Plasma Exchange for Liver Failure

(APACHE Trial)

No longer recruiting at 45 trial locations

Overseen By Alexander Kuo

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Grifols Therapeutics LLC

Must not be taking: Anticoagulants, Antiplatelets

Disqualifiers: Septic shock, Respiratory failure, Renal failure, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1-2.5 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with acute-on-chronic liver failure (ACLF), a serious condition where the liver suddenly worsens in those with existing liver disease. Researchers compare the effects of standard medical treatment alone to standard treatment combined with plasma exchange using PE-A 5% (a solution containing Human Serum Albumin 5%), which involves replacing substances in the blood. Individuals diagnosed with ACLF and at high risk of serious outcomes may be suitable candidates. Participants will receive either the new treatment combination or standard care, and researchers will monitor their health for several months. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on anti-platelet or anti-coagulant therapy, except for LMWH for DVT prophylaxis.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatment under study, plasma exchange with albumin replacement (PE-A 5%), is generally well-tolerated by people with liver failure. Earlier studies indicated that patients experienced improved blood flow to the liver, a positive indicator for liver health. These studies reported no serious side effects, suggesting the treatment is relatively safe. However, as with any medical treatment, some side effects might still occur. Prospective participants should discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for liver failure, which often focus on managing symptoms and supporting liver function, the PE-A 5% treatment is unique because it uses plasma exchange with 5% albumin (Albutein 5%) as the main replacement fluid. This method aims to directly remove toxins and replace essential proteins in the blood, potentially offering more immediate relief and stabilization for patients. Researchers are excited about this approach as it could provide a quicker and more effective intervention than traditional methods, which often include medications like diuretics and lactulose or procedures like liver transplantation.

What evidence suggests that plasma exchange using PE-A 5% could be effective for acute-on-chronic liver failure?

This trial will compare plasma exchange using a solution called human serum albumin 5% (PE-A 5%) with standard medical treatment (SMT) for liver failure. Research has shown that PE-A 5% can aid individuals with liver issues by improving liver function and addressing hepatic encephalopathy, a brain condition caused by liver failure. Plasma exchange is considered safe and may also benefit the kidneys, brain, and blood circulation. A small study suggested that PE-A 5% is practical and safe for patients with acute-on-chronic liver failure (ACLF). Overall, this treatment appears promising for improving the health of those with serious liver conditions. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for men and women aged 18-79 with cirrhosis experiencing acute-on-chronic liver failure (ACLF) grades 1b, 2, or 3a. Participants must be able to consent or have a representative who can. Exclusions include severe infections, respiratory failure, certain cancers, pregnancy, drug addiction (except alcohol/marijuana), recent participation in other trials, and various severe health conditions.

Inclusion Criteria

Subjects with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization (must be ACLF-1b, -2, or -3a within the Screening Period [a maximum of 10 days])

If I'm unable to consent, a family member or legal representative will do so for me.

Willing and able to provide written informed consent or have an authorized representative able to provide written informed consent on behalf of the subject in accordance with local law and institutional policy

Exclusion Criteria

I have severe lung disease (GOLD stage III or IV).

My liver failure condition improved or worsened during the screening period.

I have had a liver transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard medical treatment (SMT) + PE-A 5% or SMT only, with treatment duration between 7 and 17 days depending on ACLF evolution

1-2.5 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

What Are the Treatments Tested in This Trial?

Interventions

• PE-A 5%

Trial Overview The study compares standard medical treatment (SMT) alone versus SMT combined with plasma exchange using human serum albumin 5% (PE-A 5%) in patients with ACLF. It's randomized and open-label; participants will receive treatments for up to 17 days based on their condition's progression followed by a three-month follow-up.

How Is the Trial Designed?

Group I: SMT+ PE-A 5% Experimental Treatment 1 Intervention

PE-A 5% will be performed using 5% albumin (Albutein 5%) as the main replacement fluid administered intravenously.

Group II: Standard Medical Treatment (SMT) Active Control 1 Intervention

Standard medical treatment (SMT) will be administered according to institution standards.

PE-A 5% is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Human Serum Albumin 5% for:

• Hypovolemia
• Hypoalbuminemia
• Acute-on-chronic liver failure

Approved in Canada as Albumin (Human) 5% Solution for:

• Hypovolemia
• Hypoalbuminemia
• Acute-on-chronic liver failure

Approved in European Union as Human Serum Albumin 5% for:

• Hypovolemia
• Hypoalbuminemia
• Acute-on-chronic liver failure

Who Is Running the Clinical Trial?

Grifols Therapeutics LLC

Lead Sponsor

Trials

59

Recruited

6,000+

Instituto Grifols, S.A.

Industry Sponsor

Trials

30

Recruited

4,100+

Published Research Related to This Trial

In a study of 77 patients with liver failure, combining plasma exchange (PE) with hemofiltration (HF) significantly improved survival rates (68.4% for PE+HF) compared to PE alone (48.7%) and a control group (29.3%).

The combination treatment also led to better recovery from hepatic encephalopathy and more effective correction of electrolyte and acid-base imbalances compared to PE alone, indicating enhanced efficacy and safety of the combined approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of curative effect of low flow rate plasma exchange combined with hemofiltration for treatment of liver failure]. Yang, YF., Huang, P., Zhang, N., et al.[2009]

In a study involving 40 patients undergoing therapeutic plasmapheresis, Albumex 5 showed a reaction rate of 12.1%, compared to 8.3% for 5% normal serum albumin (5% NSA), but this difference was not statistically significant (p = 0.37).

Both Albumex 5 and 5% NSA had low rates of adverse events, with none classified as serious, indicating that Albumex 5 can be considered a safe option for plasma replacement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A safety study of Albumex 5, a human albumin solution produced by ion exchange chromatography. Wolf, M., Kronenberg, H., Dodds, A., et al.[2019]

In a study of 154 subjects undergoing 1195 plasma exchanges with Zenalb 4.5, the overall incidence of adverse reactions (ADRs) was low at 1.7%, indicating that this treatment is generally well tolerated.

The study found no significant differences in tolerability between plasma sourced from the UK and the US, or between different manufacturing methods, suggesting that Zenalb 4.5 is a safe option for therapeutic plasma exchange.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience of using human albumin solution 4.5% in 1195 therapeutic plasma exchange procedures. Pusey, C., Dash, C., Garrett, M., et al.[2016]

A 3-year-old dog with a life-threatening type III hypersensitivity reaction after receiving human serum albumin (HSA) was successfully treated with therapeutic plasma exchange (TPE), which involved exchanging 2.7 plasma volumes over 4 days.

Post-treatment, the dog's serum albumin levels improved significantly, kidney function normalized, and there were no significant adverse effects, leading to complete clinical resolution of symptoms after hospitalization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic plasma exchange for the management of a type III hypersensitivity reaction and suspected immune-mediated vasculitis assumed to be caused by human albumin administration in a dog. Klainbart, S., Segev, G., Kelmer, E., et al.[2022]

Half-dose plasma exchange combined with a dual plasma molecular adsorption system significantly lowers bilirubin and albumin levels in patients with liver failure compared to simple plasma exchange, indicating improved efficacy in treatment.

This combined therapy also results in higher effective and survival rates, while reducing the amount of plasma needed and causing fewer adverse effects related to hemoglobin depletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Meta-analysis of the therapeutic value of plasma exchange simple or combined with dual plasma molecular adsorption system for liver failure]. Zhang, RX., Liu, LX.[2023]

In a study involving 80 patients undergoing their first plasma exchanges, no significant difference in overall safety was found between human plasma albumin and placental albumin solutions, with failure rates of 23 out of 40 and 15 out of 40, respectively.

However, patients receiving plasma albumin experienced significantly more febrile episodes and shivering fits compared to those receiving placental albumin, suggesting that the preparation method may influence the type of adverse reactions during plasma exchanges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Side effects of therapeutic plasma exchange. A controlled prospective study]. Mercatello, A., Laville, M., Leizorovicz, A.[2016]

In a study involving 34 healthy volunteers, Albunex, an ultrasound contrast agent made from heat-aggregated human albumin, did not induce any immunological response, as no IgE or IgG antibodies were detected after multiple injections.

Additionally, tests showed that Albunex did not cross-react with cat albumin-specific IgE, indicating it is unlikely to provoke allergic reactions in individuals with cat allergies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of an immune response to Albunex, a new ultrasound contrast agent based on air-filled albumin microspheres. Christiansen, C., Vebner, AJ., Muan, B., et al.[2018]

In a study of 40 patients with acute liver failure, standard-volume plasma-exchange (SVPE) significantly improved 21-day transplant-free survival rates (75% vs. 45% for standard medical treatment alone), indicating its efficacy in this critical condition.

SVPE was found to be safe, with no treatment-related deaths, and it effectively reduced levels of harmful substances like ammonia and pro-inflammatory cytokines, suggesting it may help mitigate the inflammatory response associated with acute liver failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Maiwall, R., Bajpai, M., Singh, A., et al.[2022]

In a study of 15 patients with liver failure (13 acute and 2 chronic), plasma exchange (PE) showed a survival rate of 31% in acute cases, with better outcomes for patients without chronic liver disease (60% survival).

PE effectively reduced jaundice and improved overall condition in chronic liver failure patients, suggesting it can serve as a supportive treatment while awaiting liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood purification for postoperative liver failure with special reference to chronic hepatic support for those awaiting liver transplantation. Omokawa, S., Asanuma, Y., Yoshida, S., et al.[2016]

In a study of 251 patients with acute-on-chronic liver failure, plasma exchange (PE) combined with double plasma molecular adsorption system (DPMAS) showed significantly better treatment effectiveness in early-stage liver failure compared to simple PE, with effectiveness rates of 83.7% and 55.6% respectively.

The combined treatment also led to greater reductions in bilirubin and bile acid levels, while maintaining a similar safety profile to simple PE, indicating that DPMAS can enhance treatment outcomes without increasing adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Plasma exchange combined with double plasma absorption therapy improve the prognosis of acute-on-chronic liver failure]. Zhong, S., Wang, N., Zhao, J., et al.[2019]

In a study of 70 patients with acute on chronic liver failure (AoCLF), plasma exchange (PE) significantly reduced plasma ammonia levels (PAL) more effectively than standard medical treatment, indicating its potential as a supportive therapy.

Patients receiving PE showed a dramatic decrease in PAL after 30 days, which was associated with improved survival rates compared to those receiving only medical treatment, highlighting the importance of ammonia levels in AoCLF outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes of ammonia levels in patients with acute on chronic liver failure treated by plasma exchange. Ye, JL., Ye, B., Lv, JX., et al.[2014]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1665268123002958

P-5 APACHE STUDY DESIGN TO EVALUATE THE ... A pilot study suggested that plasma exchange with human serum albumin 5% (PEA5%) as a replacement fluid is feasible and safe in ACLF patients.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38544553/

Effect of plasma exchange with albumin replacement on ... PE-A5% was a safe procedure associated with positive effects on albumin functionality, and circulatory, renal, cerebral, and liver function in patients with ...

3. elsevier.es elsevier.es/en-revista-annals-hepatology-16-articulo-p-5-apache-study-design-to-S1665268123002958

Annals of Hepatology Liver transplantation is the only treatment to improve survival. A pilot study suggested that plasma exchange with human serum albumin 5% (PEA5%) as a ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10966298/

Effect of plasma exchange with albumin replacement on ... PE using albumin 5% (PE-A5%) as a replacement fluid is an effective and safe treatment in patients with acute liver failure, improving hepatic encephalopathy ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03702920

NCT03702920 | Short-term Survival of Subjects With Acute ... Plasma exchange treatment (PE-A 5%) will be performed using 5% albumin solution (Albutein 5%). Fresh frozen plasma will be given to prevent coagulopathy. IVIGs ...

6. elsevier.es elsevier.es/en-revista-annals-hepatology-16-resumen-p-5-apache-study-design-to-S1665268123002958

P-5 APACHE STUDY DESIGN TO EVALUATE THE ... ... of end-stage liver disease. See more Open Access Option. Indexed in ... LIVER FAILURE AT HIGH RISK OF HOSPITAL MORTALITY. Visits. 547. Download PDF.

7. researchgate.net researchgate.net/publication/377617648_Effect_of_plasma_exchange_with_albumin_replacement_on_albumin_functionality_and_organ_dysfunction_in_acute-on-chronic_liver_failure

Effect of plasma exchange with albumin replacement on ... ... albumin functionality and organ dysfunction in acute-on-chronic liver failure ... PE increased hepatic blood flow in patients with liver failure,. 38. This ...