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Nonalcoholic steatohepatitis, a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma.Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, doubleblind, placebo-controlled, phase 2b trial randomized 247 non-alcoholic steatohepatitis (NASH) patients (101, 98, 48 in aramchol 400mg, 600mg, placebo, respectively; NCT 02279524). The primary endpoint was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of aramchol. Key secondary endpoints included liver histology and ALT. Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95%CI -6.4 to 0.2, p=0.06), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13/78) of aramchol 600 mg versus 5% (2/40) of the placebo arm (OR=4.74, 95% CI:0.1-22.7) and fibrosis improvement Vlad Ratziu, Study Design, Patient Recruitment and Treatment, Data Analyses and Interpretation, member of study advisory committee, Manuscript Writing

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Melatonin serves as a signal of darkness and participates in sleep/wake regulation. Animal studies demonstrated effects of melatonin in the hippocampus, particularly suggesting involvement in synaptic plasticity. We used functional magnetic resonance imaging to identify and investigate effects of melatonin in the human hippocampus. Activity in the hippocampal complex during a memory task was examined at 22:00 hr (when endogenous melatonin levels are normally increasing) and compared with 16:00 hr (when endogenous melatonin levels are minimal). The relationship between observed activation patterns and endogenous melatonin was assessed. Finally, the effects of exogenous melatonin administered at 22:00 hr were studied in a double-blind, placebo-controlled crossover manner. Our findings indicate that activation in the left hippocampus at 22:00 hr is significantly reduced compared with afternoon hours compatible with diurnal variation in hippocampal activity. Exogenous melatonin further reduced activation in this region, only in subjects who already crossed the melatonin onset phase at this hour and in correlation with endogenous melatonin levels. As such an effect was not demonstrated with afternoon administration of melatonin, a time depended effect is suggested. Contrary, activation in the left para-hippocampus at 22:00 hr was higher in subjects that crossed the melatonin onset phase. Parahippocampal activation correlated with individual endogenous melatonin levels and was not further affected by exogenous melatonin. These results demonstrate that memory related activation in the hippocampus and para-hippocampus are affected by time of day and melatonin in a differential manner and may implicate the circadian clock and melatonin in human memory processing during the night.

Sleep propensity increases sharply at night. Some evidence implicates the pineal hormone melatonin in this process. Using functional magnetic resonance imaging, brain activation during a visual search task was examined at 22:00 h (when endogenous melatonin levels normally increase). The relationships between brain activation, endogenous melatonin (measured in saliva), and self-reported fatigue were assessed. Finally, the effects of exogenous melatonin administered at 22:00 h were studied in a double blind, placebo-controlled crossover manner. We show that brain activation patterns as well as the response to exogenous melatonin significantly differ at night from those seen in afternoon hours. Thus, activation in the rostro-medial and lateral aspects of the occipital cortex and the thalamus diminished at 22:00 h. Activation in the right parietal cortex increased at night and correlated with individual fatigue levels, whereas exogenous melatonin given at 22:00 h reduced activation in this area. The right dorsolateral prefrontal cortex, an area considered to reflect homeostatic sleep debt, demonstrated increased activation at 22:00 h. Surprisingly, this increase correlated with endogenous melatonin. These results demonstrate and partially differentiate circadian effects (whether mediated by melatonin or not) and homeostatic sleep debt modulation of human brain activity associated with everyday fatigue at night. Hum Brain