Polyethylene Glycol Versus Lactulose on Hepatic Encephalopathy in Patients With Cirrhosis;(PEGHE Trial)

NCT ID: NCT04436601

Last Updated: 2023-04-19

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-09
• Study Completion Date: 2023-12-30

Brief Summary

Hepatic Encephaopathy is a common complication occurring in patients with Liver cirrhosis. Patients usually develop mild confusion, sleep disturbance or obtundation. It occurs due to accumulation of excess ammonia in the brain, as the liver is unable to metabolize the ammonia. The common gold standard treatment recommended for patients with Hepatic Encephalopathy is Lactulose syrup. This is a non absorbable sugar, often combined with an antibiotic called Rifaxamine to treat this condition.

Polyethylene glycol is in a class of medications called osmotic laxatives which works by causing water to be retained with the stool. PEG and lactulose, when used together, result in faster resolution of symptoms suggesting that PEG may be superior to standard lactulose therapy in these patients.

Non-absorbable sugars like lactulose are associated with non-serious (mainly gastrointestinal) adverse events like diarrhea and bloating Hence, due to the side effect profile, newer drugs continue to be tested for treatment of Hepatic Encephalopathy.

The aim of this research project is to compare the effect of PEG versus lactulose for treatment of HE in patients with liver cirrhosis. The investigators want to compare the resolution of HE as the main outcome. In addition, they will compare length of stay, non-serious (mainly gastrointestinal) adverse events, and 3 months outcome. The investigators hypothesize that rapid purgation of the gut using PEG may resolve HE more effectively than lactulose.

Detailed Description

Hepatic encephalopathy (HE) is a common neuropsychiatric complication of liver cirrhosis manifested by mild confusion, sleep disturbance or obtundation. Lactulose treatment has long been the standard of care, which presumably acidifies stool and eradicates toxic metabolites. However a third of these patients with hepatic encephalopathy do not respond to this standard treatment and have refractory HE. Hence newer drugs with effective improvement in HE and better side effect profile are still being tested.

Polyethylene glycol (PEG) is in a class of medications called osmotic laxatives which works by causing water to be retained with the stool. PEG and lactulose, when used together, result in rapid overt HE resolution within 24 hours compared to the standard-of-care lactulose, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE.

Rationale Non-absorbable disaccharides like lactulose are associated with non-serious (mainly gastrointestinal) adverse events like diarrhea and bloating, hence, due to the side effect profile, newer drugs continue to be tested for treatment of HE.

Hypothesis and Aim The aim of this research project is to compare the effect of PEG with Lactulose for treatment of Hepatic Encephalopathy in patients with liver cirrhosis. The investigators want to compare the resolution of HE as the main outcome. In addition, they would compare length of stay, non-serious (mainly gastrointestinal) adverse events, and 3 months outcome. The investigators hypothesize that rapid purgation of the gut using PEG may resolve HE more effectively than lactulose.

These aims are original in that the investigators aim to test this hypothesis on a different patient population (South Asian), where the predominant cause of cirrhosis is due to viral hepatitis C and B. In addition,the investigators will also look at the effect of PEG v lactulose on 3 months outcome in this study.

Significance The significance of this proposal is that if the investigators can prove the hypothesis, it will add to the currently limited evidence on use of PEG in treatment of HE in the world. PEG might have a better side effect profile when compared to lactulose. Based on current market pricing of lactulose, if PEG is found to have favorable outcome then it might be more cost effective as well. Hence PEG might be a useful alternative in 30% of those who don't respond to lactulose, if PEG shows favorable outcome.

Objective Primary: To determine the effect of PEG versus Lactulose on resolution of HE in patients with liver cirrhosis during inpatient stay at 24 hours, 48 hours and 72 hours .

Secondary: To determine the effect of Lactulose versus PEG on length of stay, and 3 months outcome in patients with liver cirrhosis.

Conditions

Hepatic Encephalopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Lactulose

90 ml of Lactulose dissolved in 750 ml of water administered orally by mouth or nasogastric tube (three doses within 24 hrs) continued up to 72 hours or until patient discharge, whichever comes first.

Group Type: ACTIVE_COMPARATOR

Lactulose

Intervention Type: DRUG

Lactulose (standard of care) will be administered to half of the study patients and their response recorded.

PEG: Polyethylene Glycol

Three or four sachet of Movicol(PEG) will be dissolved in 750 ml of water and will be given over 24 hrs as 3 doses orally by mouth or Nasogastric tube and will continue up to 72 hours or until patient discharge, whichever comes first

Group Type: EXPERIMENTAL

Polyethylene Glycols

Intervention Type: DRUG

Polyethylene glycol will be administered to half of the study patients, and their response recorded and compared with that of the Lactulose arm.

Interventions

Polyethylene Glycols

Polyethylene glycol will be administered to half of the study patients, and their response recorded and compared with that of the Lactulose arm.

Intervention Type: DRUG

Lactulose

Lactulose (standard of care) will be administered to half of the study patients and their response recorded.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. All patients of 18-80 years admitted to Aga Khan University Hospital

2. With Chronic liver disease: Chronic liver disease will be defined based on ultra-sonographic evidence of chronic liver disease including shrunken liver, dilated portal vein, splenomegaly.

3. With Hepatic encephalopathy; Hepatic encephalopathy will be defined as the onset of disorientation or asterixis according to The International Society for Hepatic Encephalopathy and Nitrogen Metabolism consensus and will be assessed using HESA score

4. Presence of first degree relative for consent (Next of kin)

Exclusion Criteria

1. Allergy to PEG

2. Bowel obstruction or perforation diagnosed clinically or on Xray

3. Major psychiatric illness; on benzodiazepines

4. Treated with locally acting antibiotics (rifaximin) in the previous 7 days;

5. Active gastrointestinal tract bleeding

6. Acute Liver failure:defined as coagulopathy (international normalized ratio >1.5) with any degree of AMS in the absence of underlying chronic liver disease (CLD)

7. Female patients if pregnant or lactating

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aga Khan University

OTHER

Sponsor Role: lead

Responsible Party

Om Parkash

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Om Parkash

Role: PRINCIPAL_INVESTIGATOR

Aga Khan University

Locations

Aga Khan University

Karachi, Sindh, Pakistan

Site Status: RECRUITING

Countries

Pakistan

Central Contacts

Om Parkash

Role: CONTACT

om.parkash@aku.edu

+923333509749

Asra tus Saleha Siddiqui

Role: CONTACT

asra.siddiqui@aku.edu

+923323262516

Facility Contacts

Om Parkash

Role: primary

om.parkash@aku.edu

+923333509749

References

Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2007 Feb;25 Suppl 1:3-9. doi: 10.1111/j.1746-6342.2006.03215.x.

Reference Type: BACKGROUND

PMID: 17295846 (View on PubMed)

Rahimi RS, Rockey DC. Novel Ammonia-Lowering Agents for Hepatic Encephalopathy. Clin Liver Dis. 2015 Aug;19(3):539-49. doi: 10.1016/j.cld.2015.04.008. Epub 2015 May 30.

Reference Type: BACKGROUND

PMID: 26195207 (View on PubMed)

Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial. N Engl J Med. 1969 Aug 21;281(8):408-12. doi: 10.1056/NEJM196908212810803. No abstract available.

Reference Type: BACKGROUND

PMID: 4894464 (View on PubMed)

Sharma P, Sharma BC, Sarin SK. Predictors of nonresponse to lactulose in patients with cirrhosis and hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010 May;22(5):526-31. doi: 10.1097/MEG.0b013e3283341b7d.

Reference Type: BACKGROUND

PMID: 20009938 (View on PubMed)

Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc. 2015 May;90(5):646-58. doi: 10.1016/j.mayocp.2015.03.003. Epub 2015 Apr 9.

Reference Type: BACKGROUND

PMID: 25865476 (View on PubMed)

Romero-Gomez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galan JJ, Montoliu C, Baccaro E, Guevara M, Cordoba J, Soriano G, Navarro JM, Martinez-Sierra C, Grande L, Galindo A, Mira E, Manes S, Ruiz A. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med. 2010 Sep 7;153(5):281-8. doi: 10.7326/0003-4819-153-5-201009070-00002.

Reference Type: BACKGROUND

PMID: 20820037 (View on PubMed)

Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012 Dec;44(12):1027-31. doi: 10.1016/j.dld.2012.07.002. Epub 2012 Aug 9.

Reference Type: BACKGROUND

PMID: 22883217 (View on PubMed)

Wijdicks EF. Hepatic Encephalopathy. N Engl J Med. 2016 Oct 27;375(17):1660-1670. doi: 10.1056/NEJMra1600561. No abstract available.

Reference Type: BACKGROUND

PMID: 27783916 (View on PubMed)

Zuberi BF, Alvi H, Zuberi FF, Rasheed T, Nawaz Z, Fatima-Tuz-Zohra. Frequency of minimal hepatic encepalopathy in illeterate patients with compensated cirrhosis. Pak J Med Sci. 2016 May-Jun;32(3):595-8. doi: 10.12669/pjms.323.9655.

Reference Type: BACKGROUND

PMID: 27375696 (View on PubMed)

Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs. 2000 Dec;60(6):1353-70. doi: 10.2165/00003495-200060060-00008.

Reference Type: BACKGROUND

PMID: 11152016 (View on PubMed)

Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016 May 6;2016(5):CD003044. doi: 10.1002/14651858.CD003044.pub4.

Reference Type: BACKGROUND

PMID: 27153247 (View on PubMed)

Williams R, Bass N. Rifaximin, a nonabsorbed oral antibiotic, in the treatment of hepatic encephalopathy: antimicrobial activity, efficacy, and safety. Rev Gastroenterol Disord. 2005;5 Suppl 1:S10-8.

Reference Type: BACKGROUND

PMID: 15976747 (View on PubMed)

Kimer N, Krag A, Moller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment Pharmacol Ther. 2014 Jul;40(2):123-32. doi: 10.1111/apt.12803. Epub 2014 May 21.

Reference Type: BACKGROUND

PMID: 24849268 (View on PubMed)

Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350--electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014 Nov;174(11):1727-33. doi: 10.1001/jamainternmed.2014.4746.

Reference Type: BACKGROUND

PMID: 25243839 (View on PubMed)

Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Alexeeva O, Zupanets IA, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klaryts'ka I, Morozov V, Grewal P, McCashland T, Reddy KG, Reddy KR, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt BF; HALT-HE Study Group. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology. 2014 Mar;59(3):1073-83. doi: 10.1002/hep.26611.

Reference Type: BACKGROUND

PMID: 23847109 (View on PubMed)

American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014 Sep;61(3):642-59. doi: 10.1016/j.jhep.2014.05.042. Epub 2014 Jul 8. No abstract available.

Reference Type: BACKGROUND

PMID: 25015420 (View on PubMed)

Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016 Apr 18;4:CD003044. doi: 10.1002/14651858.CD003044.pub3.

Reference Type: BACKGROUND

PMID: 27089005 (View on PubMed)

Shehata HH, Elfert AA, Abdin AA, Soliman SM, Elkhouly RA, Hawash NI, Soliman HH. Randomized controlled trial of polyethylene glycol versus lactulose for the treatment of overt hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2018 Dec;30(12):1476-1481. doi: 10.1097/MEG.0000000000001267.

Reference Type: BACKGROUND

PMID: 30234645 (View on PubMed)

Naderian M, Akbari H, Saeedi M, Sohrabpour AA. Polyethylene Glycol and Lactulose versus Lactulose Alone in the Treatment of Hepatic Encephalopathy in Patients with Cirrhosis: A Non-Inferiority Randomized Controlled Trial. Middle East J Dig Dis. 2017 Jan;9(1):12-19. doi: 10.15171/mejdd.2016.46.

Reference Type: BACKGROUND

PMID: 28316761 (View on PubMed)

Friedman S, Schiano T. Cirrhosis and its sequelae. Cecil Textbook of Medicine 22nd ed Philadelphia, Pa: Saunders. 2004:936-44.

Reference Type: BACKGROUND

American College of R. Expert Panel on Gastrointestinal Imaging. Liver lesion characterization Reston, Va: American College of Radiology. 2002.

Reference Type: BACKGROUND

Hassanein TI, Hilsabeck RC, Perry W. Introduction to the Hepatic Encephalopathy Scoring Algorithm (HESA). Dig Dis Sci. 2008 Feb;53(2):529-38. doi: 10.1007/s10620-007-9895-0. Epub 2007 Aug 21.

Reference Type: BACKGROUND

PMID: 17710551 (View on PubMed)

Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology. 2012 Mar;55(3):965-7. doi: 10.1002/hep.25551. No abstract available.

Reference Type: BACKGROUND

PMID: 22213561 (View on PubMed)

Mendez-Sanchez N, Aguilar-Ramirez JR, Reyes A, Dehesa M, Juorez A, Castneda B, Sanchez-Avila F, Poo JL, Guevara Gonzalez L, Lizardi J, Valdovinos MA, Uribe M, Contreras AM, Tirado P, Aguirre J, Rivera-Benitez C, Santiago-Santiago R, Bosques-Padilla F, Munoz L, Guerroro A, Ramos M, Rodriguez-Hernandez H, Jacobo-Karam J; Grupo de Estudio, Asociacion Mexicana de Hepatologia. Etiology of liver cirrhosis in Mexico. Ann Hepatol. 2004 Jan-Mar;3(1):30-3.

Reference Type: BACKGROUND

PMID: 15118577 (View on PubMed)

Other Identifiers

191002MED

Identifier Type: -

Identifier Source: org_study_id