Liver Failure, AcuteNCT05778461
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.
A study testing L-ornithine L-Aspartate in people with Liver Failure, Acute, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
Trial 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. Read more about this study
- Who is it for?
- Ages 5 to 18 years
- Conditions the study is for
- Liver Failure, Acute
- What is being tested?
- L-ornithine L-Aspartate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 32 participants
- Where
- 1 siteIndia
- Study dates
- 15 Mar 2023to 30 Oct 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Pediatric Acute Liver Failure as defined by PALF-Study Group
- 5-18 years of age
- INR > 2
- Hepatic encephalopathy (defined by West Haven criteria)
- Ammonia >100mcg/dL
Who cannot join
- Irreversible neurological injury
- Previous treatment with LOLA within 48 hours before admission.
- Acute kidney injury.
- Acute on chronic liver failure
- Those not giving consent
Trial locations and contacts
1 site in 1 country.
India1 site
Institute of Liver and Biliary Sciences
New Delhi, 110070
Tamoghna Biswas, MD, 7439983747, tamoghnab@gmail.com
Bikrant Bihari Lal, DM, 9540951063, bikrant18may@gmail.com
About this study
Official title: 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: A Randomized Controlled Trial
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.
Read the detailed description
Methodology:
- Study population
Pediatric acute liver failure patients aged 5-18 years of age, INR > 2, Hepatic encephalopathy (defined by West Haven criteria) and arterial ammonia >100mcg/dL
Study Design:
Interventional - Placebo controlled RCT.
Allocation: Randomized
Method of randomization: Block randomization using Interactive Web Response System (IWRS) with block size 4
Intervention Model: Parallel Assignment
Masking: Double. Patients and investigators will be blinded to treatment assignments. Both intervention and placebo will be prepared and administered by trial nurse.
- Study period
24 months (Feb 2023-Feb 2025)
-- Sample size
As this is a pilot study, a sample size of 16 patients in each arm will be taken.
- Intervention
- In Intervention Arm 1 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. In Control Arm, placebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively. Placebo will be procured from the same pharmaceutical company manufacturing LOLA. Patients and investigators will be blinded to treatment assignments. Both intervention and placebo will be prepared and administered by trial nurse.
- STATISTICAL ANALYSIS:
- Primary outcome measure: Mann -Whitney U test
- Secondary outcome measures
- Fisher's exact test for categorical data
- Mann-Whitney U test for continuous data
- IBM® SPSS® Statistics 29 will be used for statistical analysis. P<0.05 will be considered as statistically significant.
- Adverse effects
- Stopping rule
- Interim analysis will be done after 16 patients. If significant increase in mortality or worsening grade of encephalopathy is seen in the LOLA arm, trial will be stopped. The trial will also be stopped if any significant safety signals related to the adverse effect profile of the study drug is identified in the interim analysis. (c) Expected outcome of the project:
The investigators expect LOLA and therapeutic plasma exchange will act synergistically to lower ammonia more effectively and this lowering of ammonia will lead to better native liver survival among children with acute liver failure.
- Conditions
- Liver Failure, Acute
- Being tested
- L-ornithine L-Aspartate, Placebo
- Medical subject headings
- Liver Failure, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-ornithine L-AspartateDrug
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.
PlaceboDrug
Placebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Comparison of change in ammonia (baseline to day 3) in the 2 groups
Measured: 72 hours
Secondary outcomes (9)
Comparison of proportion of participants dying by Day 7 and Day 14 between two groups
Measured: Days 7 and 14
Comparison of proportion of participants requiring liver transplant by Day 7 and Day 14 between two groups
Measured: Day 7 and Day 14
Comparison of overall survival at Day 7 and Day 14 between two groups
Measured: Days 7 and 14
Comparison of change in grade of encephalopathy assessed by West Haven scale by day 3 and day 7
Measured: Day 3 and Day 7
Comparison of optic nerve sheath diameter measured by ultrasound at 24,48 and 72 hours in the 2 groups
Measured: 24 hours, 48 hours and 72 hours
To compare the cumulative requirement of mannitol and propofol in the first 72 hours in the 2 groups
Measured: 72 hours
Comparison of plasma and dialysate glutamine levels after first cycle of High Volume Plasma Exchange between two groups
Measured: 72 hours
Comparison of number of episodes of clinically raised intracranial pressure in the 2 groups
Measured: 72 hours
Compare the adverse events in the 2 groups
Measured: 72 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2023
- Study start15 Mar 2023 (estimated)
- Primary completion30 Oct 2024 (estimated)
- Study completion30 Oct 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver Failure, AcuteStudies of the same condition, open and under way.
- More trials run by Institute of Liver and Biliary Sciences, IndiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 32 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Liver and Biliary Sciences, India
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Dr Tamoghna Biswas, MD, Principal investigator, Institute of Liver and Biliary Sciences, India
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05778461
- Sponsor's protocol ID
- ILBS-ALF-06
- Status last verified
- Feb 2023
- First submitted
- 8 Feb 2023
- Last updated
- 21 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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: A Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT05778461
- Acronym / sponsor ID
- ILBS-ALF-06
- Conditions
- Liver Failure, Acute
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 32 participants (estimated)
- Lead sponsor
- Institute of Liver and Biliary Sciences, IndiaUniversity, hospital or other
- Study start
- 15 Mar 2023 (estimated)
- Primary completion
- 30 Oct 2024 (estimated)
- Study completion
- 30 Oct 2024 (estimated)
- First posted
- 21 Mar 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Methodology:
- Study population
Pediatric acute liver failure patients aged 5-18 years of age, INR > 2, Hepatic encephalopathy (defined by West Haven criteria) and arterial ammonia >100mcg/dL
Study Design:
Interventional - Placebo controlled RCT.
Allocation: Randomized
Method of randomization: Block randomization using Interactive Web Response System (IWRS) with block size 4
Intervention Model: Parallel Assignment
Masking: Double. Patients and investigators will be blinded to treatment assignments. Both intervention and placebo will be prepared and administered by trial nurse.
- Study period
24 months (Feb 2023-Feb 2025)
-- Sample size
As this is a pilot study, a sample size of 16 patients in each arm will be taken.
- Intervention
- In Intervention Arm 1 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. In Control Arm, placebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively. Placebo will be procured from the same pharmaceutical company manufacturing LOLA. Patients and investigators will be blinded to treatment assignments. Both intervention and placebo will be prepared and administered by trial nurse.
- STATISTICAL ANALYSIS:
- Primary outcome measure: Mann -Whitney U test
- Secondary outcome measures
- Fisher's exact test for categorical data
- Mann-Whitney U test for continuous data
- IBM® SPSS® Statistics 29 will be used for statistical analysis. P<0.05 will be considered as statistically significant.
- Adverse effects
- Stopping rule
- Interim analysis will be done after 16 patients. If significant increase in mortality or worsening grade of encephalopathy is seen in the LOLA arm, trial will be stopped. The trial will also be stopped if any significant safety signals related to the adverse effect profile of the study drug is identified in the interim analysis. (c) Expected outcome of the project:
The investigators expect LOLA and therapeutic plasma exchange will act synergistically to lower ammonia more effectively and this lowering of ammonia will lead to better native liver survival among children with acute liver failure.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| L-ornithine L-Aspartate | Experimental | Drug: L-ornithine L-AspartateLOLA 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. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively. |
Who may qualify
- Ages
- 5 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Pediatric Acute Liver Failure as defined by PALF-Study Group
Key exclusion criteria (5 listed)
- Irreversible neurological injury
- Previous treatment with LOLA within 48 hours before admission.
- Acute kidney injury.
- Acute on chronic liver failure
- Those not giving consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-ornithine L-AspartateLOLA 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 |
| PlaceboPlacebo will be administered via continuous infusion for 72h, along with HVPE (2x plasma volume) starting at 8h, 32h and 56h respectively. | Drug | Placebo |
Primary outcome
Comparison of change in ammonia (baseline to day 3) in the 2 groups
Time frame: 72 hours
9 secondary outcomes
Comparison of proportion of participants dying by Day 7 and Day 14 between two groups
Time frame: Days 7 and 14
Comparison of proportion of participants requiring liver transplant by Day 7 and Day 14 between two groups
Time frame: Day 7 and Day 14
Comparison of overall survival at Day 7 and Day 14 between two groups
Time frame: Days 7 and 14
Comparison of change in grade of encephalopathy assessed by West Haven scale by day 3 and day 7
Time frame: Day 3 and Day 7
Comparison of optic nerve sheath diameter measured by ultrasound at 24,48 and 72 hours in the 2 groups
Time frame: 24 hours, 48 hours and 72 hours
To compare the cumulative requirement of mannitol and propofol in the first 72 hours in the 2 groups
Time frame: 72 hours
Comparison of plasma and dialysate glutamine levels after first cycle of High Volume Plasma Exchange between two groups
Time frame: 72 hours
Comparison of number of episodes of clinically raised intracranial pressure in the 2 groups
Time frame: 72 hours
Compare the adverse events in the 2 groups
Time frame: 72 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Mar 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dr Tamoghna Biswas, MD principal investigator
Institute of Liver and Biliary Sciences, India
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-ornithine L-Aspartate in people with Liver Failure, Acute, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dr Tamoghna Biswas, MD (7439983747, tamoghnab@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Comparison of change in ammonia (baseline to day 3) in the 2 groups (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Mar 2023.