A Study of Controlled Lactulose Withdrawal

Study Overview
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Brief Summary
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After resolution of the initial episode of hepatic encephalopathy (HE), lactulose is routinely continued indefinitely as maintenance therapy. Although widely used for this indication, lactulose has never been shown in randomized, controlled trials to be effective for preventing exacerbations of HE. Indeed, lactulose was found to be ineffective at preventing HE when administered prophylactically to patients undergoing portosystemic shunt insertion. While some patients may be lactulose dependent following an initial episode of HE, it is likely that most could have their lactulose discontinued with no adverse consequences. This goal is worth pursuing because lactulose is not innocuous. It has an unpleasant taste, and it routinely produces gastrointestinal symptoms, including bloating, gas and diarrhea. In high doses it can cause incontinence, dehydration and electrolyte derangements. Patients universally dislike taking lactulose and often are noncompliant with treatment. A recent trial showed that patients on lactulose had a substantial risk of hospital admissions due to lactulose-related complications and treatment non-compliance.

Detailed Description
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In this pilot study we propose to perform controlled lactulose withdrawal in selected patients with HE whose initial presentation follows a clearly defined, reversible precipitating event or those with stable, chronic HE. We hypothesize that a majority of these patients can be withdrawn from daily lactulose therapy without deterioration of cognitive function, and that lactulose withdrawal will improve symptoms and quality of life for these individuals. We propose to carry out a comprehensive battery of clinical, laboratory, microbiological and psychometric evaluations before and after lactulose withdrawal. We will closely follow changes in cognitive function and re-institute lactulose therapy at the first sign of clinical deterioration. Through multivariate analysis we propose to develop a model to discriminate between treatment dependent and treatment independent patients.

Official Title
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Is Continuous Lactulose Therapy Necessary for Patients With Hepatic Encephalopathy? A Prospective Study of Controlled Lactulose Withdrawal

Conditions
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Hepatic Encephalopathy

Intervention / Treatment
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* Drug: lactulose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of hepatic cirrhosis based on biopsy, clinical and/or radiological findings. Stable HE (chronic): On daily lactulose for more than 6 months without hospitalization for HE within 3 months of enrollment. Treated with lactulose on a daily basis, with restoration of mental status to baseline. Lives with an adult individual who is willing to serve as a full-time caregiver. Able and willing to give informed consent. Exclusion Criteria: Use of antibiotics, including rifaximin. Patient without an adult caregiver. Pre-existing focal neurological deficits, seizures or other indication of structural neurological disorder. Actively abusing illicit drugs or alcohol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lactulose withdrawal<br>Patients who were started on lactulose as a result of a precipitated HE episode underwent analysis while they were on lactulose; after this they underwent a controlled lactulose withdrawal with 3 visits post-withdrawal at 2 days, 14 days and 30 days after lactulose withdrawal | Drug: lactulose<br>* withdrawal of lactulose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychometric function and relapse into clinical HE |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MR Spectroscopy |  | 30 days | 
| Pro-inflammatory cytokines |  | 30 days | 
| Stool bacterial DNA analysis |  | 30 days | 
| Urine and blood for metabolomics |  | 30 days | 
| Quality of life |  | 30 days |