- Enrollment: 1056
- Actual Study Start Date:August 9, 2012
- Estimated Study Completion Date:March 23, 2022
- Estimated Primary Completion Date:March 23, 2022
Why so long? It shows you how difficult it is to recruit for trials that are unlikely to benefit study subjects. Those randomised to either the low-dose fingolimod, or Copaxone, arms are likely to on average do worse than the full-dose fingolimod arm. Knowing this would you volunteer for this trial? Sometimes clinical practice has to be driven by pragmatic considerations.
|Thing-1 (0.5 mg) vs. Thing-2 (0.25 mg)|
The real-life study below may help. This is an analysis of the outcome of relapsing patients who were switched to every other day fingolimod, or half dose (average daily dose 0.25 mg), due to low lymphocyte counts and were compared to a group of patients on standard daily fingolimod 0.5 mg per day. It is clear that the patients receiving every other day fingolimod did worse than those taking daily fingolimod.
Does this study make the randomised study above irrelevant? No. The study below was not randomised and therefore there the results could be explained by some other factors associated with the need to go onto a lower dose of fingolimod, but not the actual dose of fingolimod itself, or the subjects on the full dose arm could have been biased to include fingolimod responders. Therefore, we can’t be sure if half-dose fingolimod is inferior to full-dose fingolimod.
In Europe the EMA have mandated lymphocyte monitoring and dose interruption when the lymphocyte counts drop below 200/mm3. In comparison, the FDA have not mandated lymphocyte monitoring. The FDA decision was based on data that showed no link between lymphocyte counts and fingolimod efficacy and adverse events. At Barts-MS we have taken a pragmatic approach and use a lymphocyte cut-off of 100/mm3; this is somewhere between the EMA and FDA guidance. This means we rarely have to reduce the dose of fingolimod and hence are not putting many patients at risk of breakthrough activity.
OBJECTIVES: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients.
METHODS: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were compared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions was tested using propensity score-adjusted Cox and linear regressions.
RESULTS: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89-0.99, p = 0.026), and female sex and lower baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98, 95% CI = 1.07-8.27, p = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinating lesions (combined outcome, HR = 2.07, 95% CI = 1.06-4.08, p = 0.034). Within FTY-EOD, treatment with natalizumab before FTY and lower age were positively associated with risk of developing relapses and combined outcome, respectively (HR = 25.71, 95% CI = 3.03-217.57, p = 0.002 and HR = 0.85, 95% CI = 0.77-0.96, p = 0.005). FTY-EOD was overall well tolerated.
CONCLUSION: Disease reactivation was observed in a significant proportion of patients treated with FTY-EOD. Neurologists should be cautious when reducing FTY administration to every other day, especially in younger patients and those previously treated with natalizumab.