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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

A total of 40 patients taking proton pump inhibitors (PPIs) who undergo transjugular intrahepatic portosystemic shunt (TIPS) creation as part of routine clinical care will be randomized in 1:1 fashion to either continue or discontinue their PPIs to determine whether these commonly used gastric acid suppressing agents increase risk of post-TIPS hepatic encephalopathy (HE). Patients will be assessed for symptoms of minimal HE (MHE), using the established psychometric hepatic encephalopathy score (PHES) battery of tests. MHE assessment will be conducted at two timepoints: at baseline prior to randomization and TIPS creation and approximately 4 weeks after randomization and TIPS creation. Stool samples will also be collected at both timepoints to allow characterization of the gastrointestinal (GI) tract microbiome using 16S rRNA sequencing. The pre to post-TIPS change in PHES scores will be compared between patients randomized to continue versus discontinue their PPIs. Quality of life (QOL) will also be assessed. 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.

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.

How does the drug for hepatic encephalopathy differ from other treatments?

The treatment involves deprescribing proton pump inhibitors (PPIs), which are typically used to reduce stomach acid, rather than directly targeting hepatic encephalopathy. This approach is unique because it focuses on reducing potential side effects or complications from PPIs that may worsen liver conditions, rather than adding new medications. ^{1 2 3 4 5}

Research Team

James Ronald, MD PhD

Principal Investigator

Duke University

Eligibility Criteria

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 18 years old or older.

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Gadoxetic Acid-Enhanced MR Imaging Predicts Simeprevir-Induced Hyperbilirubinemia During Hepatitis C Virus Treatment: A Pilot Study. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir-induced hyperbilirubinemia during treatment of hepatitis C. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Inhibitors of Organic Anion-Transporting Polypeptides 1B1 and 1B3: Clinical Relevance and Regulatory Perspective. [2021]

5. England pubmed.ncbi.nlm.nih.gov

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