Efficacy of L-ornithine L-aspartate and Therapeutic Plasma Exchange Versus Plasma Exchange Alone in Lowering Ammonia and Improving Outcomes in Pediatric Acute Liver Failure.

NCT05778461 | Unknown DMC

• 1 other identifier: ILBS-ALF-06
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Pediatric acute liver failure (PALF) is associated with very high mortality and morbidity with native liver survival varying between 21 to 75%.Hyperammonemia manifesting as hepatic encephalopathy and causing cerebral edema isresponsible for poor neurological outcome in ALF. Ammonia lowering measures have led to improvement in HE and higher native liver survival. L-ornithine L-aspartate (LOLA), a salt of natural amino-acids ornithine and aspartate, is an importantammonia scavenging drug. It acts as a substrate for urea cycle in liver and also converts ammonia to glutamine in perivenous hepatocytes as well as in the muscles.This drug has been shown to reduce ammonia and improve hepatic encephalopathy in cirrhoticadults.However, the issue with this drug is that the glutamine formed can reconvert to ammonia by the action of glutaminase, possibly, the reason why it failed to show decrease in ammonia and improvement in native liver survival in a randomized controlled trial in adult ALF. In western countries, ornithine phenylacetate has been used where ornithine converts ammonia to glutamine and phenylacetate then binds to this glutamine to form phenylacetylgutamine and eliminates it. Therapeutic plasma exchange (TPE), both high volume and standard volume has been shown to improve native liver survival in adults with ALF and is the standard of care in management of ALF and a grade 1 recommendation by all eminent liver societies.TPE leads to decreased ammonia. Although rate of ammonia formation is multiple times higher than rate of ammonia removal by plasmapheresis, this ammonia reduction is an indirect effect of glutamine removal by TPE. Glutamine, thus, acts as a reservoir for clearance of ammonia (in muscles and perivenous hepatocytes).In contrast to adults, the response to therapeutic plasma exchange has not been as encouraging inchildren, yet, most centers continue to use it based on recommendations in adults. Based on the knowledge that LOLA converts ammonia to glutamine and TPE clears glutamine from plasma, the investigators hypothesize that LOLA would act in synergestic way with TPE to lower ammonia levels, resulting in improvement in HE and better native liver survival in pediatric ALF. The goal of this clinical trial is to compare L-ornithine L-aspartate and therapeutic plasma exchange versus plasma exchange alone in lowering ammonia and improving outcomes in patients with pediatric acute liver failure.

Conditions

Liver Failure, Acute

Outcome Measures

Primary Outcomes (1)

• Comparison of change in ammonia (baseline to day 3) in the 2 groups

  72 hours

Secondary Outcomes (9)

• Comparison of proportion of participants dying by Day 7 and Day 14 between two groups

  Days 7 and 14

• Comparison of proportion of participants requiring liver transplant by Day 7 and Day 14 between two groups

  Day 7 and Day 14

• Comparison of overall survival at Day 7 and Day 14 between two groups

  Days 7 and 14

• Comparison of change in grade of encephalopathy assessed by West Haven scale by day 3 and day 7

  Day 3 and Day 7

• Comparison of optic nerve sheath diameter measured by ultrasound at 24,48 and 72 hours in the 2 groups

  24 hours, 48 hours and 72 hours

Study Arms (2)

L-ornithine L-Aspartate

EXPERIMENTAL

LOLA will be administered via continuous intravenous infusion at a dosage of 0.75g/kg/day for 72h (maximum 30g/day). High volume plasma exchange (2x plasma volume) will be started at least 8 hours after initiation of LOLA, and will be completed within 4-5 hours depending on the volume of exchange. Three consecutive cycles of HVPE will be performed, starting at 8h, 32h and 56h respectively.

Drug: L-ornithine L-Aspartate

Placebo

PLACEBO COMPARATOR

Placebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively.

Drug: Placebo

Interventions

L-ornithine L-Aspartate DRUG

LOLA will be administered via continuous intravenous infusion at a dosage of 0.75g/kg/day for 72h (maximum 30g/day). High volume plasma exchange (2x plasma volume) will be started at least 8 hours after initiation of LOLA, and will be completed within 4-5 hours depending on the volume of exchange. Three consecutive cycles of HVPE will be performed, starting at 8h, 32h and 56h respectively.

L-ornithine L-Aspartate

Placebo DRUG

Placebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively.

Placebo

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Pediatric Acute Liver Failure as defined by PALF-Study Group
• years of age
• INR \> 2
• Hepatic encephalopathy (defined by West Haven criteria)
• Ammonia \>100mcg/dL

You may not qualify if:

• Irreversible neurological injury
• Previous treatment with LOLA within 48 hours before admission.
• Acute kidney injury.
• Acute on chronic liver failure
• Those not giving consent

Sponsors & Collaborators

• Institute of Liver and Biliary Sciences, India: lead

Study Sites (1)

Institute of Liver and Biliary Sciences

New Delhi, 110070, India

Location

MeSH Terms

Conditions

Liver Failure, Acute

Interventions

ornithylaspartate

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases

Study Officials

• Dr Tamoghna Biswas, MD

  Institute of Liver and Biliary Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr Tamoghna Biswas, MD

CONTACT

7439983747; tamoghnab@gmail.com

Dr Bikrant Bihari Lal, DM

CONTACT

9540951063; bikrant18may@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2023
• First Posted: March 21, 2023
• Study Start: March 15, 2023
• Primary Completion: October 30, 2024
• Study Completion: October 30, 2024
• Last Updated: March 21, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)