THE MI-KRISTAL RCT: LACTULOSE INITIATED ON THE BASIS OF POOR PATIENT REPORTED OUTCOMES

Background: Hepatic encephalopathy (HE) is associated with increased mortality, falls, and frequent hospitalizations. Patient reported outcomes (PROs) are useful tools to assess health-related quality of life (HRQOL) measures such as impairment of sleep, cognition, or activity. PROs have also been shown to be reliable & valid tools to detect early signs of HE. Many clinicians initiate lactulose when patients present with poor PROs without cognitive testing, however data are limited regarding the efficacy of this strategy.
Methods: The Mi-Kristal trial is a single-center, randomized study to determine whether a 28-day regimen of Kristalose^®, a crystalline lactulose therapy (20g BID) improves HRQOL in people with poor PROs. We enrolled patients with cirrhosis, portal hypertension, no prior HE, & Activity Impairment attributed to cirrhosis >3 (scale 0-10) because this score was highly predictive of overt HE in prior studies. Endpoints included the short form-8 (SF-8), animal naming test (ANT), falls, and a 4-point Likert scale rating sleep quality (very bad to very good).
Results: Fifty-six subjects were randomized, 52 subjects completed the protocol; 25 Kristalose and 27 no treatment. Median Baseline MELD-Na was 11 and ANT was 19 without differences between the groups at baseline. At Day 28 no significant difference was observed using the SF-8: subjects on Kristalose had an 8.1 point increase (95%CI 3.7-12.4) compared to 6.6 (95%CI 2.3-10.8) in control (p=0.6). Significant improvements were observed in subjects on Kristalose using the ANT which increased by 3.7 (95%CI 2.1-5.4) vs control - -0.2 (95%CI -1.7-1.4); 32% on Kristalose had a 5-point increase in ANT vs 11% of control. Falls were reported by 11% in control and 4% on Kristalose. At the end of the trial, 92% on Kristalose reported good sleep compared to 52% of control. Compared to control, Kristalose was associated with a significant 0.6 (95%CI0.3-1.0) point improvement in sleep quality and a significant 1.7 (95%CI0.3-3.1) point decrease in activity impairment.
Conclusion: Among patients with activity impairment at risk for HE, a 28-day crystalline lactulose regimen led to improved sleep, cognitive function & activity impairment. No significant difference in HRQOL was observed using the SF-8 possibly because the instrument is insensitive to change in this context or a longer treatment duration is required. A 6-month trial is planned. Our findings support the use of PROs to assess for benefit of HE-therapy and that early treatment improves select PROs.