Plasma Exchange for Liver Failure

(APACHE Trial)

Recruiting at 40 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

275 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 3, multicenter, randomized, controlled, parallel-group, open-label study to evaluate the effects of plasma exchange using human serum albumin 5% (PE-A 5%) in acute-on-chronic liver failure (ACLF) subjects. The study will involve approximately 40 study centers in the United States, Canada, and Europe with expertise in the management of subjects with ACLF. Subjects with ACLF at a high risk of hospital mortality will be enrolled. The study will consist of a Screening Period during which subjects will be randomized (1:1) to receive either standard medical treatment (SMT) + PE-A 5% (treatment group) or SMT only (control group), followed by a Treatment Period, and a Follow-up Period. The Treatment Period for subjects in the SMT+ PE-A 5% treatment group will be between 7 and 17 days, depending on ACLF evolution. The Treatment Period for subjects in the SMT control group will be a minimum of 7 days for all subjects and up to 17 days depending on the ACLF evolution. Subjects in this group will receive SMT according to the institution's standards. The Follow-up Period for subjects in both groups will be 90 days.

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.

What data supports the idea that Plasma Exchange for Liver Failure is an effective treatment?

The available research shows that Plasma Exchange (PE) is an effective treatment for liver failure. One study found that PE combined with another method called double plasma molecular adsorption system (DPMAS) was more effective than using PE alone, especially in the early stages of liver failure. This combination improved the treatment efficiency and reduced the need for plasma. Another study showed that PE helps lower harmful substances in the blood, like ammonia, which is important for patients with liver failure. Additionally, a meta-analysis of several studies found that combining PE with DPMAS improved survival rates and treatment effectiveness compared to using PE alone. These findings suggest that PE, especially when combined with other methods, is a beneficial treatment for liver failure. ^{1 2 3 4 5}

What safety data is available for plasma exchange using human albumin solutions?

Several studies have evaluated the safety of human albumin solutions used in plasma exchange. A study on Albumex 5 found a low adverse event rate, with no serious events reported. Another study compared two albumin solutions and found no significant difference in overall safety, though preparation methods affected the type of adverse reactions. A large survey of Zenalb 4.5% solution reported a low incidence of adverse reactions, with no significant impact from plasma source or manufacturing method. Additionally, Albunex, an albumin-based ultrasound contrast agent, showed no immunogenic response in volunteers. Overall, human albumin solutions are generally well-tolerated in plasma exchange procedures. ^{6 7 8 9 10}

Is the treatment PE-A 5% a promising treatment for liver failure?

Yes, PE-A 5% is a promising treatment for liver failure. Plasma exchange, which includes treatments like PE-A 5%, has been shown to help patients with liver failure by improving survival rates, reducing harmful substances in the blood, and supporting patients until they can receive a liver transplant. ^{1 2 3 4 11}

Eligibility Criteria

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.

I am between 18 and 79 years old with liver cirrhosis.

Exclusion Criteria

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

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

I have had a liver transplant.

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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 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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. [2022]

2. China pubmed.ncbi.nlm.nih.gov

[Comparison of curative effect of low flow rate plasma exchange combined with hemofiltration for treatment of liver failure]. [2009]

3. China pubmed.ncbi.nlm.nih.gov

[Plasma exchange combined with double plasma absorption therapy improve the prognosis of acute-on-chronic liver failure]. [2019]

4. Greece pubmed.ncbi.nlm.nih.gov

Changes of ammonia levels in patients with acute on chronic liver failure treated by plasma exchange. [2014]

5. China 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]. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A safety study of Albumex 5, a human albumin solution produced by ion exchange chromatography. [2019]

7. France pubmed.ncbi.nlm.nih.gov

[Side effects of therapeutic plasma exchange. A controlled prospective study]. [2016]

8. England pubmed.ncbi.nlm.nih.gov

Experience of using human albumin solution 4.5% in 1195 therapeutic plasma exchange procedures. [2016]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Lack of an immune response to Albunex, a new ultrasound contrast agent based on air-filled albumin microspheres. [2018]

10. United States 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. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Blood purification for postoperative liver failure with special reference to chronic hepatic support for those awaiting liver transplantation. [2016]