Clinical trial NCT01458990
Conditions: Cirrhosis Healthy
Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center
Start date: 2011-10-01; Completion date: 2018-02-01
Enrollment: 60 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out whether the use of medications that suppress acid in your stomach can change the composition of your bowel bacteria.

Detailed description:

Arms: arm 1: Adding 40mg omeprazole QD for 14 days arm 2: The intervention here is systematically withdrawing chronic PPI for 14 days
Interventions: intervention 1: Omeprazole
Intervention descriptions: intervention 1: 20mg PO BID for 20 days

Protocol documents:
Prot_000.pdf: 
11/29/17 
NCT01458990: Proton Pump Inhibitors and Dysbiosis in Cirrhosis 


Protocol Outline for Decompensated cirrhosis portion of the study 
(the compensated cirrhosis and healthy control portion is published in 
AJP 2014 and the publication has been uploaded) 
RESEARCH PLAN 
This will be a prospective 14-day study of outpatients with decompensated cirrhosis (Study 
overview is presented in the figure). We will recruit subjects from the hepatology clinics at the 
McGuire VA and VCU Medical Center.  
There will be two age-matched patient groups: 
Group 1: Patients not on PPI therapy who will be started on omeprazole 40mg/Qday before 
breakfast 
Group 2: Patients on 40mg/day omeprazole or equivalent for an unapproved indication who will 
be withdrawn from the PPI 
Inclusion criteria for both groups: 
1. Cirrhosis diagnosed using biopsy, or radiologic/endoscopic evidence of cirrhosis and/or
varices in the setting of chronic liver disease.
2. Evidence of decompensation: ascites or hepatic hydrothorax by history, examination due to
cirrhosis or controlled using diuretics, history of variceal bleeding or jaundice (bilirubin >5mg/dl)
at time of enrollment.
3. Able to give consent
Exclusion criteria for both groups: 
1. unclear diagnosis of cirrhosis or of decompensation
2. Alcohol/illicit drug use in the last 3 months
3. Unable to give consent
4. Current hepatic encephalopathy treatment (lactulose, rifaximin), SBP prophylaxis, probiotics
5. Recent (<2 months) infections or treatments with systemic antibiotics or upper GI bleed
6. Allergic to PPI therapy
7. Patients on H2 receptor blockers
Special inclusions/exclusions for Group 2:  we will only consider cirrhotic patients on 40mg/day 
omeprazole equivalent for PPI withdrawal if they are 
1. Willing to withdraw this therapy
2. Are on PPI therapy for an indication other than the FDA-approved ones listed below22:
(a) Healing and maintenance of erosive esophagitis, (b) Treatment of gastro esophageal reflux
disease, (c) Risk reduction for peptic ulcer with non-steroidal anti-inflammatory drugs (d)
Helicobacter pylori eradication, in combination with antibiotics; (e) Pathological hyper-secretory
conditions, including Zollinger-Ellison syndrome; (f) Short-term treatment and maintenance of
peptic ulcer therapy.
Justification for study design and inclusion/exclusion criteria: our prior work and previous studies 
have shown that 14 days can change gut microbiota adequately with therapies. Since a large 
proportion of patients with decompensated cirrhotics are already on PPI, both a withdrawal and 
an introduction design will be used to increase the generalizability of the study results. We will 
exclude patients on recent/current antibiotics, probiotics and hepatic encephalopathy treatment 
to minimize the confounding factors for microbiota analysis. We chose 40mg/day before 


breakfast since this was the dose the majority of our current decompensated cirrhotics are on 
and also to increase adherence with once-a-day dosing. Additionally this was also the regimen 
used in our preliminary study9. 
Screening: we will bring potential patients in for re-confirming their eligibility, evaluation of their 
indication and adherence to PPI use and in those who potentially fall in group 2, to gauge their 
willingness to stop PPIs for 14 days. Once eligibility is confirmed and informed consent is 
obtained, a standard diet (35Kcal/kg/day and 1.2-1.5g/kg/day of protein) will be prescribed and 
a food diary will be issued. Subjects will be given stool collection kits (with RNAlater) and asked 
to return for visit 2 within 7-14 days after the first visit.  
Visit 1: We will reconfirm eligibility and adherence. Blood will be collected for gastrin, calculation 
of MELD score, and metabolomics; stool will be collected for microbial composition and 
function; and urine will be collected for metabolomics.  After collection of the specimens, 
patients from group 1 will be started on omeprazole 40mg/day before breakfast for 14 days 
while those in group 2 will be asked to withdraw their PPI therapy. All subjects will continue on 
the same diet. Subjects will be given the contact information of the study team in case they 
experience any change in their medications, urgent clinic visits, antibiotic use or hospitalizations 
in the interim. Subjects will be paid $50 for completing the first visit activities and will be given a 
stool collection kit to bring with them for visit 2. 
Telephone call one week after visit 1: to reconfirm that study conditions, diet conditions are 
being met and that there are no changes in the patients’ underlying status. In case of initiation of 
antibiotics, change in PPI dose or re-initiation of PPI (group 2), we will attempt to bring those 
patients in as soon as possible to analyze microbiota changes.  
Visit 2: At the end of 14 days, we will re-evaluate subjects’ adherence on the study protocol and 
will perform all procedures regarding the study samples as in visit 1. At this point, the study 
participation for subjects will end. At this time, subjects will be paid $125 for their participation. 
Detailed analyses of samples: Blood: MELD score laboratories (bilirubin, INR, creatinine)24 
and will be analyzed through the VA hospital clinical laboratory. Stool: Stool: Stool in RNAlater 
will be used to extract both DNA and RNA at the MBAC at George Mason University, VA using 
published techniques.  
Statistical analysis: in the separate document 
Expected outcomes: We expect a significant change in microbiota function and composition 
with a reduction in dysbiosis and microbial genes activated towards formation of toxic 
metabolites and altered microbial-mammalian co-metabolites when PPIs are taken out of the 
patients’ systems. We do not expect any additional adverse events, including infections to occur 
associated with PPI given the relatively short duration of the study but all complications will be 
noted. To ensure adequate numbers we are accounting for a 15% dropout rate. We will 
increase enrollment if there are more dropouts than planned.  

SAP_001.pdf: 
11/29/17 
NCT01458990: Proton Pump Inhibitors and Dysbiosis in Cirrhosis 
Safety analysis: 
A. Adverse events: related to PPI initiation (allergy, GI upset etc) or withdrawal (recurrence
of symptoms, GI bleeding etc) will be analyzed using non-parametric tests.
B. Withdrawal from study
Microbiota analysis: 
Will be performed using multi-tagged sequencing of stool samples in pre vs post PPI (initiation) 
and before/after PPI withdrawal. Wilcoxon signed-rank matched pairs tests and Kruskal Wallis 
test will be used.