MILAN — , results of a phase 2 randomized controlled trial show.
“Not only was FMT more beneficial, but also it didn’t matter which route of administration was used — oral or enema — which is good because people don’t really like enemas,” said Jasmohan S. Bajaj, MD, AGAF, professor, School of Medicine, Virginia Commonwealth University, Richmond, and hepatologist at Richmond VA Medical Center.
Dr. Jasmohan S. Bajaj
Donor background (including vegan or omnivore) and dose range also did not affect the efficacy of FMT, Dr. Bajaj said.
Dr. Bajaj presented the findings (Abstract GS-001) at the opening session of the annual European Association for the Study of the Liver (EASL) Congress 2024.
Hepatic encephalopathy is a complication of advanced liver disease that causes a dementia-like state. Standard treatment with lactulose and rifaximin often results in a lack of patient response, meaning the patient is constantly being readmitted to the hospital, Dr. Bajaj said.
“This is a burden for the family as well as the patients,” and is very difficult to manage from a clinical and psychosocial perspective, he said in an interview.
With FMT, “we are transferring an ecosystem of good microbes,” which modifies the gut microbiome in patients with advanced liver disease and reduces associated brain toxicity, Dr. Bajaj explained.
Resetting the Gut
The double-blind, randomized, placebo-controlled trial enrolled a total of 60 patients with cirrhosis who had experienced hepatic encephalopathy. Aged 61-65 years, participants had Model for End-Stage Liver Disease (MELD) scores of 12-13, all were taking lactulose and rifaximin, and all had experienced their last hepatic encephalopathy episode 8-13 months prior.
Participants had similar baseline cognition, Sickness Impact Profile (SIP), and cirrhosis severity. Those with recent infections, taking other antibiotics, with a MELD score > 22, had received a transplant, or were immunosuppressed were excluded.
Study participants were divided into four dose administration groups (n = 15 each): oral and enema active FMT therapy (group 1), oral active FMT and enema placebo (group 2), oral placebo and enema active FMT (group 3), and oral and enema placebo (group 4).
The range of FMT dose frequency was zero (all placebo), or one, two, or three FMT administrations, each given 1 month apart.
Two thirds of those receiving active FMT were given omnivore-donor FMT, and one third were given vegan-donor FMT, in addition to receiving standard of care.
“Colony-forming units were standard and the same whether given via oral capsule or enema,” Dr. Bajaj said. This is “similar to what we used in our phase 1 study.”
Intent-to-treat (ITT) analysis was performed with 6-month data. The primary outcomes were safety and hepatic encephalopathy recurrence defined as ≥ grade 2 on West-Haven criteria. Secondary outcomes included other adverse events, changes in infections, severity of cirrhosis and cognition, and patient-reported outcomes. A statistical regression for hepatic encephalopathy recurrence was also performed. Patients were followed for 6 months or until death.
One Dose of FMT Better Than None
Hepatic encephalopathy recurrence was highest (40%) in group 4 patients, compared with those in group 1 (13%), group 2 (13%), and group 3 (0%), as were liver-related hospitalizations (47% vs 7%-20%).
SIP total/physical and psych scores improved with FMT (P = .003).
When all patients were included in the analysis, the hepatic encephalopathy recurrence was related to dose number (odds radio [OR], 0.27; 95% CI, 0.10-0.79; P = .02), male sex (OR, 0.16; 95% CI, 0.03-0.89; P = .04), and physical SIP (OR, 1.05; 95% CI, 1.01-1.10, P = .05). However, when analyzing results from FMT recipients only, FMT dose, route of administration, and donor source were not found to affect recurrence.
Of those on placebo alone, six patients (40%) had a recurrence, compared with four on FMT (8.8%) in the combined FMT groups.
“As long as a patient received at least one FMT dose, they had a better response than a patient who had none,” Dr. Bajaj said.
Six patients dropped out; two in group 1 died after hepatic encephalopathy and falls, and one in group 2 died after a seizure. Three others did not return for follow-up visits. Four patients developed infections, including spontaneous bacterial peritonitis, cholecystitis, and cellulitis, all unrelated to FMT.
“I think many patients in Western countries are underserved because apart from lactulose and rifaximin, there is little else to give them,” Dr. Bajaj said. “The assumption is because rifaximin kills everything, we shouldn’t give FMT. But here, we administered it to a harsh and hostile wasteland of microbiota, and it still got a toehold and generated a reduction in hepatic encephalopathy.”
He pointed out that in smaller prior studies, the effects lasted up to 1 year.
Setting the Stage for Phase 3 Trials
Dr. Bajaj noted that this phase 2 study sets the stage for larger phase 3 trials in patients not responding to first-line therapy.
“Given how well-tolerated and effective FMT appears to be in these patients, if the larger phase 3 trial shows similar results, I can imagine FMT becoming a standard therapy,” said Colleen R. Kelly, MD, AGAF, gastroenterologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved in the study.
Dr. Colleen R. Kelly
This study was built on Dr. Bajaj’s prior work that established the safety of FMT by enema, she added, stressing that this new research was incredibly important in these immunocompromised patients who are at higher risk for infection transmission.
That the administration route doesn’t matter is also an important finding as oral administration is much more feasible than enema, said Dr. Kelly, who went on to point out the importance of finding an alternative to rifaximin and lactulose, which are often poorly tolerated.
The study highlights the central role played by the gut microbiota in dysbiosis in the pathophysiology of hepatic encephalopathy, Dr. Kelly said. “It is another exciting example of how gut microbiota can be manipulated to treat disease.”
Dr. Bajaj and Dr. Kelly report no relevant financial relationships to this study.
A version of this article appeared on Medscape.com.