The tetracycline antibiotic minocycline, commonly used to treat such conditions as severe acne and mood disturbances in fragile X syndrome, may also be beneficial in treating preliminary stages of multiple sclerosis (MS), newly published research suggests.
The randomized controlled trial enrolled 142 adult patients in Canada with a recent clinically isolated syndrome (CIS). Participants who received 100 mg of oral minocycline twice daily had a significantly lower rate of conversion from CIS to MS within 6 months of treatment compared with those who received matching placebo (the primary endpoint).
In addition, there was a significantly greater change in lesion volume and fewer new enhancing and unique lesions at 6 months for the minocycline group. However, there were no significant between-group differences for any of these outcomes, including conversion from CIS to MS, at 24 months.
Still, lead author, Luanne M. Metz, MD, neurologist and professor in the Department of Clinical Neurology at the Cumming School of Medicine at the University of Calgary, Alberta, Canada, told Medscape Medical News she views this as a positive trial.
“For a person who has a clinically isolated syndrome, there’s a large benefit to patients in reducing their risk of further disease activity over the first 6 months of treatment,” said Dr Metz.
“This is a drug that any physician can simply write a prescription for without hassle around insurance or injection training. And it’s an accessible treatment to start very early on,” she added.
The findings are published in the June 1 issue of the New England Journal of Medicine.
“Attractive Therapy”
Initial results from the study were presented at the 2015 Congress of the European Committee for Treatment and Research in MS (ECTRIMS), and reported at the time by Medscape Medical News.
This phase 3 trial was carried out after the success of some earlier pilot trials, Dr Metz said. “This was an attractive therapy, being a generic medication, and had a long history of chronic use, so a lot of the safety issues were known.”
She added that the investigators studied patients with CIS because they felt that using placebo in this population was reasonable. “Given information from the previous CIS trials, the rate of converting to definite MS by 6 months is so very high, it made the trial feasible.”
Between January 2009 and July 2013, 142 patients aged 18 to 60 years (mean age, 35.8 years; 68.3% women) were enrolled at 12 Canadian MS clinics. All were randomly assigned to receive 100-mg minocycline capsules (n = 72) or matching placebo (n = 70).
All of the participants had had a first clinical demyelinating event within 180 days before start of treatment.
Cranial MRIs were conducted at screening and at months 3, 6, 12, and 24. Interestingly, the placebo group had more members with symptom onset in the spinal cord and more members with more than one enhancing lesion at baseline than did the minocycline group (P = .04 for both comparisons).
Conversion Rates
The primary outcome was conversion to MS at 6 months, based on 2005 McDonald criteria.
The unadjusted risk for conversion to a second demyelinating event at this timepoint was 33.4% for the patients receiving minocycline and 61.0% for those receiving placebo, for a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 – 43.9 percentage points; P = .001). This topped the prespecified “clinically meaningful” difference of 25 percentage points.
The conversion risk difference after adjustment for number of enhancing lesions at baseline was still significant at 18.5 points (95% CI, 3.7 – 33.3 points; P = .01).
Further adjustment for the 2010 McDonald criteria and for spinal cord symptom onset “did not attenuate the between-group differences,” report the investigators.
At 6 months, the minocycline group also had greater changes in mean lesion volume on T2-weighted MRI, lower cumulative number of new lesions enhanced on T1-weighted MRI, and fewer cumulative combined number of unique lesions — defined as new enhancing lesions on T1 and new and newly enlarged lesions on T2.
Table. Six-Month MRI Outcomes for Minocycline vs Placebo Groups
| Outcome | Unadjusted Mean Difference (95% CI) | P Value | Adjusted Mean Differencea (95% CI) | P Value |
|---|---|---|---|---|
| Change in lesion volume (mm3) | 661 (96 – 1226) | .02 | 584 (3 – 1166) | .049 |
| Cumulative no. new lesions | 0.77 (0.29 – 1.26) | < .001 | 0.35 (0.05 – 0.65) | .02 |
| Cumulative no. unique lesions | 2.40 (0.80 – 3.39) | < .001 | 1.01 (0.25 – 1.77) | .007 |
| aAdjusted for baseline number of enhancing lesions. | ||||
The unadjusted difference in conversion to MS just missed statistical significance at 24 months (P = .06). All adjusted outcomes were also not significant at this time point.
However, post hoc analysis showed that the unadjusted risk for conversion was significantly lower for those receiving minocycline at 12 months.
Adverse events more frequently reported in the minocycline vs placebo groups included the following:
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Rash: 15.3% vs 2.9%, respectively (P = .01);
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Dizziness: 13.9% vs 1.4% (P = .005); and
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Dental discoloration: 8.3% vs 0% (P = .01).
“We showed that this treatment was effective over the first year,” said Dr Metz. “After that, it’s up to the physician and patient to determine, based on the individual response to the treatment, if it’s something the patient should continue longer.”
“Compelling,” but Early Days
In an accompanying editorial, Zongqi Xia, MD, PhD, Pittsburgh Institute for Neurodegenerative Disease, and Robert M. Friedlander, MD, Neuroapoptosis Laboratory at the University of Pittsburgh School of Medicine, Pennsylvania, note that the high cost of current therapies has increased interest in “repurposing” existing drugs for treating patients with MS.
“One appealing candidate is minocycline, a relatively safe and inexpensive synthetic tetracycline that crosses the blood–brain barrier,” they write.
However, they add that the current trial had several limitations, “as the authors acknowledge.”
This included the small sample size, which could have led to the study being underpowered to detect a positive outcome at 24 months; that the 6-month period is shorter than for other MS treatment trials, so “has limited applicability in clinical practice”; and the fact that the placebo group had more enhancing lesions and more spinal cord involvement at baseline, which may have biased the results.
“Although there was an adjustment…in sensitivity analyses of the primary outcome, there was no adjustment for this covariate in the analyses of secondary clinical or MRI outcomes,” they write.
The editorialists also point out that because of the commonly reported adverse events of rash and tooth discoloration, true blinding could have been difficult.
“Given the safety profile and low cost of minocycline, these intriguing results, notwithstanding their limitations, make a compelling case for further study,” write Dr Xia and Dr Friedlander.
“However, use of minocycline in multiple sclerosis is not supported until its benefit can be confirmed in larger long-term clinical trials,” they conclude.
“Put It Into Perspective”
When asked about the editorial, Dr Metz noted that she would have liked to have included more patients, but there were several challenges during recruitment.
“I feel that we’ve come to the conclusion of being able to recruit patients into a longer placebo-controlled trial for CIS,” she said. “The number of these people willing to stay on placebo is small.”
As for the editorialists writing that the study results are intriguing but too early for clinical use, Dr Metz said that “we always want a confirmatory trial, but we function on much less than level 1 evidence in most of medicine.” So clinicians should weigh the evidence they have available against the challenges of their patients.
“Not everyone has the ability or money to go on to current therapies. I think there is enough evidence to use this medication, but of course it has to be considered that it works in the short term; we don’t know it if continues to work.”
Still, she noted that other treatments have data for 2 years, “but we use them for a decade. So I think we need to put it all into perspective.”
The study was funded by the Multiple Sclerosis Society of Canada (MSSC). Dr Metz reports receiving grant support from the MSSC during the conduct of the study and grant support from Hoffmann-La Roche outside of the study. Disclosures for the coauthors are in the paper. The editorialists report grants from the National Institutes of Health, “outside the submitted work.”
N Engl J Med. 2017;376:2122-2133, 2191-2193. Abstract, Editorial
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