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Minocycline Harmful in Patients With ALS, Trial Shows CME News Author: Susan Jeffrey CME Author: Charles Vega, MD Disclosures
Release Date: November 1, 2007; Valid for credit through November 1, 2008 Credits Available
Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians; Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians
November 1, 2007 -- Results of a randomized phase 3 trial of minocycline in patients with amyotrophic lateral sclerosis (ALS) show a 25% increase in the rate of decline in those treated with minocycline vs those receiving placebo. The results have implications for ongoing studies in other neurologic settings such as stroke and Parkinson's disease, the researchers say.
"This trial underscores the importance of clinical trials in assessment of a therapy; the two-sided tests show that a putative therapy had an adverse effect rather than a benefit or no effect," the researchers, with corresponding author Paul H. Gordon, MD, from the Eleanor and Lou Gehrig MDA/ALS Research Center, Neurological Institute, Columbia University in New York, NY, conclude.
"The trial also generates the need to re-examine both the justification for other trials of minocycline in patients with neurological disorders, and the present approach to translational neuroscience in ALS," they write.
The findings are published in the November 1 Online First issue of the Lancet Neurology.
Promising Preliminary Findings
Minocycline is a semisynthetic second-generation derivative of tetracycline. It has antiapoptotic and anti-inflammatory effects in vitro and extends survival in mouse models of various neurologic conditions, the study authors write. Phase 2 trials suggested that minocycline could be taken safely by patients with ALS, and several phase 2 or phase 3 trials are planned or in progress to investigate minocycline in other neurologic diseases, the study authors write. These other diseases include Huntington's disease, Parkinson's disease, stroke, and multiple sclerosis.
The current study, from the Western ALS Study Group including 31 US centers, was a randomized placebo-controlled, phase 3 trial of minocycline in 412 patients with ALS. After a 4-month lead-in phase, patients were randomized to receive minocycline in escalating doses up to 400 mg/day or placebo for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures included forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety.
The researchers report that deterioration in the ALSFRS-R score was significantly faster in the minocycline group vs placebo. Nonsignificant tendencies to faster decline in the secondary endpoints and greater mortality were also seen with treatment vs placebo.
Table 1. Primary and Secondary Outcome Measures: Minocycline vs Placebo* Outcome Minocycline Placebo 95% CI for Difference P ALSFRS-R Score Deterioration (units/month) -1.30 -1.04 -0.44 to -0.08 .005 FVC -3.48 -3.01 -1.03 to 0.11 .11 MMT -0.30 -0.26 -0.80 to 0.01 .11
Quality-of-life-scores did not differ between the groups.
In terms of safety, Dr. Gordon and colleagues report that nonserious gastrointestinal tract and neurologic adverse events were more common with minocycline treatment, but these events were not significantly related to the decline seen in the ALSFRS-R score, they note.
"Our results are contrary to many published reports from laboratories, and thus have implications for trials of minocycline in other neurological conditions, for the preclinical evaluation of potential neuroprotective therapies, and for the design of future clinical trials in ALS," the study authors conclude.
The trial was funded by a grant from the National Institute of Neurological Disorders and Stroke, and by the Muscular Dystrophy Association. Dr. Gordon has disclosed receiving financial support from Avicena and Pfizer for a different study. The complete list of disclosures from the coauthors is available in the original article.
Design Challenges in ALS
In an editorial accompanying the publication, Michael Swash, MD, from the Department of Neurology, Royal London Hospital in London, United Kingdom, writes that the current study by Gordon and colleagues "joins many others that have failed in ALS, including trials of anti-excitotoxic, neurotrophic, and anti-apoptotic compounds that all have beneficial effects in a standard mouse model of the disease. Clearly, all is not well in this area of translational research. For people with ALS and their families, a randomised controlled trial is a prolonged and emotionally exhausting experience; for organisations and investigators, such trials are difficult and expensive to run. Therefore, the time has come for a thorough reassessment."
In addition, although some of the failed treatments may have had more benefit if given earlier, there are difficulties still with early diagnosis of ALS, including the absence of a specific diagnostic test, he notes.
New approaches to trial design are needed in ALS, Dr. Swash concludes. "The aim must be to design informative, short, inexpensive, and sensitive phase 1/2 studies before large phase 3 studies are attempted. In this context, specificity is not important, and careful clinical and neurophysiological studies of single nerve-muscle systems might be sufficient to identify potentially active compounds," he writes. "Nonetheless, the need for early diagnosis is a major issue that will not go away."
Echoing this issue, the investigators also called into question the currently used transgenic mouse model, calling it a "poor representation of sporadic ALS."
Dr. Swash has disclosed no relevant financial relationships.
Lancet Neurol. Published online November 1, 2007.
Clinical Context ALS leads to death within an average of 3 years after the diagnosis, and there is no distinct diagnostic hallmark of early disease. In addition, no treatment has consistently improved motor function for patients with ALS.
The pathophysiology of ALS has not been fully elucidated, but inflammation and apoptosis within the central nervous system seem to play a role. Minocycline can reduce inflammation and has been demonstrated to improve survival among transgenic mice models of ALS. The current study examines the efficacy and safety of minocycline for adults with ALS.
Study Highlights Patients eligible for study participation had probable or definite ALS according to modified El Escorial criteria.
Study subjects were between the ages of 21 and 85 years, had a FVC of at least 75% that of the predicted value, and had the onset of weakness 3 years or less before study enrollment.
Those with a history of other unstable medical condition or persistent ventilatory support were excluded from the study.
After a 4-month run-in period, subjects were randomized to receive minocycline, which was titrated from 100 mg twice daily to up to 400 mg daily, as tolerated, or matching placebo. The treatment period was 9 months.
The main outcome of the study was the ALSFRS-R, and secondary outcomes included MMT, FVC as a percentage of predicted FVC, and a quality-of-life measure.
412 patients underwent randomization. Approximately two thirds of the study cohort were men, and the mean age at enrollment was 58 years.
20% of participants experienced the onset of ALS in the bulbar vs extremity muscles.
The 2 randomized groups were similar in baseline characteristics, save for a slightly shorter time of symptom onset to study entry among subjects receiving minocycline (496 vs 550 days in the minocycline and control groups, respectively).
A higher number of subjects discontinued treatment in the minocycline vs control group (91 vs 71, respectively).
Minocycline was associated with a 25% faster decline in the ALSFRS-R vs placebo, a significant difference. The difference in rate of decline was mostly because of a deficit in gross motor function.
MMT and FVC values also declined more rapidly among subjects receiving minocycline, although the difference in this outcome between the minocycline and control groups did not reach statistical significance.
There was no difference between study groups in quality of life.
Participants receiving minocycline were more likely to experience nausea, diarrhea, constipation, dizziness, and fatigue vs subjects receiving placebo.
The dose of minocycline did not affect the higher rate of adverse events associated with the antibiotic or the efficacy in the main study outcome.
Approximately two thirds of each study group used riluzole, and the use of riluzole did not significantly affect study outcomes.
Pearls for Practice
ALS causes death at an average of approximately 3 years after the diagnosis. There is no hallmark diagnostic test for early ALS, and no medications improve the motor function of ALS. The current study by Gordon and colleagues suggests that minocycline may harm function among patients with ALS to a greater degree than placebo. Minocycline also increased the rate of neurologic and gastrointestinal tract adverse events vs placebo.
CaliforniaLyme
Frequent Contributor (5K+ posts)
Member # 7136
posted
Thank you forposting this!!! Orals can speed up progression in a subset of patients with ALS!!!
ASL Lyme- I only know of 1 person who lived on orals. Everyone else who lived was IV Rocephin or IM BIcillin!!!
Thank you for postinG!!! Sincerely, Sarah
-------------------- There is no wealth but life. -John Ruskin
All truth goes through 3 stages: first it is ridiculed: then it is violently opposed: finally it is accepted as self evident. - Schopenhauer Posts: 5639 | From Aptos CA USA | Registered: Apr 2005
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johnnyb
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quote:Originally posted by CaliforniaLyme: ASL Lyme- I only know of 1 person who lived on orals. Everyone else who lived was IV Rocephin or IM BIcillin!!!
Ouch, that's true, Sarah? Everyone who had ALS-like lyme symptoms died except one? I had substantial worsening of muscle weakness when on minocycline. Thought I was going to die (what else is new there, though).
I guess I have to push for getting IM Bicillin again. Did any of the orals include Amoxicillin though? Because I thought this (or a similar) study attributed the decline to tetracycline type ABX.
So maybe oral penicillins would be OK, similar to bicillin IM ?
- JB
Posts: 1197 | From New Jersey | Registered: Jul 2005
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CaliforniaLyme
Frequent Contributor (5K+ posts)
Member # 7136
posted
NOPE!!! A few mis-readings in your answer!!!
ALS like symptoms- heck, there's many of us who have lived with orals with those!!!
ALS DIAGNOSIS, a true, done-with-muscle-testing (NO not ART kind, the ELECTRODE kind!!!) ALS diagnosis- that's a different story.
I only know ONE guy who lived JUST with orals with that, yes. (Maybe other people know more? Chime in- I am talking about Mike from SC County my ex-husbands ex-business partner- he was diagnosed ALS one day and the VERY NEXT DAY diagnosed Lyme & began Lyme tx- so he was caught RIGHT AWAY!!!)
Other people- ALS diagnosis- all had IV Rocephin or IM Bicllin who lived. Not a single survivor do I know except Mike who just did orals-
I try to repeat this not to be mean but because IF YOU WERE DIAGNOSED ALS YOU WILL DIE IN MY NON_PROFESSIONAL OPINION IF YOU ARE JUST ON ORALS
I know, I sound mean, but it is peoples only chance-
Best wishes to LIVE, Sarah
-------------------- There is no wealth but life. -John Ruskin
All truth goes through 3 stages: first it is ridiculed: then it is violently opposed: finally it is accepted as self evident. - Schopenhauer Posts: 5639 | From Aptos CA USA | Registered: Apr 2005
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posted
JB, I also had worsening of muscle weakness and motor symptoms on minocycline to the point of not walking; I could never have taken the full dose at first. I had to ramp up slowly over a very long period of time, and it DID help those symptoms in the long run - a lot - so I'm glad I stuck with it after that very nasty herx.
This is just my experience, and I never had an actual ALS diagnosis which as Sarah pointed out is a big difference.
Posts: 621 | From US | Registered: Jun 2006
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posted
We don't know what dose of mino the patients were given. What happens when Lymies are given too much abx?
I believe some of the deaths could have been caused by herxheimer reactions.
People with 'MS' take small amounts of mino so that they do not have to contend with the herx reactions.
-------------------- The Canadian Lyme Disease Foundation www.canlyme.com Posts: 128 | From Canada | Registered: Sep 2006
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johnnyb
Frequent Contributor (1K+ posts)
Member # 7645
posted
Whew! Thanks, Sarah. This is one of those times I am very happy to be wrong!
I might try the oral amoxicillin again, but if this doesn't work out, I guess its back to the bicillin again. I know I've said this like 100 times, but NOTHING has done as much for me as the IM bicillin.
- JB
Posts: 1197 | From New Jersey | Registered: Jul 2005
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"People with 'MS' take small amounts of mino so that they do not have to contend with the herx reactions. " --------------------------------------------------------------------------------
Doesn't a herx reaction mean they have a Lyme (or syphillis) infection?
I was dx'd MS, and that was the case for me. I'm now being treated by a LLMD.
Posts: 78 | From Rhode Island | Registered: Jul 2006
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