Oral vs Intravenous High-dose Methylprednisolone for Multiple Sclerosis Patients in Relapse

Elizabeth Lai, Mercer University College of Pharmacy

According to the National Multiple Sclerosis Society, multiple sclerosis (MS) is an immune-mediating response of the body’s immune system, often a disabling disease of the central nervous system disrupting the flow of information in the brain, and between the brain and body.1  The New England Journal of Medicine states that relapses are a common feature of relapse-remitting MS but is also seen in patients with secondary progressive MS with superimposed relapses.  However, patients with primary progressive MS may also experience relapses.2

The McDonald criteria for diagnosis of MS defines a relapse as an episode of neurological disturbance of the kind seen in MS, when the clinopathological studies have established that the causative lesions are inflammatory and demyelinating in nature.3 The European Federation of Neurological Societies (EFNS) Guideline on Treatment of Multiple Sclerosis Relapses states that high-dose methylprednisolone is the routine therapy for relapses and short-term treatment should be considered for relapses of MS based on a level A recommendation.4

 

Title: Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomized, controlled, double-blind, non-inferiority trial5
Design Randomized, controlled, double-blind, non-inferiority trial; N = 199
Objective Assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration
Study Groups Oral methylprednisolone (n = 100) and intravenous methylprednisolone group (n = 99)
Methods Patients were enrolled through 13 multiple sclerosis (MS) centers in France and had relapsing-remitting MS.  The 2005 McDonald criteria and an Expanded Disability Status Scale (EDSS) score of five or less before relapse were also considered in the enrollment process.  Patients were randomly allocated into an oral or intravenous (IV) group and given methylprednisolone 1000 mg once a day for three days.
Duration January 29, 2008 to June 14, 2013
Primary Outcome Measure Proportion of patients who improved by day 28 (decrease of at least one point in most affected score on Kurtze Functional System Scale) without need for retreatment with corticosteroids, in per-protocol population
Baseline Characteristics Oral methylprednisolone group Intravenous methylprednisolone group
Median age (years) 35.0 34.7
Women 74% 75%
Median residual EDSS score before inclusion relapse 1.0 1.5
Median time from relapse onset (days) 6.5 7.0
Change in EDSS score due to relapse 2.0 2.0
Results Day 28 Oral (n = 82) IV (n = 90) P-value
Patients improved by at least one point on most affected functional system scale without retreatment 66 72
Patients retreated for two days 7 12 0.31
Patients improved by at least one point on the most affected functional system 72 84 0.21
Patients improved by at least one EDSS point from baseline 63 68 0.84
Patients fully recovered from relapse 32 40 0.47
Change in EDSS score from baseline -1.5 -1.3 0.57
Change in most affected functional system scale from baseline -1.7 -1.6 0.79
Day 180 Oral (n = 83) IV (n = 87) P-value
Patients improved by at least one EDSS point from baseline 65 68 0.98
Patients fully recovered from relapse 59/90 62/93 0.87
Time to total recovery from relapse (months) 1.8 1.3
Change in EDSS score from baseline -1.6 -1.5 0.69
Change in most affected functional system scale from baseline -2.1 -2.0 0.30
Number of relapses per patient, treated by methylprednisolone 0.4 0.3 0.79
Relapse-free patients 63/90 62/93 0.76
Adverse Events Common Adverse Events: metallic taste (oral = 75%, IV = 81%), headache (oral = 72%, IV = 64%), hot flashes (oral = 63%, IV = 59%), insomnia (oral = 77%, IV = 64%)
Serious Adverse Events: nausea (oral = 32%, IV = 34%), vomiting (oral = 14%, IV = 12%), epigastric pain (oral = 43%, IV = 45%)
Percentage that Discontinued due to Adverse Events:
Study Author Conclusions Oral administration of high-dose methylprednisolone for three days was not inferior to intravenous administration for improvement of disability scores one month after treatment and had a similar safety profile.  This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians.

The study revealed that high-dose methylprednisolone was noninferior to IV methylprednisolone for the treatment of relapse in MS patients.  With an 80% power, approximately 80% of patients improved at day 28 in the oral and IV groups without undergoing retreatment with methylprednisolone and including 90 patients per group.  With similar tolerability in both groups, insomnia was an adverse event that was more prevalent in the oral group compared to the IV group and may have been caused by longer bioavailability.  Results may have been affected by patient access to treatment, patient comfort, and cost of managing relapses in MS.

References

  1. National Multiple Sclerosis Society. Definition of MS. Available at: http://www.nationalmssociety.org/What-is-MS/Definition-of-MS. Accessed July 2, 2015. Accessed on July 1, 2015.
  2. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Eng J Med 2000;343(20):1430-8.
  3. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121-7.
  4. Filippi M, Agosta F, Barkhof F, et al. EFNS task force: the use of neuroimaging in the diagnosis of dementia. Eur J Neurol. 2012 Dec;19(12):e131-40, 1487-501.
  5. Page EL, Veillard D, Laplaud DA, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. The Lancet. 2015.
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