Acute Liver FailureCRITICALNCT06987604
Continuous Renal Replacement Therapy Intensity in Hyperammonemia
A study testing High-dose continuous renal replacement therapy and Conventional-dose continuous renal replacement therapy in people with Acute Liver Failure and Acute on Chronic Liver Failure (ACLF), run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
Trial summary
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life-threatening conditions often associated with hyperammonemia, hepatic encephalopathy, and multi-organ dysfunction. Ammonia plays a central role in the pathogenesis of cerebral edema and neurotoxicity. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Liver Failure, Acute on Chronic Liver Failure (ACLF), Acute Kidney Injury
- What is being tested?
- High-dose continuous renal replacement therapy and Conventional-dose continuous renal replacement therapy
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 152 participants
- Where
- 1 siteBrazil
- Study dates
- 14 Mar 2025to 14 May 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Diagnosis of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) Presence of hyperammonemia, defined as: Arterial ammonia >72 μmol/L and hepatic encephalopathy grade ≥2 or Arterial ammonia >100 μmol/L regardless of encephalopathy grade
- Indication for continuous renal replacement therapy (CRRT), as determined by the attending medical team
- Informed consent provided by the patient or legal representative
Who cannot join
- Age < 18 years
- Pregnancy
- Diagnosis of acute liver failure (ALF) in the context of severe hemodynamic instability
- ALF secondary to ischemic hepatic injury
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Brazil1 site
Hospital de Clinicas de Porto Alegre
Porto Alegre, Rio Grande do Sul, 90410-000
About this study
Official title: Continuous Renal Replacement Therapy Intensity in TreatIng Critical Ammonemia Levels
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life-threatening conditions often associated with hyperammonemia, hepatic encephalopathy, and multi-organ dysfunction. Ammonia plays a central role in the pathogenesis of cerebral edema and neurotoxicity. Continuous renal replacement therapy (CRRT) has been shown to effectively reduce serum ammonia levels and may improve transplant-free survival in ALF. However, the optimal dialysis dose for ammonia clearance and neurological recovery remains uncertain. This randomized, multicenter clinical trial aims to compare conventional-dose (25-35 mL/kg/h) versus high-dose (45-55 mL/kg/h) CRRT in patients with ALF or ACLF and arterial ammonia >72 μmol/L. The primary outcome is the number of coma- and delirium-free days. Secondary outcomes include ammonia clearance and additional parameters of cerebral function monitoring.
Read the detailed description
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are critical conditions characterized by rapid deterioration in hepatic function, coagulopathy, hepatic encephalopathy, and multi-organ failure. Elevated serum ammonia levels are frequently observed in these patients and are strongly associated with cerebral dysfunction, including coma and delirium. Ammonia contributes to the development of brain edema through mechanisms involving astrocyte swelling, oxidative stress, and altered neurotransmission. Rapid and effective reduction of ammonia is a key therapeutic target in the management of these patients.
Continuous renal replacement therapy (CRRT) is commonly used in critically ill patients with ALF or ACLF, particularly in those with hyperammonemia. While CRRT is effective in lowering ammonia levels, there is currently no consensus regarding the optimal dialysis dose to maximize ammonia clearance and improve neurological outcomes. Observational data and small interventional studies suggest a potential benefit of higher CRRT doses in terms of ammonia removal and clinical improvement, but robust evidence from randomized trials is lacking.
This study is a randomized, controlled, multicenter clinical trial designed to compare the effects of two different CRRT dosing strategies on cerebral function in patients with ALF or ACLF and arterial ammonia levels >72 μmol/L. Eligible patients will be randomized to receive either conventional-dose CRRT (25-35 mL/kg/h) or high-dose CRRT (45-55 mL/kg/h). All other aspects of clinical management will follow current standard-of-care protocols.
The primary endpoint is the number of coma- and delirium-free days during the intervention period. Secondary outcomes include the degree of ammonia clearance, time to normalization of ammonia levels, filter lifespan, need for rescue therapies (e.g., liver transplantation), mortality, and neurological function monitoring using noninvasive technologies. The study seeks to generate high-quality evidence to guide CRRT dosing decisions in the context of hyperammonemia due to liver failure.
Protocol Amendment - Change in Stratification Ratio The original protocol assumed a balanced enrollment of patients with Acute Liver Failure (ALF) and Acute-on-Chronic Liver Failure (ACLF), with an intended 1:1 distribution across both strata. However, after initiating recruitment and observing actual prevalence patterns at participating centers, it became evident that the number of eligible patients with ACLF significantly exceeds that of ALF.
In response, the study protocol was amended to reflect a revised stratification ratio of 1:5 (ALF: ACLF). Within each stratum, randomization to treatment arms (conventional-dose vs. high-dose CRRT) remains 1:1.
This adjustment enhances recruitment feasibility and reflects the real-world distribution of liver failure phenotypes, without altering the study's scientific objectives, eligibility criteria, or outcome measures.
- Conditions
- Acute Liver Failure, Acute on Chronic Liver Failure (ACLF), Acute Kidney Injury, Ammonia Metabolism
- Being tested
- High-dose continuous renal replacement therapy, Conventional-dose continuous renal replacement therapy
- Keywords
- ammonia, continuous renal replacement therapy, acute liver failure, acute on chronic liver failure, acute kidney injury
- Medical subject headings
- Liver Failure, Acute, Acute-On-Chronic Liver Failure, Acute Kidney Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-dose continuous renal replacement therapyDevice
Continuous renal replacement therapy administered at an effluent dose of 45-55 mL/kg/h using standard equipment and protocols for critically ill patients with ALF or ACLF and hyperammonemia.
Conventional-dose continuous renal replacement therapyDevice
Continuous renal replacement therapy administered at an effluent dose of 25-35 mL/kg/h using standard equipment and protocols for critically ill patients with ALF or ACLF and hyperammonemia.
| Study group | Role | What they receive |
|---|---|---|
| High-Dose CRRT | Experimental | Participants in this group will receive continuous renal replacement therapy (CRRT) at a high effluent dose of 45-55 mL/kg/h for the treatment of hyperammonemia in the context of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). Receives: Device: High-dose continuous renal replacement therapy |
| Conventional-Dose CRRT | Active comparator | Participants in this group will receive continuous renal replacement therapy (CRRT) at a conventional effluent dose of 25-35 mL/kg/h for the treatment of hyperammonemia in the context of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). Receives: Device: Conventional-dose continuous renal replacement therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of coma- and delirium-free days
The number of days during the first 28 days after randomization in which the patient is alive and free of coma or delirium, assessed using standardized neurological evaluation tools such as the Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU).
Measured: Day 1 to Day 28 post-randomization
Secondary outcomes (7)
Ammonia clearance at 12, 24, 48, and 72 hours
Serial arterial ammonia levels will be measured to calculate the reduction in ammonia concentration from baseline at 12, 24, 48, and 72 hours after initiation of CRRT.
Measured: Baseline to 72 hours
Length of hospital stay
Total number of days from hospital admission to discharge
Measured: Up to 90 days
28-day mortality
All-cause mortality within 28 days after randomization
Measured: 28 days post randomization
90-day mortality
All-cause mortality within 90 days after randomization.
Measured: 90 days post-randomization
Number of ventilator-free days within 28 days
Number of days within the first 28 days post-randomization during which the patient is alive and not receiving invasive mechanical ventilation.
Measured: 28 days post-randomization
Incidence of safety outcomes, such as hypophosphatemia, dialysis disequilibrium syndrome, and rapid correction of hyponatremia
Adverse events will be monitored and recorded during CRRT, including laboratory-confirmed hypophosphatemia (phosphate <2.5 mg/dL), clinical signs of dialysis disequilibrium syndrome, and serum sodium correction >10 mmol/L in 24 hours.
Measured: From CRRT initiation up to 7 days or until therapy discontinuation
Improvement in cerebral compliance
Cerebral compliance will be assessed using the Brain4care noninvasive monitoring system. Improvement will be defined as normalization or favorable trend in intracranial compliance waveform patterns compared to baseline.
Measured: Baseline to Day 28 post-randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 May 2025
- Study start14 Mar 2025
- Primary completion14 May 2029 (estimated)
- Study completion14 May 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Liver FailureStudies of the same condition, open and under way.
- 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
- Model description
- Participants will be randomly assigned in a 1:1 ratio to receive either conventional-dose (25-35 mL/kg/h) or high-dose (45-55 mL/kg/h) continuous renal replacement therapy. Each participant will remain in their assigned treatment arm throughout the study period.
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 152 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital de Clinicas de Porto Alegre
- Sponsor type
- University, hospital or other
- Collaborators
- FIPE - Fundo de Incentivo a Pesquisa do Hospital de Clínicas de Porto Alegre
- Responsible party
- Principal investigator, Gabriel Sartori Pacini, Hospital de Clinicas de Porto Alegre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06987604
- Sponsor's protocol ID
- 88020325.3.1001.5327
- Acronym
- CRITICAL
- Status last verified
- May 2025
- First submitted
- 16 May 2025
- Last updated
- 24 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Continuous Renal Replacement Therapy Intensity in TreatIng Critical Ammonemia Levels
- ClinicalTrials.gov ID
- NCT06987604
- Acronym / sponsor ID
- CRITICAL / 88020325.3.1001.5327
- Conditions
- Acute Liver Failure, Acute on Chronic Liver Failure (ACLF), Acute Kidney Injury, Ammonia Metabolism
- Keywords
- ammonia, continuous renal replacement therapy, acute liver failure, acute on chronic liver failure, acute kidney injury
- Study type
- Interventional
- Recruitment status
- Enrolling by invitation
- Enrolment
- 152 participants (estimated)
- Lead sponsor
- Hospital de Clinicas de Porto AlegreUniversity, hospital or other
- Collaborators
- FIPE - Fundo de Incentivo a Pesquisa do Hospital de Clínicas de Porto Alegre
- Study start
- 14 Mar 2025 (actual)
- Primary completion
- 14 May 2029 (estimated)
- Study completion
- 14 May 2029 (estimated)
- First posted
- 23 May 2025 (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.
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life-threatening conditions often associated with hyperammonemia, hepatic encephalopathy, and multi-organ dysfunction. Ammonia plays a central role in the pathogenesis of cerebral edema and neurotoxicity. Continuous renal replacement therapy (CRRT) has been shown to effectively reduce serum ammonia levels and may improve transplant-free survival in ALF. However, the optimal dialysis dose for ammonia clearance and neurological recovery remains uncertain. This randomized, multicenter clinical trial aims to compare conventional-dose (25-35 mL/kg/h) versus high-dose (45-55 mL/kg/h) CRRT in patients with ALF or ACLF and arterial ammonia >72 μmol/L. The primary outcome is the number of coma- and delirium-free days. Secondary outcomes include ammonia clearance and additional parameters of cerebral function monitoring.
Detailed description
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are critical conditions characterized by rapid deterioration in hepatic function, coagulopathy, hepatic encephalopathy, and multi-organ failure. Elevated serum ammonia levels are frequently observed in these patients and are strongly associated with cerebral dysfunction, including coma and delirium. Ammonia contributes to the development of brain edema through mechanisms involving astrocyte swelling, oxidative stress, and altered neurotransmission. Rapid and effective reduction of ammonia is a key therapeutic target in the management of these patients.
Continuous renal replacement therapy (CRRT) is commonly used in critically ill patients with ALF or ACLF, particularly in those with hyperammonemia. While CRRT is effective in lowering ammonia levels, there is currently no consensus regarding the optimal dialysis dose to maximize ammonia clearance and improve neurological outcomes. Observational data and small interventional studies suggest a potential benefit of higher CRRT doses in terms of ammonia removal and clinical improvement, but robust evidence from randomized trials is lacking.
This study is a randomized, controlled, multicenter clinical trial designed to compare the effects of two different CRRT dosing strategies on cerebral function in patients with ALF or ACLF and arterial ammonia levels >72 μmol/L. Eligible patients will be randomized to receive either conventional-dose CRRT (25-35 mL/kg/h) or high-dose CRRT (45-55 mL/kg/h). All other aspects of clinical management will follow current standard-of-care protocols.
The primary endpoint is the number of coma- and delirium-free days during the intervention period. Secondary outcomes include the degree of ammonia clearance, time to normalization of ammonia levels, filter lifespan, need for rescue therapies (e.g., liver transplantation), mortality, and neurological function monitoring using noninvasive technologies. The study seeks to generate high-quality evidence to guide CRRT dosing decisions in the context of hyperammonemia due to liver failure.
Protocol Amendment - Change in Stratification Ratio The original protocol assumed a balanced enrollment of patients with Acute Liver Failure (ALF) and Acute-on-Chronic Liver Failure (ACLF), with an intended 1:1 distribution across both strata. However, after initiating recruitment and observing actual prevalence patterns at participating centers, it became evident that the number of eligible patients with ACLF significantly exceeds that of ALF.
In response, the study protocol was amended to reflect a revised stratification ratio of 1:5 (ALF: ACLF). Within each stratum, randomization to treatment arms (conventional-dose vs. high-dose CRRT) remains 1:1.
This adjustment enhances recruitment feasibility and reflects the real-world distribution of liver failure phenotypes, without altering the study's scientific objectives, eligibility criteria, or outcome measures.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Participants will be randomly assigned in a 1:1 ratio to receive either conventional-dose (25-35 mL/kg/h) or high-dose (45-55 mL/kg/h) continuous renal replacement therapy. Each participant will remain in their assigned treatment arm throughout the study period.
| Arm | Type | Receives |
|---|---|---|
| High-Dose CRRT | Experimental | Device: High-dose continuous renal replacement therapyParticipants in this group will receive continuous renal replacement therapy (CRRT) at a high effluent dose of 45-55 mL/kg/h for the treatment of hyperammonemia in the context of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). |
| Conventional-Dose CRRT | Active comparator | Device: Conventional-dose continuous renal replacement therapyParticipants in this group will receive continuous renal replacement therapy (CRRT) at a conventional effluent dose of 25-35 mL/kg/h for the treatment of hyperammonemia in the context of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age ≥ 18 years
- Diagnosis of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) Presence of hyperammonemia, defined as: Arterial ammonia >72 μmol/L and hepatic encephalopathy grade ≥2 or Arterial ammonia >100 μmol/L regardless of encephalopathy grade
- Indication for continuous renal replacement therapy (CRRT), as determined by the attending medical team
- Informed consent provided by the patient or legal representative
Key exclusion criteria (4 listed)
- Age < 18 years
- Pregnancy
- Diagnosis of acute liver failure (ALF) in the context of severe hemodynamic instability
- ALF secondary to ischemic hepatic injury
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 |
|---|---|---|
| High-dose continuous renal replacement therapyContinuous renal replacement therapy administered at an effluent dose of 45-55 mL/kg/h using standard equipment and protocols for critically ill patients with ALF or ACLF and hyperammonemia. | Device | High-Dose CRRT |
| Conventional-dose continuous renal replacement therapyContinuous renal replacement therapy administered at an effluent dose of 25-35 mL/kg/h using standard equipment and protocols for critically ill patients with ALF or ACLF and hyperammonemia. | Device | Conventional-Dose CRRT |
Primary outcome
Number of coma- and delirium-free days
Time frame: Day 1 to Day 28 post-randomization
The number of days during the first 28 days after randomization in which the patient is alive and free of coma or delirium, assessed using standardized neurological evaluation tools such as the Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU).
7 secondary outcomes
Ammonia clearance at 12, 24, 48, and 72 hours
Time frame: Baseline to 72 hours
Length of hospital stay
Time frame: Up to 90 days
28-day mortality
Time frame: 28 days post randomization
90-day mortality
Time frame: 90 days post-randomization
Number of ventilator-free days within 28 days
Time frame: 28 days post-randomization
Incidence of safety outcomes, such as hypophosphatemia, dialysis disequilibrium syndrome, and rapid correction of hyponatremia
Time frame: From CRRT initiation up to 7 days or until therapy discontinuation
Improvement in cerebral compliance
Time frame: Baseline to Day 28 post-randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2025.
- Individual participant dataSharing planned: Yes
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High-dose continuous renal replacement therapy and Conventional-dose continuous renal replacement therapy in people with Acute Liver Failure and Acute on Chronic Liver Failure (ACLF), run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
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 4 inclusion and 4 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: enrolling by invitation, as of the sponsor's last update on 24 Jun 2025. 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 Brazil. 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. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of coma- and delirium-free days (time frame: Day 1 to Day 28 post-randomization). 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 24 Jun 2025.