L-citrulline treatment of nitric oxide deficiency in MELAS a phase I dose-finding and safety study

There is evidence that nitric oxide deficiency occurs in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and may result in impaired blood perfusion in small blood vessels, contributing to stroke-like episodes (SLEs). The primary aim of this phase one study was to estimate the maximum tolerated dose (MTD) of L-citrulline in adults with MELAS. The primary safety outcome was the occurrence of a dose limiting toxicity (DLT) in the first eight weeks after treatment initiation. Secondary outcomes included changes in cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and plasma citrulline, arginine, and ornithine levels from baseline to end of treatment (week four). Plasma guanidino compounds were assessed from baseline to week one for potential arginine toxicity and plasma lactate and alanine from baseline to end of treatment as pharmacodynamic biomarkers. Ten consecutive patients were screened, enrolled and assigned to the following doses: 10 g (n = 1), 20 g (n = 1), 30 g (n = 2), and 40 g (n = 6). There were no DLTs observed with any of the doses. However, analysis of plasma guanidino compounds demonstrated analyte outliers (Z-scores >2) with higher doses of L-citrulline (30 and 40 g). CBF increased from baseline in seven study participants, six of whom were on the highest dose. The highest CBF increase was observed in the occipital region. With the highest dose of L-citrulline, substantial increases in plasma arginine and citrulline were observed at week four when compared to baseline. While no DLTs were observed, the increase of guanidino compounds with 30 g and 40 g of L-citrulline needs to be further interrogated with serial measurements in a future study to ensure safety of these doses and determine whether the increase is sustained long term. A randomized placebo-controlled trial will be required to evaluate the efficacy of L-citrulline in individuals with MELAS.