Reanalyze outcomes in French(Desnuelle 2001)/German(Graf 2004)riluzole-vitamin-E[α-tocopherol]clinical trials.

High-dose vitamin E[α-tocopherol]-riluzole trials:  French –289 subjects over 12 months who did/did not receive 1000mg vitamin E[α-tocopherol]; German –160 subjects over 18 months who did/did not receive 5000mg vitamin E[α-tocopherol].  Both human CNS/respiratory effects are not seen at doses below vitamin E[α-tocopherol]– 1000mg daily. At least 12 months is required to achieve increased stable CNS vitamin E[alpha-tocopherol]levels evaluated with cerebrospinal fluid(CSF).

German trial analysis comparing [1]time to event for primary and secondary endpoints, [2]prevalence of non-invasive-ventilation(NIV) in 18 month completers, [3]prevalence of NIV/permanent-assisted-ventilation(PAV)/tracheostomy-invasive-ventilation(TIV)in ALS subjects who did/did not receive 5000mg vitamin-E[α-tocopherol].

In French trial –only 39/112 vitamin E[α-tocopherol]treated ALS subjects progressed from early to advanced ALS Health States(stages)characterized by requiring respiratory assist devices compared with 53/109 placebo-treated ALS subjects[P-value=0.046772]. Oxidative stress biomarkers were significantly reduced in vitamin E[α-tocopherol]cohort.  In German trial [1]– time to achieving primary and secondary endpoints was statistically significantly[P-value=< 0.0001]prolonged in vitamin-E[α-tocopherol]cohort(p 654), [2]– proportion of ALS completers on NIV was statistically significantly lower[P-value=0.00195] in vitamin E[α-tocopherol]cohort(p 655), and [3] – 4/77 ALS subjects on vitamin E[α-tocopherol]required NIV/PAV/TIV compared with 13/83 ALS subjects on placebo(p 654)[P-value=0.031802].

Reanalysis of the German vitamin E[α-tocopherol]clinical trial provides evidence that the transition to later stages of ALS, defined by use of respiratory support devices, may actually have been slowed by vitamin E[α-tocopherol]use, as was the case in the French trial.  Edaravone in vitro pre-clinical effects are enhanced by addition of vitamin E[α-tocopherol].  Quantifying use of respiratory assist devices may be a way to measure transition from early to advanced ALS stages in future clinical trials of adjuvant effects of vitamin E[α-tocopherol]in riluzole-edaravone treated ALS subjects. Suspected ALS patients should be started on high dose vitamin E[α-tocopherol]even prior to riluzole to shorten time to effective dose-level.