Effectiveness of Oral Lactulose Versus Lactulose Enema in Hepatic Encephalopathy

Effectiveness Of Oral Lactulose Versus Lactulose Enema On The Time To Recovery From Overt Hepatic Encephalopathy

Patients with chronic liver disease due to hepatitis B or C viruses, Non-alcoholic fatty liver disease, autoimmune hepatitis, wilson disease, cryptogenic hepatitis etc are prone to develop complications. Hepatic encephalopathy is one of such complications. It is graded into four types depending on severity of clinical features, which range through altered sleep pattern to coma. The current study aims to compare the effectiveness of lactulose enema with oral lactulose in time to recovery from higher grade of encephalopathy to lower grade of encephalopathy.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatic Encephalopathy; Chronic Liver Disease
• Intervention / Treatment: Drug: Tap water; Drug: Lactulose

Detailed Description

Hepatic encephalopathy (HE) is defined as neuropsychiatric disorder due to liver failure. It is characterized by mild cognitive impairment, stupor and coma. The most common reasons for pathogenesis include the role of neurotoxins, impaired neurotransmission due to metabolic changes in liver failure, changes in brain energy metabolism, systemic inflammatory response and alterations of the blood brain barrier. Neurotoxin ammonia is related to precipitating HE, for which the gastrointestinal tract is the primary source. Colonic bacteria catabolise the nitrogenous sources into ammonia.

Lactulose is the initial treatment for HE. It produces diarrhea by osmosis and reduces pH of colonic contents, which leads to reduced absorption of ammonia by converting it to ammonium ion (NH4). Understandingly, it does not cure the underlying liver disease however, it does prevent deterioration of the mental status in HE.

Initial oral dose of lactulose is 30 ml once a day or twice daily. For retention enema the dose is 300 ml lactulose plus 700 ml water, administered every 4 hours. It can be increased as tolerated. At least, 2-4 loose stools per day should be passed by the patient.

Lactulose is also effective as primary prophylaxis against the development of HE.

Constipation is one very common precipitating factor for hepatic encephalopathy which is routinely managed with oral lactulose or kleen enema (21.4g (18.1% w/v) Sodium Dihydrogen Phosphate Dihydrate and 9.4g (8.0% w/v) Disodium Phosphate Dodecahydrate). Lactulose enema is also given to patients in hepatic encephalopathy either alone or in combination with oral lactulose. However it is not clear whether there is any difference in the efficacy of oral or enema lactulose in patients with hepatic encephalopathy in terms of improvement of encephalopathy grade and time to improvement. This study aims to determine the efficacy of oral versus enema lactulose in the achievement of these goals.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Aliena Badshah; Phone Number: 0092-335-5950615; Email: aliena.badshah@kmc.edu.pk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female cirrhotic patients in grades 3 or 4 of hepatic encephalopathy
• Patient with constipation as the precipitating factor will be included in the study

Exclusion Criteria:

• Patients with dehydration
• Electrolyte abnormalities
• Spontaneous bacterial peritonitis (SBP),
• Fever
• Using sedative / hypnotic medications as predisposing factors for hepatic encephalopathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo arm / tap water enema arm; This arm will receive oral lactulose as per treatment protocol for hepatic encephalopathy i.e. 30ml twice daily. And will receive tap water enema as placebo i.e. 1000ml tap water enema twice daily.	Drug: Tap water; Oral lactulose in a dose of 30ml BD and tap water enema 1000ml BD; Other Names: tap water enema
Experimental: Lactulose enema arm; This arm will receive oral lactulose in a dose of 30ml twice daily alongwith lactulose enema (300ml lactulose plus 700ml water) twice daily.	Drug: Lactulose; Oral lactulose in a dose of 30ml BD and lactulose enema (300ml lactulose and 700ml water) in a dose of 1000ml BD.; Other Names: Lactulose enema

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in grade of hepatic encephalopathy	Change in HE grade from grade 4 to grade 3 or grade 3 to grade 2	Over 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relief of constipation	Frequency of 2-3 soft stools per 24 hours	Over 48 hours

Collaborators and Investigators

• Sponsor: Khyber Medical College, Peshawar
• Investigators: Principal Investigator: Aliena Badshah, Khyber Medical College

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2023
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): November 1, 2023

Study Registration Dates

• First Submitted: March 14, 2023
• First Submitted That Met QC Criteria: March 26, 2023
• First Posted (Actual): March 29, 2023

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Diseases, Metabolic; Liver Diseases; Hepatic Encephalopathy; Brain Diseases; Gastrointestinal Agents; Lactulose
• Other Study ID Numbers: 700

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patients confidentiality shall be maintained at all stages. Other patient characteristics e.g grade of encephalopathy, serum ammonia levels before and after initiation of intervention, response to lactulose enema can be shared if required.
• IPD Sharing Time Frame: Data will become available once patients are recruited into the study
• IPD Sharing Access Criteria: not specified yet
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No