Proton Pump Inhibitor Deprescribing for Hepatic Encephalopathy
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Duke University
Must be taking: PPIs
Disqualifiers: Grade IV esophagitis, Ulcer, Pregnancy, others
No Placebo Group
Approved in 4 Jurisdictions
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.
12345Eligibility 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.
+2 more
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.
+2 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Active Control
Group I: PPI deprescribing armExperimental Treatment1 Intervention
Patients taking a PPI (at least 20 mg omeprazole equivalent daily) will be instructed to stop taking their PPI.
Group II: PPI continuation armActive Control1 Intervention
Patients will be instructed to continue taking their PPI (at least 20 mg omeprazole equivalent daily) as usual.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Duke University HospitalDurham, NC
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Who Is Running the Clinical Trial?
Duke UniversityLead Sponsor
References
Gadoxetic Acid-Enhanced MR Imaging Predicts Simeprevir-Induced Hyperbilirubinemia During Hepatitis C Virus Treatment: A Pilot Study. [2018]Simeprevir is a substrate for organic anion-transporting polypeptides (OATPs) that transport bilirubin. Hyperbilirubinemia is an adverse event reported during treatment of chronic hepatitis C patients with simeprevir plus pegylated interferon and ribavirin. Because gadoxetic acid is also a substrate of OATPs, pretreatment gadoxetic acid-enhanced magnetic resonance imaging (MRI) may predict hyperbilirubinemia during treatment. This prospective study therefore evaluated 11 consecutive patients with chronic hepatitis C who underwent gadoxetic acid-enhanced MRI prior to treatment with simeprevir plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin for an additional 12 weeks. Their contrast enhancement index (CEI), an index of liver parenchymal enhancement during the hepatobiliary phase, was assessed before treatment. Plasma trough concentrations (Ctrough ) of simeprevir were determined 7 days after its administration, and serum bilirubin concentrations were measured throughout the course of treatment. Six patients (55%) developed hyperbilirubinemia (≥1.6 mg/dL) during treatment. Ctrough was significantly higher in patients with than without hyperbilirubinemia (P = .009), with a strong inverse relationship between CEI and Ctrough (r = -0.911, P < .001). CEI was significantly lower in patients with than without hyperbilirubinemia (P = .009), but there were no significant differences between the 2 groups in pretreatment serum albumin concentrations and FIB-4 index, an index of liver fibrosis. Hepatic enhancement with gadoxetic acid was related to Ctrough of simeprevir. Gadoxetic acid-enhanced magnetic resonance imaging may predict the development of hyperbilirubinemia during treatment of hepatitis C patients with simeprevir plus pegylated interferon and ribavirin.
Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. [2020]Inhibition of the bile salt export pump (BSEP) by a drug has been implicated as a risk factor for a drug's potential to cause drug-induced liver injury (DILI) and is thought to be an important mechanism leading to DILI. For a wide variety of drugs a correlation has been observed between the potency of in vitro BSEP inhibition and its propensity to cause DILI in humans. These findings were interpreted to suggest that BSEP inhibition could be an important mechanism to help explain how some drugs initiate DILI. Because the Biopharmaceutics Drug Disposition Classification System (BDDCS) can be useful in characterizing and predicting some important transporter effects in terms of drug-drug interactions, we evaluated the information provided by BDDCS in order to understand the inhibition propensity of BSEP. Here we analyze the relationship between a compound's ability to inhibit BSEP function and cause liver injury in humans using a compilation of published DILI datasets that have screened for BSEP inhibitors, other hepatic transporters and other mechanism-based toxicity key events. Our results demonstrate that there is little support for in vitro BSEP inhibition being universally DILI predictive. Rather we show that most potent BSEP inhibitors are BDDCS class 2 drugs, which we have demonstrated previously is the BDDCS class most likely to be DILI related. Since BDDCS class is not related to any proposed DILI mechanistic hypotheses, we maintain that if measures of BSEP inhibition alone or together with inhibition of other transporters cannot be differentiated from class 2 assignment, there is no support for in vitro BSEP inhibition being DILI predictive.
Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir-induced hyperbilirubinemia during treatment of hepatitis C. [2021]Paritaprevir inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, which transport bilirubin. Hyperbilirubinemia is an adverse event reported during hepatitis C treatment. Gadoxetic acid is also transported by OATP1B1/1B3. We evaluated whether the enhancement effect in gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the plasma concentration of paritaprevir and might anticipate the development of hyperbilirubinemia.
Inhibitors of Organic Anion-Transporting Polypeptides 1B1 and 1B3: Clinical Relevance and Regulatory Perspective. [2021]Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.
The role of hepatic transporters in drug elimination. [2019]Hepatic drug transporters of the solute carrier (OATPs, OAT2, OCT1, NTCP) and ABC transporter superfamilies (MDR1, MRPs, BCRP, BSEP) can significantly modulate drug ADME routes.