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

NCT04436601 | Unknown Phase 4 DMC

• 1 other identifier: 191002MED
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 1

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.

Conditions

Hepatic Encephalopathy

Outcome Measures

Primary Outcomes (1)

• Resolution of Hepatic Encephalopathy

  Calculated using Hepatic Encephalopathy scoring Algorithm (HESA). Resolution is defined as reduction of at least 1 grade of HESA score after 24 hours, 48 hours and if applicable 72 hours of therapy during hospital stay

  Change in HESA score at 24 hours, 48 hours and if applicable, 72 hours of drug administration

Secondary Outcomes (2)

• Mean Length of inpatient stay in hours

  at time of patient discharge, an average of 72 hours

• 3 months outcome (readmission with Hepatic Encephalopathy)

  The three month outcome will be assessed at clinic follow-up at 3 month or by phone call if patient is lost to follow up

Study Arms (2)

Lactulose

ACTIVE COMPARATOR

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.

Drug: Lactulose

PEG: Polyethylene Glycol

EXPERIMENTAL

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

Drug: Polyethylene Glycols

Interventions

Polyethylene Glycols DRUG

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

PEG: Polyethylene Glycol

Lactulose DRUG

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

Lactulose

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients of 18-80 years admitted to Aga Khan University Hospital
• 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.
• 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
• Presence of first degree relative for consent (Next of kin)

You may not qualify if:

• Allergy to PEG
• Bowel obstruction or perforation diagnosed clinically or on Xray
• Major psychiatric illness; on benzodiazepines
• Treated with locally acting antibiotics (rifaximin) in the previous 7 days;
• Active gastrointestinal tract bleeding
• 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)
• Female patients if pregnant or lactating

Sponsors & Collaborators

• Aga Khan University: lead

Study Sites (1)

Aga Khan University

Karachi, Sindh, 75290, Pakistan

RECRUITING

Related Publications (24)

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  PMID: 17295846 BACKGROUND

• 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.

  PMID: 26195207 BACKGROUND

• 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.

  PMID: 4894464 BACKGROUND

• 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.

  PMID: 20009938 BACKGROUND

• 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.

  PMID: 25865476 BACKGROUND

• 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.

  PMID: 20820037 BACKGROUND

• 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.

  PMID: 22883217 BACKGROUND

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

  PMID: 27783916 BACKGROUND

• 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.

  PMID: 27375696 BACKGROUND

• 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.

  PMID: 11152016 BACKGROUND

• 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.

  PMID: 27153247 BACKGROUND

• 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.

  PMID: 15976747 BACKGROUND

• 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.

  PMID: 24849268 BACKGROUND

• 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.

  PMID: 25243839 BACKGROUND

• 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.

  PMID: 23847109 BACKGROUND

• 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.

  PMID: 25015420 BACKGROUND

• 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.

  PMID: 27089005 BACKGROUND

• 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.

  PMID: 30234645 BACKGROUND

• 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.

  PMID: 28316761 BACKGROUND

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

  BACKGROUND

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

  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.

  PMID: 17710551 BACKGROUND

• 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.

  PMID: 22213561 BACKGROUND

• 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.

  PMID: 15118577 BACKGROUND

MeSH Terms

Conditions

Hepatic Encephalopathy

Interventions

Polyethylene Glycols; Lactulose

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Ethylene Glycols; Glycols; Alcohols; Organic Chemicals; Polymers; Macromolecular Substances; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Study Officials

• Om Parkash

  Aga Khan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Om Parkash

CONTACT

+923333509749; om.parkash@aku.edu

Asra tus Saleha Siddiqui

CONTACT

+923323262516; asra.siddiqui@aku.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: It would be a double blinded study. Investigator assessing the participants and following the patient will be masked to the allocation of treatment group. Participants would be masked to their treatment group as well.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: May 23, 2020
• First Posted: June 18, 2020
• Study Start: March 9, 2020
• Primary Completion: December 30, 2023
• Study Completion: December 30, 2023
• Last Updated: April 19, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

PA (1)