MS Speaks

SUMMARY AND COMMENT | NEUROLOGY


Minocycline for Early Multiple Sclerosis

Robert T. Naismith, MD Reviewing Xia Z and Friedlander RM., N Engl J Med 2017 Jun 1; 376:2191

In a placebo-controlled trial, clinical benefits were apparent at 6 months, but other endpoints were inconsistent.

Minocycline showed early promise as a disease-modifying therapy for multiple sclerosis (MS) with favorable pricing. In this multicenter study, conducted from 2009 through 2013, investigators recruited 142 participants with clinically isolated syndrome (by 2005 McDonald criteria) or early MS (by 2010 criteria), and randomized them 1:1 to 100 mg minocycline twice daily or placebo.

A significant reduction in confirmed diagnosis by 2005 McDonald criteria was observed at 6 months (the primary endpoint); after adjustment for baseline magnetic resonance imaging (MRI) enhancing lesion number, rates of conversion were 43% with minocycline versus 62% with placebo. However, conversion and MRI outcomes were not significant at 24 months. Side effects included rash, teeth discoloration, and dizziness.

Comment

Minocycline has inconsistent effects on MS disease activity and requires further investigation before being recommended to patients. This trial was underpowered and did not require patients to continue through 24 months. An imbalance in randomization resulted in more placebo patients having features concerning for early conversion: presence of gadolinium enhancing lesions at onset, spinal cord presentation, and multifocal presentation. Indeed, more placebo recipients would have been classified at study entry as having clinically definite MS by the McDonald 2010 criteria, based on the presence of an asymptomatic gadolinium enhancing lesion at baseline. Although adjusted analyses continued to show an unsustained 6-month benefit, one cannot recommend minocycline based on this placebo-controlled trial as a viable substitute for an approved disease-modifying therapy. Whether minocycline can be added to another therapy was not studied and remains unknown.

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Editor Disclosures at Time of Publication

Disclosures for Robert T. Naismith, MD at time of publication

Consultant / Advisory board

Alkermes; Acorda Therapeutics; Bayer HealthCare; Biogen Idec; EMD Serono; Genzyme Corp./Sanofi; Genentech; Novartis

Speaker’s bureau

Acorda Therapeutics; Biogen Idec; Genzyme Corp./Sanofi

Grant / Research support

National Multiple Sclerosis Society; National Institutes of Health

Trial of Minocycline in Clinically Isolated Syndrome of Multiple Sclerosis

To the Editor:

The conclusion of Metz et al. (June 1 issue) — that the risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo at 6 months — may not be entirely well founded. The baseline imbalance between the two randomly assigned groups may have penalized the placebo group by including a larger proportion of patients with spinal cord and multifocal symptoms at onset, a larger proportion of patients with two or more enhancing lesions on magnetic resonance imaging, and a larger number of patients fulfilling the 2010 McDonald criteria of multiple sclerosis. The results are inconsistent with other studies such as the RECYCLINE trial.

A recent Cochrane review showed that early treatment with nearly all disease-modifying drugs reduced the probability of short-term conversion to multiple sclerosis, although the clinical benefit with respect to long-term relapse and disability worsening remains uncertain.

Maria Donata Benedetti, M.D., Ph.D.
Verona University Hospital, Verona, Italy
mariadonata.benedetti@ospedaleuniverona.it

Graziella Filippini, M.D.

Alessandra Solari, M.D.
Istituto Neurologico Carlo Besta, Milan, Italy

Dr. Solari reports having been a board member of Merck Serono and Novartis and having received speaker’s fees from Almirall, Excemed, Merck Serono, Sanofi Genzyme, and Teva Pharmaceutical Industries. No other potential conflict of interest relevant to this letter was reported.
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The authors reply:

Benedetti et al. suggest weaknesses of our trial. Despite debate among statisticians, stratified and regression analyses are commonly used to adjust the estimate of treatment effect for confounding variables that have arisen because of imbalanced prognostic factors between trial groups. A thorough examination of these variables was carried out in our trial, and only the number of enhancing lesions affected the estimate of treatment effect (Table S5 in the Supplementary Appendix of our article, available at NEJM.org). Multifocal symptom onset was not considered because it does not consistently influence prognosis. Although adjustment for the number of enhancing lesions attenuated the treatment effect, the risk of conversion from a clinically isolated syndrome to multiple sclerosis remained significantly lower with minocycline than with placebo over a period of 6 months.

The RECYCLINE trial mentioned by Benedetti and colleagues was underpowered and evaluated minocycline as an add-on therapy to treatment with interferon beta-1a. The lack of an additive effect in that trial is not evidence that minocycline alone is ineffective.

Luanne M. Metz, M.D.
University of Calgary, Calgary, AB, Canada
lmetz@ucalgary.ca

Misha Eliasziw, Ph.D.
Tufts University, Boston, MA

Since publication of their article, the authors report no further potential conflict of interest.