Duy Le, MD

De Maria R, Campolo J, Marina Frontali M, Taroni F, Federico A, Inzitari D, et al. Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL: A Randomized Controlled Trial. Stroke. 2014. 

De Maria et al bravely go where no study has gone before, and they should be commended for their efforts. They evaluated the effects of tetrahydrobiopterin (BH4), an essential co-factor for nitric oxide synthesis in endothelial cells, in CADASIL patients. This was a multi-center randomized, double blinded, placebo-controlled trial. Sixty-one CADASIL patients ages 30-65 were randomized to receive placebo or sapropterin, 200-400 mg BID, depending on their weight to target 5 mg/kg. Primary outcome was peripheral arterial tonometry (RH-PAT) performed at 24 months. The thought was that an increase RH-PAT value was determined to be a favorable outcome; meaning that there was more vasodilation and flow. The ITT population included 61 patients. RH-PAT was increased after 24 months in 37% of patients on sapropterin and 28% in placebo. However, when controlling for age, sex and clinical characteristics, improvement was not associated with the treatment arm.

Peripheral arterial tonometry was chosen by De Maria et al as an indirect and surrogate marker for amelioration of endothelial dysfunction seen in CADASIL based on the following thoughts 1) Previous studies in CADASIL patient describe impaired vasoreactivity in both cerebral and peripheral circulation. 2) PAT is independently shown to be associated with incident cardiovascular events in high risk patients. De Maria et al should be applauded for attempting to quantify a method which may be predictive of deterioration in CADASIL patients. However, while it does seem that there is a relationship in CADASIL patients between peripheral arteries and CNS arteries; we still do not know what the extent of that relationship is. More-over, how does that translate to development of disease progression or clinical deterioration?

Ultimately, this study should be lauded for its unique niche and massive undertaking to perform a RTC in such a rare disease entity. The primary outcome was not reached. If the thought is that there may be some improved benefit still of the sapropterin, this could be due either to a sample size that is too small (albeit very large for such a rare disease), a dosing that is too low, an effect is not actually seen in in the 24 month window, or the parameter used to measure improved outcome in these patients may actually be flawed. This was a phase-two study designed to show safety, and that outcome was achieved. While there is the potential to pursue a large scale RCT to evaluate for treatment effect, feasibility of such a process would be called into question as this is a rare disease.