Resultaten PLEASE studie

[Josie]

De presentatie van de PLEASE-studie, zie: (15 minuten)
Anneleen Berende
http://eccmidlive.org/resources/persistent-lyme-empiric-antibiotic-study-europe-please-a-randomized-controlled-trial-of-prolonged-antibiotic-treatment-in-patients-with-persistent-symptoms-attributed-to-lyme-borreliosis--2


De samenvatting van de studie:

O150
1-hour Oral Session
Towards a better understanding of Lyme disease

Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) - a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis
A. Berende[1], H. ter Hofstede[1], F. Vos[3,4], R. Donders[3], H. van Middendorp[6,7], R. Kessels[6], H. Knoop[7], M. Vogelaar[4], M. Tromp[1], F. van den Hoogen[8], A. Evers[13,14], B. Kullberg[1]

1. Department of Medicine and Radboud Center for Infectious Diseases- Radboud university medical center, Nijmegen, Netherlands
2. Department of Medicine- Sint Maartenskliniek, Nijmegen, Netherlands
3. Department for Health Evidence- Radboud university medical center, Nijmegen, Netherlands
4. Department of Medical Psychology- Radboud university medical center, Nijmegen, Netherlands
5.Institute of Psychology- Health, Medical, and Neuropsychology Unit, Leiden University, Leiden, Netherlands
6.Department of Medical Psychology and Donders Institute for Brain- Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
7. Expert Centre for Chronic Fatigue- Radboud university medical center, Nijmegen, Netherlands 8Department of Rheumatology- Sint Maartenskliniek, Nijmegen, Netherlands


Objectives

Major controversy exists about the origin and treatment of persistent symptoms attributed to Borrelia. These symptoms, also referred to as post-Lyme disease syndrome, may follow an erythema migrans or other Lyme manifestations, and may persist despite primary treatment. The present study (PLEASE) is the first randomised, controlled trial in Europe to determine whether prolonged antibiotic treatment leads to better outcomes than standard treatment in patients with borreliosis-attributed persistent symptoms.

Methods

In this nationwide, double-blind, randomised, placebo-controlled study, patients were included with borreliosis-attributed persistent symptoms (e.g., pain and sensory or cognitive disturbances), either temporally related to a proven symptomatic borreliosis or accompanied by a positive B. burgdorferi IgG or IgM immunoblot. All patients received open-label ceftriaxone for 2 weeks and were then randomised (ratio 1:1:1) to blinded oral follow-up treatment for 12 weeks with doxycycline, clarithromycin combined with hydroxychloroquine, or placebo. Randomisation was computerised and balanced by minimisation for age, gender, duration of symptoms, and baseline Global Health Composite score of the RAND-36 Health Status Inventory (RAND SF-36). The primary outcome was the health-related quality of life at End of Treatment (EOT, week 14), assessed by the physical component summary score (PCS) of the RAND SF-36. Analysis of covariance, correcting for baseline PCS and gender, was used to compare the three treatment arms. Follow-up was performed at 26, 40, and 52 weeks. Secondary outcomes included physical and mental aspects of health-related quality of life (RAND SF-36 subscales), fatigue, cognitive performance, and physical activity.

Results

Of 281 patients randomised, 280 were included in the modified intention-to-treat analysis: 86 patients randomised to doxycycline, 96 to clarithromycin/hydroxychloroquine, and 98 to placebo. Baseline characteristics were similar in all treatment groups. The mean PCS was significantly improved at EOT compared to baseline (p<0.001, for all groups). At EOT, the PCS did not differ significantly between the three treatment arms (p>.05), and remained similar across the groups during follow-up until week 52 (p>.05). None of the secondary outcomes studied yielded significant differences between the groups. Adverse events were similar between groups (p>.05). Four drug-related serious adverse events occurred during treatment with ceftriaxone, and one during clarithromycin/hydroxychloroquine.

Conclusion

Long-term treatment with 2 weeks of ceftriaxone followed by 12 weeks of doxycycline or clarithromycin/hydroxychloroquine does not significantly improve quality of life compared to short-term treatment in patients with persistent symptoms attributed to Lyme borreliosis. (Funded by the Netherlands Organization for Health Research and Development; ClinicalTrials.gov: NCT01207739).

Josie

[Josie]

De officiële publicatie op 31 maart 2016 van de PLEASE studie in The New England Journal of Medicine, volledige tekst is hier te lezen:

http://www.nejm.org/doi/full/10.1056/NEJMoa1505425

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; 374:1209-1220March 31, 2016DOI: 10.1056/NEJMoa1505425

Josie

[Josie]

En de reactie hierop van Lorraine Johnson:
Zeer de moeite waard om te lezen!!

Kopieer en plak evt. in google translate: http://translate.google.nl/?hl=nl

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

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 now sits on the editorial board of the NEJM 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 lbjohnson@lymedisease.org. On Twitter, follow her @lymepolicywonk. If you have not signed up for our patient centered big data project, MyLymeData, please register now.

References:

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/quer ... s=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

Josie

[Sproetje]

Ik val van mijn stoel, er is géén placebo groep geweest.
De PLEASE studie onderzoekers vonden het onethisch en dat is het ook, als je ernstig ziek bent.

Maar ja, daarmee is de hele studie opzet van de baan.

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.

Maar waarom wordt er in eerste instantie in de pers afgegeven dat het een placebo gecontroleerde studie was?
Mag dat eigenlijk wel?
Dat is toch opzettelijk foutief informeren van de Nederlandse bevolking?

[abx]

sproetje ga maar weer op je stoel zitten.
Er was gewoon een placebo groep en dat staat er ook!

all the patients had received 2 weeks of open-label antibiotics before entering into the longer-term randomized study-drug or placebo phase.

Lorraine Johnson, JD, MBA, who is the Chief Executive Officer of LymeDisease.org

Het effect van 2 weken ceftriaxonIV werd niet onderzocht (want niet omstreden) dus daarvoor geen placebo nodig, de conclusie van PLEASE ging over het tweede extra antibiotica deel.

Wat de studie wel ongeldig maakt is de bevooroordeelde opzet van de studie. Objectiviteit van de onderzoekers is ook voorwaarde van een wetenschappelijke studie.
Als voor het eerste ceftriaxon deel om ethische redenen geen placobo groep wordt ingezet, maar voor de tweede aanvullende kuur wel, en dit laatste niet als onethisch vooraf werd gezien blijk hieruit dat men vooraf bevooroordeeld was over de uitkomst van extra antibiotica. Er is dan een perverse prikkel om de verwachte uitkomst te doen uitkomen om niet achteraf onethisch gedrag te worden verweten.

[Sproetje]

Ja, je hebt gelijk, ik schrok al.
Het gaat over het 2e gedeelte van de studie waar o.a. de doxycycline is gebruikt voor 12 weken oraal.
en de 12 weken met clarithromycin–hydroxychloroquine of een placebo.
Maar dat was NADAT iedereen al behandeld was met 14 dagen IV ceftriaxon

Intervention

All the patients received treatment with 2000 mg of open-label intravenous ceftriaxone daily for 14 days. Patients were admitted at the study site for ceftriaxone administration during days 1 and 2; subsequent doses were given intravenously by specialized home-care nurses. After the 2-week course of ceftriaxone treatment was completed, the patients received a 12-week oral course of doxycycline (100 mg of doxycycline twice daily combined with a placebo twice daily), clarithromycin–hydroxychloroquine (500 mg of clarithromycin twice daily combined with 200 mg of hydroxychloroquine twice daily), or placebo (two different placebo capsules twice daily), as randomly assigned in a blinded manner. The study drugs and placebo were prepared as capsules with an identical appearance. Active drugs were purchased as standard tablets through the hospital pharmacy department and were placed inside size 000 capsules; placebos were prepared by filling color-matched size 000 capsules with inactive microcrystalline cellulose. Adherence was verified by means of pill counts, patient diaries, and the Medication Event Monitoring System (AARDEX Group), in which microprocessors in the cap of a medication bottle electronically record each time a bottle is opened.13 The use of specific concomitant medications was prohibited during the entire study period, as described previously.11

Mijn buurvouw met longkanker doet mee aan een studie in Amsterdam: een immuuntherapie die men wil onderzoeken, daarin komt ook een placebo voor.
Eigenlijk mag je zieke mensen niet met een placebo behandelen, daarom dat na de studie iedereen die heeft meegedaan, gewoon de behandeling weer krijgt die regulier gegeven wordt.
Als de onderzoekers van de PLEASE studie het goed hadden willen doen, dan hadden ze de IV ceftriaxon beter NA het onderzoek kunnen geven, anders beïnvloed het toch de gegevens?

Bovendien, wat die doxy betreft, dat komt wel overeen met wat andere studies zeggen, n.l. dat doxy niet helpt bij chronische lyme patiënten, maar slechts de groei van de borrelia stopt, en alleen van toepassing is voor lyme, helemaal in het begin.

[abx]

Bovendien, wat die doxy betreft, dat komt wel overeen met wat andere studies zeggen, n.l. dat doxy niet helpt bij chronische lyme patiënten, maar slechts de groei van de borrelia stopt, en alleen van toepassing is voor lyme, helemaal in het begin.

Ja.

Als de onderzoekers van de PLEASE studie het goed hadden willen doen, dan hadden ze de IV ceftriaxon beter NA het onderzoek kunnen geven, anders beïnvloed het toch de gegevens?

Men wilde niet het effect van antibiotica testen (welke ab dan ook) maar het effect van extra antibiotica. De "beinvloeding" van een standaard korte kuur vooraf was dus nodig, gewild en voor alle groepen hetzelfde.

Verder zullen de meeste patienten wel door hebben of ze wel of geen doxy krijgen, ivm uv-overgevoeligheid hierdoor. Thus into the bin PLEASE.

[Sproetje]

Prof Ahern:

“…the study was not designed to provide new knowledge. It was designed to perpetuate existing dogma. …wouldn’t a more cost effective and scientifically useful approach be to try something new?”

“The PLEASE article does conclude that patients with “Persistent Lyme” have a very poor quality of life. At least they got that right.”


http://www.poughkeepsiejournal.com/stor ... /82750826/

[abx]

http://www.poughkeepsiejournal.com/stor ... /82750826/

Heel goed argument van Ahern:

In the PLEASE study, statistically significant improvements in symptoms occurred during the first “open label” phase of the study in all of the patient groups. These improvements leveled off once the study advanced into the “randomized” phase with oral antibiotics, leading to the conclusion that “long-term” antibiotics gave no relief. The authors considered the “open label” phase to be a “short-term” treatment.

Except the study design only included people who had been diagnosed and previously treated for Lyme disease. Therefore, shouldn’t it be noted somewhere in the article, press releases, or media coverage, that the IV antibiotic re-treatment of patients with “Lasting Lyme,” produced significant improvement in their debilitating symptoms?

What might have happened if the “short-term” IV treatment had been continued for longer, or if it had been administered in a non-continuous dosing process? We’ll never know, because the study was not designed to provide new knowledge. It was designed to perpetuate existing dogma.

Ik kan de vraag "what might have happenend if...." uit eigen ervaring wel beantwoorden:
uiteindelijk wint antibiotica, verliest Borrelia, en blijft de schade.

[Sproetje]

Brian Fallon Norvect 2015

NorVect 2015, Lecture 14, Brian Fallon, MD, MPH, MED: Neuropsychiatric Lyme – madness or reality?

http://norvect.no/the-norvect-movies-2015/

Het 18e filmpje
Daar zie je het grote onderzoek van Brian Fallon mbt iv ceftriaxon bij lymepatienten
De STOP-LD Study (Krupp, Neurology 2003) komt ook nog langs.
Ook wordt de studie van Klempner (2001) besproken.


En hier nog een stuk van Donta over het gebruik van doxycycline mbt chronische (late) lyme:

Issues in the Diagnosis and Treatment of Lyme Disease
Sam T Donta
2012

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520031/

.....
Doxycycline is effective treatment for early Lyme disease, but does not appear to be curative in relapsing, persisting Lyme disease.
This likely is because of two factors, ie dose, and protein-binding. Most of absorbed doxycycline remains highly protein-bound in the circulation, meaning that the amount of free drug to diffuse into cells is limited. This may be the explanation as to why the original parent compound tetracycline appears to be more effective [10]. The dose of tetracycline used in our published observations that was found to be effective was 1500mg/day; in contrast, doxycycline dosage is 200mg/day, and tetracycline is not highly protein-bound, allowing more free tetracycline to diffuse into cells. In treating patients with tetracycline, a minimum of three months is needed to demonstrate progress, and in patients who have been ill for more than one or two years, 18 months of treatment may be needed to resolve the illness. Whether increasing the dose of doxycycline to 300-400mg/day would be more effective remains uncertain.
.....

Waarom er überhaupt dan nog 100 mg. doxycycline is gebruikt in de PLEASE studie, blijft een open vraag.