relapses were recorded in the PLP10 group (n=10; 0.40 ARR) versus 25 relapses in the placebo group (n=12; 1.04 ARR), representing a 64% adjusted relative rate reduction for the PLP10 group (RRR 0.36, 95% CI 0.15 to 0.87, p=0.024). In a subgroup analysis that excluded patients on monoclonal antibody (natalizumab) treatment, the observed adjusted RRR became stronger (72%) over the 2 years (RRR 0.28, 95% CI 0.10 to 0.79, p=0.016). The per-protocol analysis for the secondary outcome at 2 years, the time to disability progression, was significantly longer only for PLP10. The cumulative probability of disability progression at 2 years was 10% in the PLP10 group and 58% in the placebo group (unadjusted log-rank p=0.019). In a subgroup analysis that excluded patients on natalizumab, the cumulative probability of progression was 10% for the 10 patients in the PLP10 group and 70% for the 12 patients in the placebo group, representing a relative 86% decrease in the risk of the sustained progression of disability in the PLP10 group (unadjusted log-rank p=0.006; adjusted HR, 0.11; 95% CI 0.01 to 0.97, p=0.047). No adverse events were reported. Interventions A (10 patients) and C (9 patients) showed no significant efficacy.

CONCLUSIONS: In this small proof-of-concept, randomised, double-blind clinical trial; the PLP10 treatment significantly reduced the ARR and the risk of sustained disability progression without any reported serious adverse events. Larger studies are needed to further assess the safety and efficacy of PLP10.


"Do you find these results interesting? Are they too good to be true? Possibly. The results are driven by the large number of relapses in the placebo group; 25 relapses is a large number. An AAR of 1.04 is an outlier in terms of contemporary trials, most current trials have AAR of less than 0.5 in the placebo groups. Will I be recommending Ω-3 and Ω-6 polyunsaturated fatty acids to all MSers in my care? No, the level of evidence in this study is not good enough to be confident that this trials result was due to a type 1 or false positive error. This is why regulatory authorities require two positive trials."


29 comments:

  1. Prof. G, but this does not explain that the pre-treatment ARR on the Group C of this study was actually higher than the placebo one (1.16 vs. 1.05)- This one was also higher than current average and nevertheless was significantly reduced.
    On the other hand, may I ask you your opinion on a similar Omega-3/ Omega-6 approach from the Iranian university of Tabriz? (based on hemp and evening primrose oil- See attached link- 6 month trial on 23 RRMSers with EDSS going down from 2.8 to 1.8)... http://bi.tbzmed.ac.ir/JournalIssues/AllIssues/Volume3Issue1/7201331.aspx

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    1. The oil groups in this study showed no effect. Study of n=10-12 verses n=23. This a problem as is provides no answers so more studies needed

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    2. MD, actually the so-called "PLP10" group (Group B) were treated as Group A (with PUFAs Omega-3 and -6) plus gamma-tocopherol (vit. E). This group showed the RRR of 0.28 compared to placebo during the 2.5 years, as well as a significative reduction in sustained progression. Indeed n=10-12 is low, but so is the p-value obtained (p=0.016). Adhesion rate was not good, agreed. I guess they do not have so much money in Cyprus to convince patients to stick to the trial, specially if no BP is behind to support it

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    3. The reason for non compliance is many fold although one may think that they did really have any significant drug induced side effects.

      Next thought is that the drugs were percieved not to be having effect and therefore people dropped out. This could then create real bias in data given that the N is so low.

      I would hope that people are not bribed with cash to stay on trials

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    4. Check out Figure 2 for drop outs per group, and the reasons why.
      A=8, B=9, C=10, D(placebo)=7

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    5. Ta
      The drop outs were reported to be pregnancy but mainly because the stuff tasted rank or stank. Medicines never taste good. If you thought it was doing you good would you deal with the smell and taste? After all people eat kippers:-)

      However, maybe they should not have used lemon oil to mask the smell and taste or maybe they should have encapsulated the oil such that it got into the stomach so smell and taste would not have been a problem. Doomed trial for minor problems with delivery.

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    6. So much you know, so much you say... Is that easy to encapsulate almost 20ml of liquid sample?? Are you ready to take a glass full of gel capsules?? lol

      If there are people like you... is it easy to make them believe that nutraceuticals can be good for them??? I doubt it.. But you are sure that if you eat then you will live; what is food all about??? a specially designed product? No, but it is supportive to the biggest miracle of all....life and living

      Food products and diet is good enough to make you live, talk, walk, run, and you are sure for that but it cannot be good for treatment because is not made in some ones bunch or laboratory, or because there is no profits for pharmaceutical companies behind it !!!! Isn't that tragic?

      Prof G is giving food for thought and nothing else... because I believe that there are answers in the paper for his comments as well.And do not take me wrong,,, I am with you on a productive discussion and exchange of thoughts but in a better manner that does not offend people and mostly the people that are spending their lives committed in our therapy and our quality of life. Do you have any idea of the amounts of $$$$ behind drugs and companies??? Search for it.Are they going to allow these kind of therapies to emerge? That is a serious question? Do doctors play the pharmaceutical companies game? I hope not. It us the patients and on us the duty to let science be open to us, research to be published, discoveries to find their way, and yes.... then it will be on us to decide... Our duty is to get informed, updated, educated, know our illness from the root and have an opinion for us... from us....

      my 2 cent

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    7. You are right about 20ml capsules...just need to take a few. If people will not take the drug because of taste then you have a real problem before you start.

      Maybe I take neutricuticals

      "....Isn't that tragic "Yes it is! we need a mechanism to develop alternatives.....

      Do you have any idea about the amounts of $$$ behind drugs...Yep

      Do doctors play the pharmaceutical game.. some do some dont'

      Are they going to allow therapies to emerge... Importantly are Governments going to allow therapies to emerge.

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    8. I believe now we are talking the same language moucedoc!!! In a wile we will both take nutraceuticals... hahaha

      2 cent

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    9. Maybe I am already :-)looking at some 1.5ml gelatin capsules right now so "13 a day keeps the doctor away"...I made marketing slogan already.

      It didn't report on any weight effects given that you are getting about 8% of RDA calorie intake. When DoctorLove did an oil study a few years ago she put on a few pounds (kg).

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  2. Trials of n=10 when 50% were lost from the study. I wonder if ethical review panels should allow studies that tantilise but tell us nothing except do it again in a lot more people and spend another 3 years.

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  3. I take fish oil instead because why not? It's cheap, and no one will want to pay for a large trial that would have enough power to show significance. I cannot imagine that these oils will have a large effect on the course of the disease. I also don't think that they will be successful in the marketplace. Look at AMRN's problems with launching their omega-3 drug for heart disease (Vascepa). They have positive PIII results, but debatable IP protection.

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    1. I will not say "why not" but the alternative response could be "why" when there is no evidence base, so hope you can understand why we cautious with nutriceuticals just as we would be with pharmaceuticals with this level of evidence.

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  4. I believe that the first three responses are without any depth, truth,or understanding of the published paper/work. If all they understand is what they are actually comment on, then they have not read the paper as a piece of science towards this frustrating,chronic disease therapy or they have just not understand science, or they have not read the paper but only the abstract. This is a pilot study with a strong indication that a specific formula can possibly be effective, much better than any existing drug and without site effects. Formulation is not just based on the omega oils but on something else as well. Go read it and find out. As a matter of fact oils alone had no efficacy! Scientists and authors ARE DISCUSSING MUCH MORE THAN WHAT ARE YOU TRYING to penalize. Let science go ahead.. Let people with MS have choices and hope of cure because what is out there is only games of pharmaceutical companies. Has any one of you read the papers on fingolimod or natalizumab?? There are so many suspicions and questionable issues associated with all of those studies and you are coming here with such a criticism..

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    1. How are the comments penalising....it is up to the authors to put some meat on these observations but to try an caste doubts on the studies of pharmaceuticals is not the way to do it two wrongs do not make a right.

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    2. Authors by no means are suggesting for any one to go and buy PUFA, use it tomorrow as a drug or suggesting that they have resolved the multiple sclerosis therapy issue. They are just publishing a piece of a scientific work and clearly post all the limitations of it. Moreover, they are by themselves suggesting for a larger size trial. It is my opinion that the paper is well presented, with a strong background on all of the ingredients supporting the possibility of this intervention to be possibly a good therapeutic candidate. For more than a century scientists are talking for the possibility of some of these ingredients as possible therapeutic agents but the correct formulation was missing. We all should be grateful that scientists are considering several different therapeutic approaches of the disease and new type of therapies are coming in the game.
      If we are to do a criticism just for the sake of criticism then that is penalization. What someone expects out of these scientists, maybe not to publish their results ....don't we have the right to know the advances or not around our disease. These numbers you are talking about and criticize (within this paper) are MS patients and they were participating for the advances of sciences and we better give them some respect. You are talking about ethical issue of the study. Have you really read it?? Really, is there any ethical issue? I really really doubt it,,, go and read it please. Believe me there is science out there and possible therapies can emerge from places that you cannot imagine. I do not care where is, or what is Cyprus, the only think I know is that there are scientists out there working for me and my therapy.. This is what is all about. For you, stick on your world and on your criticism but at least pray for us and for some scientists like these ones that you all are ready to make them regret dealing with our disease, our good well being and quality of life.

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    3. "If we are to do a criticism just for the sake of criticism then that is penalization"

      The authors state that they could not do power calculations but intuitively such a small sample size could be a problem. The authors admit that possibility. But it is therefore appropriate that prof G mention this. They did apparently get 20% of available people in Cyprus into the study. This is open access and you can all read the paper.

      As to ethical issues, you have your opinion I have mine. The study was ethically reviewed and approved.

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    4. "For you, stick on your world and on your criticism but at least pray for us and for some scientists like these ones that you all are ready to make them regret dealing with our disease".

      We are no executioners, you sound like you believe we are some thought-police that have control what other people do...dream on!

      I think the authors are sufficiently capable to take any constructive critisism, they know what the next stage will need to be already and we do not need to tell them that. The no repeat and bigger studies, this study should help them do that although they may need to go more global to get enough Msers. However that needs to be done before people should be encouraged to take this treatment. While the data appear encouraging, you have been here before.

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  5. "It is a pity this study did not include MRI as an outcome measure;"
    Check out Table 5: 64% reduction of new/enlarging T2 lesions (80% excluding Tysabri patients)

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    1. Prof G must have missed it he was just out of bed when he posted the comment

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  6. Just so you know we are not anti-fatty acids/oils and have our own data on this.

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  7. How do you account for losing 48.75% of study participants? Eighty participants is a very small cohort for a double-blind study involving four groups, but 30 months later there are just 41. It is hard to say that there is any validity to a study so small, especially if one has no explanation for the reason(s) that 39 participants exited the study, and ultimately, at study's end, it would be useful to know to which groups the withdrawn members had been assigned. This could be really fascinating to see this research done on a large scale, perhaps for a shorter time frame which might lessen the drop out rate (just theorizing...).

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    1. Giving my 2 cents after reading the paper for 6th time, carefully and with searching at times. Figure number 2 has all the details for drop outs and they are also discussed within the paper. Even thought this is a small size study the length of a study is a factor supporting somehow the truth behind results (statistics supports this). There are numerous valuable trials with 8-15 participants per treatment arm. There is a table perfectly answering your quote "to which groups the withdrawn members had been assigned". Moreover, statisticians say that when there is significance difference then how big or small is the p value does not matter.
      Importantly, if we go back and search for the same stage of development on interferons, natalizumab, fingolimod, BG12 etc the number size do not deffer much ..and this says very much....
      Authorities accept results from even less number of participants when the design and protocol of the study is well and appropriately performed; and this is another issue supporting these findings as nobody has anything to say on this study quality. It was very well done. Much better explained, defined and analyzed vs the most that come out of the industry.
      Moreover, surging on the authors, a next stage of development is on process. They are recruiting for a phase III multicenter, randomized trial, including MRI study the "MINERAL" study.. That says very much to me. That these scientists surely believe on the product.. We are going to wait with a very much of interest ..

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    2. As is mentioned the reasons for drop out are pregnancy and that the drug tasted and smelled bad so rank and stank

      There are are stats and there are stats, type i and type ii errors you say something is different when it is not or say something is the same when it is not.

      Authorities accept results from even less number.....please give examples. But lets congratulate the authors on getting the phase III going, I wonder what happens after that are seven seas, etc. going to pay £100,000 a year to hold the licence for the mixture

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    3. Would authorities want a second trial? Just as they would ask that of pharma

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    4. http://www.controlled-trials.com/ISRCTN06166891/

      MINERAL (Magnetic-resonance Image of Nutraceutical Efficacy on Relapsing-ms Autoimmune Lesions) study: A novel nutraceutical formula PLP10 for the treatment of relapsing-remitting multiple sclerosis

      Multicenter Phase IIIa interventional randomized double-blind placebo-controlled parallel clinical trial of efficacy and safety

      During on intervention treatment it is strongly suggested for the patients to continue only on the interferon beta treatment. If a patient changes therapy to immunosuppressant or monoclonal antibody or fingolimod or any other treatment on physicians’ decision then he/she will be considered as a drop-out; but continue to be medically followed for the intention to treat analyses purposes.


      The target number of participants across all arms and all sites is 200. There are three arms.

      The intervention dosage: 20 ml, per os, daily, 30 minutes before dinner, for the six months normalization period and for the 24 months on-treatment period (total 30 months). A 12-month extension, free of drug (washout) period is included in the clinical trial design.




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    5. Yes MouceDoc lets congratulate them and all the best.. There must be a way of patenting and keep all those wolfs out of the game.

      But I believe they are talking for only two arms. One for placebo and one with the intervention but total MSers have to be on interferon treatment already.. I believe that is for ethical purposes.

      Good luck to them and lets wish them for the best; here will be waiting for the "good" news.

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    6. This has to be a joke right!! The first and last author have no other publications so zero scientific output! They own the company which makes and will sell the nutritional supplement so they have vested interest to show it works! This study cannot be taken seriously since I very much doubt it was truly double blind. If the multicenter trial is a success, which I doubt, then maybe its not snakeoil but it smells like it!

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    7. You are out of luck Anonimous (above) because...... you have no idea how to search.. Both of them are very well established scientists with multiple scientific number of publications and not only!!!!

      We better be little bit more careful on this...

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