Bhargav Patel, Mercer University College of Pharmacy
Multiple sclerosis (MS) is a demyelinating disease of the brain and spinal cord characterized by symptoms that may include muscle weakness, blindness, double vision, and coordination difficulties.  Although a cure currently does not exist for MS, several therapies including beta interferons, ocrelizumab, fingolimod, and mitoxantrone have been used for its management.  Use of these medications is stated to improve function after a symptom flare or prevent new flares but may be poorly tolerated.  Minocycline, which is being investigated of its use in MS, is a broad-spectrum tetracycline antibiotic mainly used for the treatment of acne vulgaris.  Minocycline is proposed to inhibit matrix metalloproteinases activity thereby acting to attenuate neuroinflammation. 
|Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis |
|Design||Phase 3, multicenter, randomized, double-blind, placebo-controlled; N= 142|
|Objective||To determine whether minocycline reduces the risk of conversion from a first clinical demyelinating event to MS|
|Study Groups||Minocycline (n= 72); placebo (n= 70)|
|Methods||Patients between 18-60 years of age, with a clinically isolated demyelinating event known as a clinically isolated syndrome (optic neuritis, brainstem, cerebral, or myelopathy syndrome) within the previous 180 days, and with at least two lesions larger than 3 mm in diameter on a T2-weighted brain MRI were included. Patients with an alternative explanation for the demyelinating event or a diagnosis of MS were excluded. Patients were given either minocycline 100 mg two times a day orally or placebo for up to 24 months or until a diagnosis of MS was confirmed.
The 2005 McDonald criteria was used for the diagnosis of MS. A diagnosis of relapsing–remitting MS requires evidence that inflammatory demyelination has affected at least two regions of the central nervous system and that episodes of inflammation have occurred at least twice. Post hoc adjusted risk estimates were stratified according to the number of enhancing lesions at baseline, which was not balanced between the study groups at trial entry.
Participants underwent routine blood testing, clinical assessments, and Expanded Disability Status Scale (EDSS) assessments (scores range from 0 to 10.0 with higher scores indicating greater disability) at screening; baseline; months 1, 3, 6, 12, 18, and 24; and the time of an early trial withdrawal. Participants were contacted by telephone at months 9, 15, and 21 for the assessment of adverse events.
|Duration||24 months (treatment and data collection)|
|Primary Outcome Measure||Conversion to MS within 6 months|
|Secondary Outcome Measure||Conversion to MS within 24 months|
|Adverse Events||Common Adverse Events: dental discoloration (8.3%), rash (15.3%), dizziness (13.9%), and nausea (15.3%)|
|Serious Adverse Events: severe relapse of multiple sclerosis (1.4%)|
|Percentage that Discontinued due to Adverse Events (minocycline vs. placebo): 8.3% vs. 1.4%|
|Study Author Conclusions||The decreased risk of conversion from a clinically isolated syndrome to MS was statistically significant with minocycline versus placebo over 6 months, but not over 24 months.|
Minocycline’s high oral bioavailability and low cost make it a novel treatment option that could lead to improved patient comfort, compliance and outcomes. It stands out from other treatments by not requiring prior authorizations, lab work, or painful injections. The trial’s small sample size limited its clinical impact but the groundwork is set for future trials. Minocycline being used continuously for 24 months could lead to resistant bacteria and complicated infections in patients treated for MS emphasizing the need for long-term trials.
 NINDS Multiple Sclerosis Information Page. National Institute of Neurological Disorders and Stroke. November 19, 2015. Retrieved June 2, 2017.
 Garrido-mesa N, Zarzuelo A, Gálvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169(2):337-52.
 Chen X, Ma X, Jiang Y, Pi R, Liu Y, Ma L. The prospects of minocycline in multiple sclerosis. J Neuroimmunol. 2011;235(1-2):1-8.
 Metz LM, Li DKB, Traboulsee AL, et al. Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med. 2017;376(22):2122-2133.