Active Clinical Trials in Hepatic Encephalopathy: Something Old, Something New and Something Borrowed

Based on information obtained by the clinicaltrials.gov platform, on August 19th, 2022, there were 17 active clinical trials in HE aiming to obtain more evidence about the safety and efficacy of well-known and already used agents but also to explore new possibilities in the management of this syndrome. In relation to the obtained results and according to the current knowledge of the condition, this report allows us to add some interesting considerations to the actual state of art of the syndrome.

First, based on the geographical distribution of the clinical trials, at least one nation of each continent (with the exception of Oceania) is realizing an interventional study in patients with HE. In fact, there are currently 11 ongoing clinical trials in the USA, 1 in Belgium, 1 in the Netherlands, 2 in Egypt, 1 in Pakistan and 1 in China. These results are in agreement with the incidence and prevalence of liver diseases observed in such countries. For example, Egypt had the highest age-standardized death rate of cirrhosis in all years from 1990 to 2017, despite a 22.4% decrease from 1990 (133.1 per 100,000 population) to 2017 (103.3 per 100,000 population) [38]. In 2017, 41.5% of deaths due to cirrhosis in Egypt were caused by hepatitis B and 34.4% (the highest worldwide death rate) were caused by hepatitis C [38]. Similarly, cirrhosis is one of most common causes of mortality or hospitalization in Pakistan, and most of these patients have evidence of hepatitis B (22%) or hepatitis C (28%) viral infection [39]. China also has a high age-standardized prevalence of people with compensated cirrhosis, summing to nearly 2000 cases per 100,000 inhabitants. Among high-income regions, the USA showed an unusual age pattern with an increase in cirrhosis deaths driven by alcohol-related liver disease in the 50–69 year age group from 1990 to 2017 [38].

Second, in relation to the analysis of trial categorization by clinical trial phase, it is surprising that phase I was the smallest set of clinical trials (11.8% of total studies), with four agents employed in only two trials. These numbers are probably a consequence of the COVID-19 pandemic, in which most studies and funding have been purposely prioritized for COVID-19 activities above all else. In fact, a recent long-term analysis suggests that the COVID-19 pandemic affected the initiation of clinical trials both in Europe and in the USA [40].

Phase II and phase III clinical trials were the most abundant categories, summing together 75,9% of total active studies and 14 agents. The purpose of a phase II and phase III clinical trial is to determine the right dosage and effectiveness in a larger number and in a wide variety of people who have the disease. In case of poor efficacy of treatment or unexpected serious adverse events, the permission to proceed to the next phase can be denied. In addition to the encouraging numbers in comparison with those observed in phase I, Phase II development remains the largest hurdle in drug development, showing the lowest transition success rate of the four phases. In fact, the overall success rate in phase II reported by the Biotechnology Innovation Organization (BIO) was approximately 31%, with a 36% success rate considering only the gastroenterology field [41]. Better numbers are expected in phase III, where the overall success rate is estimated to be approximately 58% (61% in gastroenterology) [41]. According to these statistics, 6 potential new drugs could reach phase IV.

Phase IV trials consist of clinical research conducted after a drug has been approved [42]. During this phase, the product can be tested in special patient populations, or further information about the risks, benefits and long-term effects can be collected. At this stage, 3 clinical trials and 5 agents were present. The first clinical trial (NCT04436601) will involve 102 participants and will compare the effect of PEG with lactulose for the treatment of HE in patients with liver cirrhosis. The investigators want to compare the resolution of HE as the main outcome. In addition, they would compare the length of stay, nonserious (mainly gastrointestinal) adverse events and 3 month outcome. This interventional study is based on investigators’ hypothesis that rapid purgation of the gut using PEG may resolve HE more effectively than lactulose. Previous phases of this clinical trial showed that PEG significantly decreased the time needed for resolution of HE and significantly shortened the hospital stay [31]. If confirmed, these data would add new evidence to the currently limited evidence on the use of PEG in the treatment of HE worldwide. In line with this hypothesis, a recent review suggests that PEG is able to improve the clinical efficacy of HE within 24 h better than lactulose and does not increase side effects [43]. Hence, PEG might be a useful alternative in 30% of those who do not respond to lactulose if favorable outcomes are demonstrated. The second study (NCT01846663) is a multicenter trial that aims to assess the pharmacokinetics of rifaximin in subjects with severe hepatic impairment and overt HE [44,45,46]. The third study (NCT04073290) is a multicenter, randomized, placebo-controlled, double-blind study involving patients undergoing elective transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites or secondary prophylaxis in variceal bleeding. Post-TIPS HE is a common (20–54%) and often severe complication [47]. The primary objective will be to assess the incidence of post-TIPS over HE within the first three months after prophylactic administration of lactulose and rifaximin versus placebo group. This clinical trial, involving 238 subjects, is estimated to be completed by September 2023, and the authors commit themselves to submit results for publication in a peer-reviewed journal [47].

Last but not least, the analysis of clinical trial categorization by class of drugs unveiled the presence of many old, few new and some borrowed agents already approved for the treatment of other pathologies.

Starting from the old drugs, lactulose and rifaximin are being used in 10 studies. In most cases, they are used as comparative drugs to test the efficacy and safety of new drugs. Notably, two studies (NCT05297448 and NCT05071716) involving 466 subjects each are randomized, double-blind, placebo-controlled, dose-ranging, multicenter studies to assess the efficacy and safety of rifaximin soluble solid dispersion (SSD) immediate release (IR) for the delay of encephalopathy decompensation in cirrhosis. Rifaximin is currently marketed as a 550 mg tablet, and SSD tablets were formulated to maximize the efficacy of rifaximin. Previous phase II clinical trials have shown that rifaximin SSD IR 40 mg may reduce hospitalization in patients with cirrhosis and shorten the duration of overt HE during hospitalization [48]. Among old drugs, TCM can also be included (NCT04073290). It is an alternative medical practice with a history of thousands of years. TCM has the advantages of low cost and high safety and modulates various biological activities, and it has been suggested to be effective in many liver conditions [49]. Currently, it is in phase III, and results are expected at the end of the year.

Among the borrowed agents, rifamycin SV MMX and nitazoxanide are antimicrobial agents that have been approved by the FDA for the treatment of some types of diarrhea [50, 51], and they are considered potential alternative therapies to rifaximin. Unlike rifaximin, rifamycin SV MMX mostly affects the colon, where the bacterial load is much larger than in the other parts of the gastrointestinal tract. This is achieved using a multimatrix structure (MMX), which creates a partially hydrophobic environment that hinders the penetration of aqueous fluids into the tablet core, thus lowering the rate of drug dissolution [52]. A recent phase I trial assessing the pharmacokinetics and safety of rifamycin SV MMX after single and multiple doses in 18 healthy subjects showed its safety and poor absorption, making this antibiotic suitable for small and large intestinal pathologies, including HE [53]. It is currently in phase II (NCT04082780), and it will be tested in cirrhotic patients with MHE. The results are expected in 2023. Encouraging results also came from nitazoxanide (NCT04161053), an antimicrobial agent that exerts its activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase-dependent electron transfer reaction, which is essential to anaerobic energy metabolism [54]. In fact, preliminary phase III data have shown a statistically significant improvement in CHESS score and mental status in addition to a significant reduction in Child score; additionally, nitazoxanide also showed a statistically significant decrease in serum ammonia, TNF-α, and octopamine levels compared to rifaximin [55]. In this category also belong VE303 (NCT04899115), a bacterial consortium, and RBX7455 (NCT04155099), a preparation of live intestinal microorganisms, both borrowed from high-risk Clostridioides difficile infection treatments and efficiently restore microbiome composition after antibiotic-induced dysbiosis. These two agents aim to safely and effectively improve cognitive function in patients with a history of overt HE by restoring microbiome composition and function, as documented in other studies [56].

As an emerging therapy for HE, colistin is an old antibiotic (new for HE) that became available for clinical use in the 1950 s, but it was largely shelved because of concerns about the potential for adverse effects, particularly nephrotoxicity [57]. It was resurrected in the 1990 s for use in cystic fibrosis patients, and it is now considered the last-line antibiotic against gram-negative pathogens. Its mechanism of action consists of solubilizing the bacterial cell membrane, resulting in a bactericidal effect [58]. Over the last decade, pharmacological and clinical interest in colistin has increased, and several conditions are testing it as a potential new treatment. As a new potential agent, it is currently in phase I (NCT05279586), and the efficacy and safety of colistin versus lactulose for secondary prophylaxis of overt HE will be tested in HE patients with liver cirrhosis.

Among the emerging therapies for HE, FMT is probably the most promising strategy. It has been demonstrated to be safe in HE [35] by possibly improving neurocognitive function and decreasing serious adverse events in HE patients by reducing ammonia synthesis and its clearance, reestablishing the integrity of the intestinal barrier and improving liver function [59]. FMT will be tested in 3 different trials (NCT03420482, NCT03796598, and NCT04932577) by two routes of administration (enema or capsule). Preliminary results from the first trial (NCT03420482) show that FMT capsules are safe and improve cognition in patients with a history of overt HE [60]. Similarly, preliminary data from the PROFIT trial have demonstrated that FMT is safe and feasible in patients with advanced stable cirrhosis, showing a striking reduction in plasma ammonia [61] and inflammation [62].

Lastly, an interventional, multicenter, three-arm, randomized, controlled trial (NCT04862221) launched this year aims to test immunosuppressive therapy for children with acute liver failure. The efficacy and safety of high doses of methylprednisolone (a widely used anti-inflammatory drug) or equine anti-thymocyte globulin (an immunosuppressive drug targeting a variety of lymphocyte surface proteins, activated B cells, bone marrow cells, and other cell types [63]) will be tested, and the survival rate will be determined. It is currently recruiting subjects, and results are expected in January 2026. If the positive outcomes are confirmed, it could also open new possibilities to treat HE or mHE patients with liver cirrhosis given that inflammation and immune response have been suggested to play a central role in the pathogenesis of HE, as demonstrated in patients and animal models [6, 8, 64,65,66]. Unfortunately, although many nonsteroidal anti-inflammatory drugs, such as ibuprofen or celecoxib, or anti-TNF-α inhibitors, including infliximab or etanercept, which have revolutionized the treatment of multiple inflammatory conditions, including rheumatoid arthritis, psoriasis and inflammatory bowel disease, have shown promising results in animal models of liver disease [6, 67,68,69,70], they have also been associated with different degrees of hepatotoxicity when tested in patients, including the reactivation of viral hepatitis, drug-induced liver injury and de novo autoimmune hepatitis [71,72,73]. Therefore, the fact that only two drugs belonging to this category have reached testing in humans indicates that more efforts are needed to reduce the enormous gap between these and the other and more classical drugs, which still dominate the pharmacological field in HE.

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