Proton Pump Inhibitor Deprescribing for Hepatic Encephalopathy

Overseen By James Ronald, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Duke University

Must be taking: PPIs

Disqualifiers: Grade IV esophagitis, Ulcer, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether stopping or continuing proton pump inhibitors (PPIs)—medications that reduce stomach acid—affects the risk of developing hepatic encephalopathy, a brain condition linked to liver disease, after a TIPS procedure. Participants who regularly take PPIs and are undergoing TIPS will be divided into two groups: one will stop taking PPIs, and the other will continue. Researchers will compare brain function and gut bacteria changes in both groups to determine if PPIs contribute to brain issues. This trial suits individuals taking PPIs and scheduled for a TIPS procedure as part of their regular medical care. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works and measure its effectiveness in an initial group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial involves patients who are currently taking proton pump inhibitors (PPIs). Participants will be randomly assigned to either continue or stop their PPIs, so you may or may not have to stop taking them depending on your group.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that stopping proton pump inhibitors (PPIs) might be safe for individuals with liver problems. The STOPPIT trial studied patients with liver cirrhosis, a serious liver condition, who discontinued PPIs. This trial found no major safety concerns from stopping these medications.

PPIs are commonly used to reduce stomach acid. However, earlier studies suggest they might increase the risk of health issues like infections and hepatic encephalopathy, a brain disorder caused by liver problems, in people with liver disease.

The trial is in its early stages, focusing on both safety and effectiveness, so there is limited safety evidence so far. However, since PPIs are already approved for other uses, this provides some reassurance about their general safety.

Stopping PPIs could alter the gut microbiome, the bacteria in the stomach, which might be important for those with liver issues. The trial aims to explore this further. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores how stopping proton pump inhibitors (PPIs) might impact hepatic encephalopathy. Unlike current treatments that often focus on managing symptoms with medications like lactulose and rifaximin, this approach examines the potential benefits of reducing medication use. By deprescribing PPIs, researchers hope to uncover whether it can improve liver-related brain conditions or reduce side effects associated with long-term PPI use. This trial could lead to a shift in how we manage hepatic encephalopathy, potentially reducing medication load for patients.

What evidence suggests that this trial's treatments could be effective for hepatic encephalopathy?

Research has shown that proton pump inhibitors (PPIs), a type of medication, might increase the risk of developing hepatic encephalopathy (HE) after a liver procedure known as TIPS. Some studies have found a connection between PPI use and a higher chance of HE in these patients, but results vary. This trial will compare two approaches: one group of participants will stop taking their PPIs (the PPI deprescribing arm), while another group will continue their usual PPI regimen (the PPI continuation arm). Stopping PPIs in people with liver problems might help lower this risk. Other studies have linked PPI use to worse outcomes, such as higher death rates in liver patients. Researchers are interested in whether stopping PPIs could benefit those undergoing the TIPS procedure. ^{3 6 7 8 9}

Who Is on the Research Team?

James Ronald, MD PhD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for adults 18 or older who are already taking proton pump inhibitors (PPIs) and will undergo a TIPS procedure as part of their usual care. They must be willing to follow the study rules and be available for its duration. People can't join if they're pregnant, have severe esophagitis or ulcers, need PPIs after certain esophageal procedures, have Zollinger-Ellison syndrome, or an active Helicobacter pylori infection.

Inclusion Criteria

Provision of signed and dated informed consent form by participant or legal representative

I am scheduled for a TIPS procedure as part of my standard treatment.

I am willing and able to follow all study rules and attend all appointments.

Exclusion Criteria

You currently have an active Helicobacter pylori infection.

I have severe esophagitis or a serious stomach or duodenal ulcer.

I am on PPIs after a procedure to treat swollen veins in my esophagus.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline assessment of minimal hepatic encephalopathy (MHE) and stool sample collection prior to randomization and TIPS creation

1 week

1 visit (in-person)

Treatment

Randomization to either continue or discontinue PPIs, with follow-up assessment of MHE and stool sample collection approximately 4 weeks after TIPS creation

4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety, quality of life, and changes in gastrointestinal tract microbiome

6-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PPI

Trial Overview The trial aims to see if stopping PPIs reduces brain dysfunction (hepatic encephalopathy) after a TIPS procedure. Participants are randomly chosen to either stop or continue their PPI medication. Their brain function and quality of life are measured before and about four weeks after the TIPS procedure.

How Is the Trial Designed?

Group I: PPI deprescribing arm Experimental Treatment 1 Intervention

Patients taking a PPI (at least 20 mg omeprazole equivalent daily) will be instructed to stop taking their PPI.

Group II: PPI continuation arm Active Control 1 Intervention

Patients will be instructed to continue taking their PPI (at least 20 mg omeprazole equivalent daily) as usual.

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Published Research Related to This Trial

In a study of 27 hepatitis C patients, gadoxetic acid-enhanced MR imaging was found to be a useful tool for predicting the risk of hyperbilirubinemia during treatment with paritaprevir, with a significant correlation between liver enhancement and paritaprevir plasma concentration.

The study revealed that a lower contrast enhancement index (CEI < 1.61) was an independent predictor of hyperbilirubinemia, indicating that monitoring liver enhancement could help anticipate this adverse effect in patients undergoing hepatitis C treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir-induced hyperbilirubinemia during treatment of hepatitis C. Okubo, H., Ando, H., Sorin, Y., et al.[2021]

Hepatic drug transporters play a crucial role in drug clearance and can significantly influence how drugs are absorbed, distributed, metabolized, and excreted (ADME), highlighting their importance in early drug research.

Challenges in studying these transporters include the lack of selective substrates and inhibitors, interference from passive permeability, and the presence of endogenous transporters in assays, which complicates the accurate assessment of drug transport mechanisms and their extrapolation to real-life scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of hepatic transporters in drug elimination. Funk, C.[2019]

In a study of 11 chronic hepatitis C patients treated with simeprevir, pegylated interferon, and ribavirin, 55% developed hyperbilirubinemia, indicating a significant adverse effect associated with the treatment.

Gadoxetic acid-enhanced MRI showed potential as a predictive tool for hyperbilirubinemia, as lower liver enhancement correlated with higher plasma concentrations of simeprevir, suggesting that imaging could help identify patients at risk for this side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gadoxetic Acid-Enhanced MR Imaging Predicts Simeprevir-Induced Hyperbilirubinemia During Hepatitis C Virus Treatment: A Pilot Study. Okubo, H., Kitamura, T., Ando, H., et al.[2018]

This study identified 13 drugs and 16 combination products that act as clinical inhibitors of the liver transporters OATP1B1 and OATP1B3, which are important for drug uptake and can significantly affect the exposure of sensitive drugs.

While cyclosporine and single-dose rifampin remain the recommended index inhibitors for studying drug-drug interactions involving OATP1B1/1B3, the study did not find any new index inhibitors, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitors of Organic Anion-Transporting Polypeptides 1B1 and 1B3: Clinical Relevance and Regulatory Perspective. McFeely, SJ., Ritchie, TK., Yu, J., et al.[2021]

Inhibition of the bile salt export pump (BSEP) has been linked to drug-induced liver injury (DILI), but this study found that in vitro BSEP inhibition is not a reliable predictor of DILI risk in humans.

Most potent BSEP inhibitors belong to BDDCS class 2 drugs, which are more likely to be associated with DILI, suggesting that BSEP inhibition alone does not adequately explain the mechanisms behind liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. Chan, R., Benet, LZ.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05070351

Deprescribing Proton Pump Inhibitors to Reduce Post-TIPS ... Study Plan ; Minimal hepatic encephalopathy, Minimal hepatic encephalopathy, as assessed by psychometric hepatic encephalopathy score, Approximately 6-8 weeks ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10989172/

Association between proton pump inhibitors and risk of ... The use of PPIs is associated with an increased risk of post-TIPS HE; however, findings on the risk relationship between PPIs and post-TIPS HE are inconsistent.

3. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06232-w

Stop of proton-pump inhibitor treatment in patients with liver ... The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6737311/

Proton pump inhibitor use increases mortality and hepatic ... PPI use in patients with decompensated liver cirrhosis was associated with higher mortality and increased risk of hepatic decompensation requiring hospital ...

5. mdpi.com mdpi.com/2813-0618/4/3/15

Prescribing Responsibly: Navigating the Tides of ... The results of the 2020 PEPTIC study, an open-label RCT with 26,828 patients, comparing the safety and efficacy of PPIs with H2RAs for SUP in critically ill ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05070351

Deprescribing Proton Pump Inhibitors to Reduce Post-TIPS ... Changes in the GI tract microbiome will be analyzed to determine whether this represents a potential biological mechanism linking PPI use with post-TIPS HE.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9003168/

Stop of proton-pump inhibitor treatment in patients with liver ... The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis.

8. dig.pharmacy.uic.edu dig.pharmacy.uic.edu/faqs/2023-2/june-2023-faqs/what-is-the-update-on-long-term-safety-evidence-with-proton-pump-inhibitor-use/

What is the update on long-term safety evidence with proton ... Since prior observational data has linked PPI therapy in cirrhotic patients with an increased risk for infection, hepatic encephalopathy, ...

9. withpower.com withpower.com/trial/phase-2-brain-diseases-9-2021-a4785

Proton Pump Inhibitor Deprescribing for Hepatic ... This Phase 1 & 2 medical study run by Duke University needs participants to evaluate whether PPI will have tolerable side effects & efficacy for patients ...