LYMEPOLICYWONK: Chronic Lyme European PLEASE Trial—You know it’s spin when treatment “success” is called “failure”?
Today a widely anticipated clinical trial on chronic Lyme disease from Europe called PLEASE was published in the New England Journal of Medicine (NEJM). The press has given the trial a twenty trumpet salute with a MedPage headline reading “Long-Term Antibiotics Fail Again in Lyme Disease–Focus on Lyme and antibiotics for persistent symptoms called unhelpful.” Here’s the thing—the findings of the study actually support retreatment. What gives?
This study found that all patient groups improved with IV Rocephin/ceftriaxone and there were very few serious adverse events associated with treatment. So how can the authors or the press spin this trial as a treatment failure. It’s all in how you define success.
Here are the key points:
- The study found clinically important improvement in all patient groups after two weeks of IV Rocephin.
- Some patients also received oral antibiotics after the IV treatment—these patients did not do better than those who only received IV Rocephin.
- There were very few serious adverse events.
- 9 patients out of 205 (3.2%) had a serious adverse event
- 5 of the serious adverse events were related to IV Rocephin.
- 4 of the these were drug allergies. (Rocephin is related to penicillin, which has a higher rate of allergic reactions.)
- No catheter (IV line) infections occurred.
Other important points to note:
- Clinically important improvement was considered to be 3 points improvement on the SF-36 (which measures quality of life). The mean improvement was 4.6 points! (Note the Klempner trial has been criticized for requiring 2 times this rate of improvement to qualify as treatment success.)
- There was no placebo because it was deemed to be unethical not to treat patients who may be infected. Because the study was designed without a placebo, treatment response of the three groups treated with IV Rocephin cannot be compared to patients who did not receive treatment.
- These patients are very sick. At baseline, patients had a poor quality of life as measured by the SF-36. (50 is considered normal. These patients were 32.)
- This is a study of Lyme disease in Europe, which is caused by a different strain of Borrelia—which has a different course of illness than US strains.
How should we define success? These authors were comparing 2 weeks of IV Rocephin against 2 weeks of IV Rocephin followed by oral antibiotics. They found no difference between those who received additional oral antibiotics and those who did not. So maybe the oral antibiotics aren’t adding much or maybe they were the wrong oral antibiotics or maybe they weren’t given long enough. Who knows?
The fact is that all of the patient groups received IV Rocephin and all groups had clinically important improvement. Shouldn’t that be the headline?
I hate to say the authors were mealy mouthed in their analysis, but let me provide their quotes and a translation free of spin:
At the 14-week visit at the end of the treatment period, the mean SF-36 physical component summary score had improved significantly from baseline regardless of the study group assignment, but quality of life remained below that of the general population.
This means that patients improved (actually significantly) but were not yet well. This will not surprise Lyme patients—
Whether improvement in the SF-36 physical component summary score at the end of the treatment period is a beneficial effect of shorter term antibiotic therapy or a nonspecific effect caused by the low level of baseline functioning, expectations associated with treatment, or placebo effects remains unclear, because all the patients had received 2 weeks of open-label antibiotics before entering into the longer-term randomized study-drug or placebo phase.
This means all groups received IV Rocephin and all groups had significant improvement. The study did not include a placebo-only group by design. (Yet, to prove cause and effect, trials need to have some patients who do not receive any treatment or who are given just placebo.) But this does not mean that treatment with Rocephin did not result in improvement. It just means they didn’t have a true placebo group.
For those who want the historic context for this article, in 2001 the NEJM first published a study by Klempner that has been used to deny Lyme patients treatment for the past 15 years. That study also was published to fanfare, with headlines reading “Chronic Lyme Disease Symptoms Not Helped by Intensive Antibiotic Treatment”. A later critique of the Klempner trial pointed to the premature termination of the trial before reaching full recruitment. The critique by DeLong and colleagues found that the measure of success (7-9 points of improvement on the SF-36) was far too high a mark to set for success. (Note in the PLEASE study, success was set at 3 points based on a pilot study of the minimal clinical improvement unit.) Klempner (who sat on the NEJM editorial board as recently as 2012) is believed to have helped grease the skids for this publication–a study that pays homage to his previous work.
The LYME POLICY WONK blog is written by Lorraine Johnson, JD, MBA, who is the Chief Executive Officer of LymeDisease.org. You can contact her at email@example.com. On Twitter, follow her @lymepolicywonk. If you have not signed up for our patient centered big data project, MyLymeData, please register now.
Berende A, ter Hofstede HJM, Vos FJ, van Middendorp H, Vogelaar ML, Tromp M, et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. New England Journal of Medicine. 2016;374(13):1209-20. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1505425.
National Institute of Allergy and Infectious Disease. Clinical Alert: Chronic Lyme disease symptoms not helped by intensive antibiotic treatment. June 12, 2001.
Klempner M, Hu L, Evans J, Schmid C, Johnson G, Trevino R, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. The New England journal of medicine. 2001 Jul 12:85-92. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11450676.
Delong AK, Blossom B, Maloney E, Phillips SE. Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo-controlled, clinical trials. Contemp Clin Trials. 2012 Aug 19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22922244.
Walsh, N. “Long-Term Antibiotics Fail Again in Lyme Disease–Focus on Lyme and antibiotics for persistent symptoms called unhelpful. ”http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/57044?isalert=1&uun=g479078d4949R5575556u&xid=NL_breakingnews_2016-03-30
- March 31, 2016 at 9:44 pm
Lorraine, This article only confirms my label of establishment medicine. I call it the Mafia criminal medical establishment. I used to blame it on the individual doctors. I still do when they refuse to listen to patients. However, i know most doctors, dentists, are brainwashed in medical, dental school. I have a science degree BS, and I had a tremendous amount of extra science credits than needed to graduate. I was brainwashed too, but did not realize it. I even made fun of my son for all his health foods and herbs. He was sick and establishment doctors were cruel to him, and so was I. He figured out on his own how to survive. I was cruel until, I began to suffer seriously from Lyme. They had given me prednisone when I was carrying my last to children. They were treating the symptoms, and Lyme passed to those two children. I was cruel too. Do we all have to get Lyme to wake up to the facts. I hope not. I hope future generations are smart enough to listen to the facts when facts stare them in the face. Most, if not all, LLMDs, are Lyme victims too. Again, do we all have to learn by debilitating experience. Change the schools to real science, and then people, doctors, dentists will wake up. Schools are the reason we hit such a brick wall in trying to make the world aware of devastating Lyme. Such a shame, and unacceptable.
- April 1, 2016 at 6:28 am
Thanks for your detailed deconstruction of a study designed by what we might refer to as the international Lyme establishment, including NEJM itself.
Another flaw of this study, in my opinion, is that neither of the two oral antibiotic regimens included tinidazole. This antibiotic showed the highest kill rates for both the spirochete and round body (dormant) forms of Lyme bacteria in a paper by Sapi, Stricker, and colleagues (Sapi et al., Evaluation of in-vitro antibiotic susceptibility of different morphological forms of Borrelia burgdorferi. Infection and Drug Resistance. May 3, 2011.)
Tinidazole tracks to bacterial DNA and disrupts it by means of nitrosative stress whether or not the bacterial form is active.
This property, when used in combination with a second antibiotic that disables or kills spirochete forms, can prevent Lyme bacteria from playing “hide and seek,” which produces a more thorough way to go about reducing the burden of Lyme bacteria in its various forms, including L-forms and persister cells. Future studies of longer-term therapy for symptoms thought to be Lyme-related should factor in this key strategic concept in Lyme treatment.
- April 1, 2016 at 7:28 am
I don’t think I can stand to read this paper. They just keep repeating crappy designs and telling us the same thing as other crappy studies in the past. If these patients were not early catches, which presumably they were not or they would not have been given IV, then two weeks will not cure them. But they did get better, only to have real treatment fail to continue long enough.
As always when these things are trumpeted as scientific findings, I notice that a reasonably intelligent high school student could find the flaws. What does this tell us about the state of modern medicine and the journal editors and reviewers? It is frightening to think our lives depend on such people.
- April 1, 2016 at 5:26 pm
Did you mention co-infections? None of the patients were tested or treated for co-infections, and treatment for Bartonella is very different than for Borrelia. Do a search on PubMed and see papers on how significant co-infections are in the Netherlands. Not a small omission.
- April 1, 2016 at 7:14 pm
Iv Rocephin saved my life along with my ID MD and my LLMD. I’m not 100%, but way better than prior to treatment. So thankful for 12 weeks then another 5 weeks a year later.
- April 1, 2016 at 7:15 pm
This makes me cringe. Will this lead to further road blocks for the many, many, many folks who are currently suffering and those suffering, yet unable to find answers or a diagnosis? I consider myself lucky that I have been under the care of a physician who understands the complexities of this illness. I have been on many antibiotics for a year now, and now am also treating a co-infection with another medicine. I feel better than I have in years. I am in the last stretches of this illness, and I can now see hope! Hope for myself, and hope for my family and anyone else who suffers from this complex and life-changing illness. My Lyme went undiagnosed for maybe more than 26 years, by doctors….without the correct medical information. I had to look back through years of medical records to realize I had these symptoms for more than 25 years. There were several periods of long bouts of sickness, but Lyme was never even considered. When will this madness stop?
- April 2, 2016 at 1:04 am
Excellent investigation and analysis! Thanks ! We saw the same kind of analysis with the Klempner NIH study. Brenda must have used the same rules of misinterpretation! TOM
- April 2, 2016 at 8:19 am
My two children are in remission due to long term antibiotics. Thank you for sharing your analysis with us! So helpful when we have to defend ourselves.
- April 2, 2016 at 11:23 am
I posted my full comment on NEJM’s FB site, but I’m quite curious about their patient selection. I looked at the Appendix and noted that participants were chosen based on a positive IgG or IgM immunoblot regardless of the ELISA test. Is this an admission that the ELISA test is useless? Because based on US CDC standards, participants should be ELISA positive as well to be considered infected with Lyme disease. I would personally like to see the ELISA results for the patients used in the study.
- April 2, 2016 at 2:32 pm
..clearly science/research will never produce a good Lyme treatement study since many carriers of Borrelia have other confections and because one drug may not address the whole slew of pathogens; until we get better labs capable of diagnosing people accurately, all official studies of Lyme should be paused–they waste everybody’s time and actually add to people’s suffering……..and people with chronic infections such as Borrelia with multiple confections deserve to be treated empirically, based on signs symptoms and also private lab results (Igenex etc.)…it is madness! …by the way, the Economist magazine published an article about up to 30% all medical studies being manipulated
- April 3, 2016 at 4:41 am
Two SF-36 charts from the published data adjusted to the more usual 0 to 100 scale, a bit easier for doctors and patients to understand. They also make the difference between baseline and outcome clearer – raising the question: what researcher would use a scale which minimises a treatment effect?
- April 5, 2016 at 4:26 pm
I’m waiting for their next study treating end stage Cancer patients for pain. All patients were treated with aspirin for 12 weeks, and almost all reported little relief as compared to placebo. Therefore, the headline will read “Painkillers useless in treating pain in end stage Cancer patients”.
- April 6, 2016 at 9:40 pm
You are so very right. Cancer patients are abused too. Treated, but not properly, until they run out of money in many cases. I watched cancer patients so abused before I ever had Lyme or even knew what Lyme disease was. I will say that Lyme patients are more abused though. There are a very few gems out there though, I had one of those conventional gems. He was a wonderful doctor and human being. And this exceptional man enabled me my Lyme treatment. He had a number of Lyme patients that he helped.
- April 9, 2016 at 7:54 pm
I think you might have missed my point a bit. I wasn’t commenting on cancer treatments, flawed as they are. I was commenting on the fact that whenever some antibiotic is used in a Lyme study, instead of the headline being that a certain antibiotic failed to cure chronic Lyme patients, its always generalized and states something like “Medical treatment useless for Chronic Lyme”, instead of what it should say “12 weeks of doxycycline not effective for Chronic Lyme”, which of course we all knew long before this study was ever published. But doing bogus Lyme research is what all the Lyme bullies are so very good at, having had 40 years of practice, so that’s what we get. Sociopaths have incredible stamina!
- April 10, 2016 at 1:19 pm
Hi Anon. I totally agree with you, especially that sociopaths have incredible stamina! My tortured Lyme brain can get things mixed up.
- April 10, 2016 at 2:59 pm
Everyone please understand the importance of preventing Lyme bacteria from playing “hide and seek.” When we use antibiotics that cover the spirochete form and the three dormant forms (round bodies, L-forms, and persister cells), we are on track to making real progress against an immune evasive infection otherwise capable of surviving antibiotic challenges. This is what the Lyme establishment is missing. It makes all the difference, and I very much wish I had the financial help needed to prove it. I am getting strong results with oral antibiotics alone that implement this strategy. If you can find a way to help I will be most grateful.
- June 2, 2016 at 8:12 am
I do not entirely agree with this conclusion.
I come from the Netherlands, where this study was done, I am an advocate for patients and I think a longer or stronger antibiotic treatment can be very important because no lymepatient is the same an Lyme persists.
Also in patients with nonspecific and subacute symptoms.
However, there is no question of spin.
The study design is not illogical.
ILADS has shown itself that the study of Klempner was in design of poor quality and that he was, so the Klempner protocol was repeated and does not work for chronic Lyme.
Donta published himself:
“Tetracycline: after 2 months of treatment, 33% of the patients ‘conditions were Significantly improved (degree of improvement, 75% -100%), and after 3 months of treatment, 61% of the patients’ conditions were Significantly improved.
Although this approach is relatief simple and inexpensive, it needs to be validated by controlled clinical trials comparing longer terms of therapy with short terms of therapy.”
That is exactly what has been done by the Dutch research group.
“Clarithromycin: 80% of patient’s self-reported had improvement or 50% or more at the end of 3 months. After two months of treatment, 20% of patient’s felt markedly improved (75-100% of normal); after 3 months of treatment, 45% were markedly improved.”
So according to Donta, even 80% improvement /healing within 3 months for chronic Lyme. That are precisely the dates where the Dutch study is based on.
One can not now argue that it is a useless trial, than the Donta studies should be repealed as incorrect.
His publications are examined, publications that also ILADS often refers, and it has shown that his conclusions are incorrect.
We as patients now know more, namely three months Donta protocol does not work for chronic Lyme.
I’m certainly not agree to exclude long-term treatment with this study. Therefore the study design was too limited, because more prolonged treatment and treatment with other protocols are not investigated, including long-term ceftriaxone. More follow-up studies are needed and improved diagnostics for active infection.
Our experience in the Netherlands was that 3 months of Klempner or Donta protocol, in practice, is not sufficient for chronic Lyme, that it is often a matter of much longer and also stronger treatment adapted to the disease duration and severity.
However, there is only examined in the Dutch study what is claimed by doctors.
So if it is otherwise in practice, these protocols and treatment durations should not be claimed as efficiently for chronic Lyme.
My experience is that the Donta protocol in a much longer duration can work in patients, I do not think it is a useless protocol, but too short. Plaquenil also need a long lead time for going to work.
- August 31, 2017 at 9:03 pm
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