Table 1.

Characteristics of Randomized Control Trials.

First Author [R] – Country	Study Type	Treatment		Sample Size			Encepha–lopathy Scale or Another Tool	Publication Year/Status	Outcomes
		Case	Control	Case	Control
Fecal Microbiota Transplantation (FMT)
Jasmohan S Bajaj41 – USA	Open label, RCT	FMT enema	Standard care	20	10		•PHES •EncephalApp Stroop	2017	•Significant improvement in cognitive and MELD score in FMT group •In the FMT group, microbiota improvement was observed
Jasmohan S Bajaj42 – USA	Phase 1, RCT	FMT capsules	Placebo	10	10		EncephalApp Stroop	2019	•In the FMT group, duodenal microbiota diversity was improved •Serum LBP and IL-6 decreased in the FMT group •Encephalopathy outcomes improved in the FMT group
Raymond Chung (responsible party)43 – USA	Phase 2, RCT	FMT Capsule	Placebo oral capsule	10 patients for the pilot study and 20 patients for RCT			•PHES •SF-36	On-going	•Primary outcome: change in PHES score •Secondary outcomes: monitoring AEs, HRQOL, ammonia level, and microbial engraftment
Radha K Dhiman (responsible party)44 – India	Open-label, RCT	FMT	Placebo	36 participants			–	On-going	•Primary outcomes: change in Survival rates •Secondary outcomes: change in MELD, MELD Na, ammonia level, IL level, the incidence of hepatic encephalopathy and variceal bleed
Probiotics
Radha K Dhiman45 – India	Double blind trial	VSL #3, 9, 10 (11)	Placebo	66		64	–	2014	•Significant improvement in CTP and MELD score in case group •Decreased HE related hospitalization in case group
Nazaril Kobylaik (responsible party)47 – Ukraine	Open label, RCT	Dietary supplement: E. coli Nissle 1917	Lactulose and Rifaximin	42 participants			–	On-going	•Primary outcomes: change in Stroop test and serum ammonia level •Secondary outcomes: changes in serum level of IL-6, IL-8, INF, and bacteria culture
Mariquit Sendelbach (responsible party)49 – USA	Double blind, RCT	Probiotic supplements	Placebo	80 participants			–	On-going	•Primary outcomes: effect on liver fibrosis •Secondary outcomes: effect on a liver enzyme, diabetic marker, BMI, and LDL
Aleksander Krag (responsible party)50 – Denmark	Open-label, RCT	Profermin Plus®	Fresubin®	56 participants			–	On-going	•Primary outcomes: to evaluate hepatic stellate cell activity •Secondary outcomes: assessment of hepatic a-SMA, hepatic inflammation, alfa smooth muscle actin concentration, hepatic venous pressure gradient, reduction in non-invasive fibrosis score, gut dysbiosis, liver vein outflow, metabolic changes
Albumin
Macarena Simon Talero54 – Spain	Double-blind, RCT	Albumin (1.5  g/kg on day 1 and 1 g/kg on day 3)	Saline and usual treatment	26	30		–	2013	•Significant decrease in mortality rate was found in the albumin group •No significant difference was found with respect to liver function and in HE development
Barjesh Chander Sharma55 – India	RCT	Albumin 1.5 /kg/day and lactulose 30–60 lml TID	Lactulose 30–60 lml TID	60	60		West Haven Criteria	2017	•A significant reduction in mortality rate was noticed in the case group. •No significant reduction in arterial ammonia level, IL-6, IL-8, TNF-α was noticed
Paolo Caraceni56 – Italy	Open label RCT	Standard treatment + albumin infusion 40 g twice weekly for 2 weeks followed by 40 g once a week	Standard treatment	218	213		–	2018	•Significant improvement in survival rate was found in the case group
Louise China57 – UK	Open label, RCT	Albumin 20% for 14 days or until discharge	Standard care	380	397		–	2021	•Targeting the level of albumin at ≥30  g/l did not show advantages compared to standard care
Hunter Holmes Mcguire Veteran Affairs Medical Center (responsible party)58 – USA	Double-blind, RCT	Albumin 25% IV weekly for 4 weeks	Saline	48 participants			•PHES •EncephalApp Stroop	On-going	•Primary outcomes: change in a psychometric score, and critical flicker frequency •Secondary outcomes: to evaluate sickness impact factor, change in PHES score, CFF, and SIP
Hospital Universitati Vall d’Hebron Research Institute (responsible party)59 – Spain	Double-blind, RCT	Albumin 1–2 days after hospitalization and at 48 ± 24 h after the first dose	Saline	128 participants			–	On-going	•Survival rate at 90 and 180 days
Aleksander Krag (responsible party)60 – Denmark	Double-blind, RCT	Albumin 20% high expected effect and albumin 20% low expected effect	Saline	240 participants			–	On-going	•To evaluate liver-related clinical outcomes
AST-120
Bajaj JS66 – USA	Double blind, RCT	AST-120 12 g (50) and AST-120 6 g (50)	Placebo	100	48		RBANS	2013	•No significant cognitive improvement was found at the end of 8 weeks
Acetyl-l-Carnitine (ALC)
Mariano Malaguarnera68 – Italy	Double blind, RCT	ALC 2 g BD for 90 days	Placebo	60	55		MMSE	2008	•Significant reduction in prothrombin time, serum bilirubin, fasting serum ammonia •Significant improvement in albumin level, MMSE score, auditory verbal learning
Mariano Malaguarnera69 – Italy	Double-blind, RCT	ALC 2 g BD for 90 days	Placebo	33	34		•PHES •BDI	2011	•Significant improvement in social, emotional, physical, and general health •Significant improvement in PHES and BDI
Michele Malaguarnera70 – Italy	Double blind, RCT	ALC 2 g BD for 90 days	Placebo	61	60		–	2011	•The trial reported significant improvement in ammonia level, liver functions, and neurophysiological function
Mariano Malaguarnera71 – Italy	Double blind, RCT	ALC	Placebo	13	11		–	2006	•Significant improvement in serum ammonia, BUN, Glasgow, and EEG was observed
Glycerol Phenyl Butyrate
Don C Rocky82 – USA	Double blind, RCT	6 lml GPB BD orally for 16 weeks	Placebo	90	88		–	2014	•The study showed a significant improvement in plasma ammonia concentration and safety profile
Polyethylene Glycol (PEG)
Mohammadreza Naderian85 – Iran	RCT	PEG-lactulose	Lactulose	21	19		HESA	2017	•Significant decrease in blood ammonia level and length of hospital stays •Subgroup analysis showed PEG lactulose can decrease the length of hospital stay more significantly in women compared to males
Om Parkash (responsible party)88 – Pakistan	Double-blind, RCT	PEG 3 or 4 sachets in 750 lml water TID until patient discharge	Lactulose 90 ml in 750 ml water TID up to 72 h or until discharge	102 participants			HESA	On-going	•Primary outcome: improvement in HE •Secondary outcome: length of hospital stays
Radha K Dhiman (responsible party)89 – India	Open-label, RCT	PEG and lactulose Q12h	Lactulose 30 ml QID	60 participants				On-going	•Primary outcomes: survival benefit, improvement in HE grades •Secondary outcomes: Reduction in seizure, ammonia, mortality, cerebral edema
Ahmed Syed86 – India	RCT	PEG 3350 and lactulose Q12h	Lactulose 30–60 ml TID	29	31		HESA	2020	•Significant reduction in HESA score in PEG group •No significant improvement in ammonia levels in both groups. Although improvement in hepatic encephalopathy was better in the PEG group
Waseem Raja87 – India	RCT	PEG 3350	Lactulose	25	25		HESA	2019	•A significant change in HESA score in the PEG group within 24 h •No significant changes in serum ammonia levels and length of hospital stay in both the groups
Nitazoxanide (NTZ)
Abd-Elsalam93 – Egypt	RCT	NTZ and lactulose	Placebo and lactulose	60	60		CHESS	2019	•Results demonstrated significant advancement in CHESS score and mental status (alertness, orientation, response to stimulation) in the NTZ group
Abd-Elsalam (responsible party)94 – Egypt	RCT	NTZ 500 mg for 6 months	Rifaximin 550 mg BD for 6 months	60 participants			–	On-going	•Primary outcome: to assess the number of encephalopathy episodes
Branched-Chain Amino Acid (BCAA)
Madhumita Premkumar (responsible party)100 – India	RCT	IV BCAA 500 ml OD for 3 days and lactulose	Lactulose	68 participants			–	On-going	•Primary outcomes: improvement in survival and encephalopathy •Secondary outcomes: reduction in ammonia, recovery time, cerebral edema, and change in mortality rate

ALC, acetyl-l-carnitine; BD, twice a day; BCAA, branched-chain amino acid; BDI, Beck Depression Inventory; BUN, blood urea nitrogen; CHESS, Clinical Hepatic Encephalopathy Staging Scale; ECT, estimated completion time; EEG, electroencephalogram; FMT, fecal microbiota transplantation; GPB, glycerol phenylbutyrate; HESA, Hepatic Encephalopathy Scoring Algorithm; HRQOL, health-related quality of life; IV, intravenous; MELD, Model for End-stage Liver Disease; MMSE, Mini-Mental State Examination; NTZ, nitazoxanide; OD, once a day; PEG, polyethylene glycol; QID, four times a day; RBNS, Repeatable Battery for the Assessment of Neuropsychological Status; RCT, randomized control trial; TID, three times a day.