Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Post by dlf » Thu 31 Mar 2016 7:14

Full text article is now available: There is also a tiny video at this link, (which given the journal's readership, I am scratching my head as to why they bothered to create it).

http://www.nejm.org/doi/full/10.1056/NE ... articleTop

Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Anneleen Berende, M.D., Hadewych J.M. ter Hofstede, M.D., Ph.D., Fidel J. Vos, M.D., Ph.D., Henriët van Middendorp, Ph.D., Michiel L. Vogelaar, M.Sc., Mirjam Tromp, Ph.D., Frank H. van den Hoogen, M.D., Ph.D., A. Rogier T. Donders, Ph.D., Andrea W.M. Evers, Ph.D., and Bart Jan Kullberg, M.D., Ph.D.

N Engl J Med 2016; 374:1209-1220
March 31, 2016
DOI: 10.1056/NEJMoa1505425

Patients with Lyme disease, which is caused by the Borrelia burgdorferi sensu lato complex (including B. afzelii and B. garinii in Europe), often report persistent symptoms.1 These symptoms are also referred to as the post–Lyme disease syndrome or chronic Lyme disease and may occur after resolution of an erythema migrans rash or after other — possibly unnoticed — manifestations of early Lyme disease, regardless of whether a patient received initial appropriate antibiotic treatment. Patients present mainly with pain, fatigue, and neurologic or cognitive disturbances.2,3

Previous randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects in patients with persistent symptoms attributed to Lyme disease.4-6 Nonetheless, the debate about this issue has continued.7 Although most guidelines do not recommend antimicrobial therapy for longer than 2 to 4 weeks,8,9 other guidelines recommend prolonged antibiotic therapy.10 We performed a randomized, double-blind, clinical trial (Persistent Lyme Empiric Antibiotic Study Europe [PLEASE]) that included three study groups to compare shorter-term treatment (ceftriaxone followed by placebo [placebo group]) with longer-term treatment (ceftriaxone followed by doxycycline [doxycycline group] or ceftriaxone followed by the combination of clarithromycin and hydroxychloroquine [clarithromycin–hydroxychloroquine group]).
There was also (predictably) another article written by Melia and Auwaerter citing this study in the same NEJM publication. The full text is available at the link, but I have included the first paragraph below:


Time for a Different Approach to Lyme Disease and Long-Term Symptoms

Michael T. Melia, M.D., and Paul G. Auwaerter, M.D.

N Engl J Med 2016; 374:1277-1278
March 31, 2016
DOI: 10.1056/NEJMe1502350
The condition of most patients with Lyme disease improves after initial antibiotic therapy; however, 10 to 20% of treated patients may have lingering symptoms of fatigue, musculoskeletal pains, disrupted sleep, and lack of customary mental functions. The plausible idea that additional antimicrobial therapy for potentially persistent bacterial infection would foster improvement has been a touchstone of hope in the 40 years since discovery of the disease in the mid-1970s. Patients with long-standing symptoms and well-documented, previously treated Lyme disease have been the focus of a number of randomized, placebo-controlled studies in North America that assessed whether additional antibiotic therapy offers a reduction in symptoms.1 Because molecular or culture methods did not find evidence of persistent infection in the enrolled patients, it was perhaps not surprising that additional antimicrobial therapy yielded neither clinically significant nor durable reductions in symptoms as compared with placebo.
To complete the information that I have found so far on this, there was also a Health Shots article from NPR:


Study: Prolonged Antibiotic Treatment Gave No Relief For Lasting Lyme Symptoms

March 30, 20165:01 PM ET

http://www.npr.org/sections/health-shot ... =hootsuite

For some people with Lyme disease, the illness seems to take a lasting toll.

Years after a standard two-week course of antibiotics against Borrellia burgdorferi or closely related organisms that cause the disease, these patients remain exhausted and foggy-headed. They suffer from chronic aches and pains and poor sleep.

In the last decade and a half, medical societies and some patient groups have fought over how to treat these people and also over the reasons why they don't get better.

Some doctors and guidelines recommend long-term antibiotic treatment for these Lyme disease patients. The National Institutes of Health and the Infectious Disease Society of America maintain, however, that prolonged antibiotics use doesn't help, and advise doctors to limit antibiotics to the initial course.

Results from a clinical trial published Wednesday in the New England Journal of Medicine support the recommendation against long-term antibiotic treatment. Researchers in the Netherlands randomly assigned 281 people with persistent symptoms who had been diagnosed with Lyme disease to three groups. First, though, all the people were treated with antibiotics for two weeks. Then, a third got a placebo, a third got one kind of antibiotic and the remaining third got different antibiotics for a period of three months.

At the end of the trial, no group of patients did better than the other. "They were not helped by prolonged antibiotic treatment," says Dr. Bart-Jan Kullberg, a senior author on the study and an infectious disease researcher at Radboud University in the Netherlands.

The study already has detractors. "You do a lousy study that's designed to fail, and you get a failed study. And that's basically what this is," says Dr. Raphael Stricker, a board member of the International Lyme and Associated Diseases Society , or ILADS, which advocates for the long-term use of antibiotics therapy.........
Rest of the article is available from the above link.
Last edited by admin on Thu 23 Jun 2016 13:57, edited 1 time in total.
Reason: Bolded and enlarged study and article titles and added white space for clarity.

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Re: Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)

Post by duncan » Thu 31 Mar 2016 14:45

1999 is calling. It wants its RCT back.

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Re: Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)

Post by dlf » Thu 31 Mar 2016 17:19

The most sensible response to this study and the resulting hoopla that I have seen so far was written by Lorraine Johnson on 30 MAR 2016.

LYMEPOLICYWONK: Chronic Lyme European PLEASE Trial—You know it’s spin when treatment “success” is called “failure”?

https://www.lymedisease.org/lymepolicyw ... d-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 by design. (Yet, to prove cause and effect, trials need to have some patients who do not receive any treatment or who are given a placebo.) But this does not mean that treatment with Rocephin did not result in improvement. It means they didn’t measure this.

For those who want the historic context for this article, in 2001 the NEJM first published a study by Klempner which 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 now sits on the editorial board of the NEJM is believed to have helped grease the skids for the publication of this study—which pays homage to his previous work.

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Re: Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)

Post by X-member » Tue 12 Apr 2016 18:45

A quote from the previous post:
clinical trial on chronic Lyme disease from Europe called PLEASE
Perhaps people from Sweden (where "chronic Lyme" stands for late borreliosis) understand this study better?

Långvarig antibiotika hjälpte inte mot borreliarelaterade symtom

http://www.dagensmedicin.se/artiklar/20 ... de-symtom/

A quote (professor Lars Hagberg say):
Deltagarna hade tidigare haft en bekräftad infektion av borrelia eller hade antikroppar i blodet mot bakterien.
The participants had previously had a confirmed infection of borreliosis, or had antibodies in the blood against the bacterium.
So some participants in this study could have had an active chronic borreliosis (i.e. late borreliosis), which may explain the effect of the first 14 day IV-treatment.

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Re: Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Post by admin » Thu 23 Jun 2016 13:46

I have split the previous 4 posts from topic Persistent Lyme Empiric Antibiotic Study Europe (PLEASE), because this published study needs to have a dedicated topic in "Published Studies".

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Re: Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Post by X-member » Wed 29 Jun 2016 19:46

Article from Norway about the Dutch study.

Ikke langvarig antibiotikabehandling ved sykdom tilskrevet borreliose


A translated quote from a comment, Dr Per Bjark (Norway), specialist in infectious diseases, say:
I do not think this article can be used for anything in the everyday of infectious diseases. What process that lies behind the publication in NEJM, is puzzling to me.

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Re: Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease

Post by X-member » Tue 14 Feb 2017 14:21

Dr Per Bjark Norway, 2016:

Re: No prolonged antibiotic therapy for disease attributed to borreliosis


A quote:
If we interpret the title’s formulation «symptoms attributed to Lyme disease» to mean that in reality, Lyme borreliosis is not involved, but rather various symptoms that the patients would like to attribute to this cause, there is hardly any disagreement between Eikeland and myself. I persist in my claim that the Dutch article includes patients who cannot reasonably be thought to have active Lyme borreliosis.

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