COLLABORATIVE PROJECTS AND CLINICAL TRIALS

The EFClif participates as a partner or advisor in a wide variety of external research projects, either funded by the European H2020 program or by private companies:

Development of DIALIVE, A novel LIVER Dialysis Device for the treatment of patients with Acute on Chronic Liver Failure (ACLF). ALIVER.

Randomised Controlled Clinical Trial Rajiv Jalan (UCL, Royal Free Hospital. London, United Kingdom)

Funder: H2020-EU.3.1.2- 7733057
Start date: 01/01/2017
End date: 30/09/2020

The ALIVER programme was designed to evaluate a novel approach to treating patients with acute-on chronic liver failure (ACLF) using a novel dialysis device, DIALIVE™. Its design is based on the understanding that albumin is destroyed, in patients with liver failure and allows removal and replacement of albumin and removal of DAMPs and PAMPS.

During 2020 the randomised controlled clinical trial of Dialive™ in adult patients with ACLF was completed and data analysis started. All indicates that Dialive™ treated patients experience an improvement of biomarkers, thought to be associated with the cytokine storm and organ failure in ACLF. If confirmed, it will mean that patients on Dialive™ show statistically significant benefits, compared to the control arm, ten days after the start of the treatment protocol of three to five sessions of eight to 12 hours each. Yaqrit Discovery Ltd., a spin off company from University College London, where DIALIVE was discovered will perform the next phase of clinical trials so that, the device can start to save lives of ACLF patients.

www.aliver.info

CARBALIVE.

Randomised Controlled Clinical Trial Rajiv Jalan (UCL, Royal Free Hospital. London, United Kingdom)

Funder: H2020-EU.3.1.2- 634579
Start date: 01/05/2015
End date: 31/01/2021

Carbalive™ is a product for the treatment of patients with decompensated cirrhosis, specifically designed to remove harmful bacterial toxins from the gut, reduce gut inflammation and its permeability, preventing them from leaking into the rest of the body. This research was led by the members of the Liver Failure Group at University College London.

Data from the trial also showed trends in the improvements of a wide range of biomarkers of systemic inflammation, which is especially notable because Carbalive™ is not systemically absorbed. Measures of gut-specific health also improved in Carbalive™ patients compared to those on the placebo arm. These improvements were associated with trends towards reduction in the markers of gut inflammation, and less translocation (leakiness) of the gut wall; characteristic problems associated with cirrhosis and its complications. Yaqrit Discovery Ltd., will perform the next phase of clinical trials before it becomes available for use to treat patients with decompensated cirrhosis.

www.carbalive.eu

LIVERHOPE.

Randomised Controlled Clinical Trial Pere Ginès (Hospital Clínic-IDIBBAPS. Barcelona, Spain)

Funder: H2020-EU.3.1.2- 731875
Start date: 01/01/2017
End date: 31/06/2022

The objective of LIVERHOPE project is to evaluate a novel therapeutic strategy for patients with cirrhosis based on a combination of rifaximin and simvastatin, targeting the main pathophysiological mechanisms of disease progression, namely the impairment in the gutliver axis and the persistent hepatic and systemic inflammatory response.

The LiverHope project is unique in that it represents the first approach to develop a new combination therapy, able to prevent the progression of the disease. If the results are positive this may represent a treatment to stabilize the disease and prevent it from progressing. This will have a huge impact in the natural history of the disease, by decreasing mortality and improving quality of life of patients and their families, and will reduce costs, by decreasing the number of hospitalizations.

SCOTCH Trial Supplemental Corticosteroids in Cirrhotic Hypotensive Patients with Suspicion of Sepsis.

Randomised Controlled Clinical Trial Alexander Wilmer (UZ Leuven. Leuven, Belgium)
Julia Wendon (King’s College. London, United Kingdom)
Javier Fernández (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)

Promoter: Catholic University of Leuven
Start date: 01/04/2015
End date: 31/12/2020 (early terminated)

Double-blind, phase IV, randomized, placebo-controlled multicentre trial, involving 356 patients with cirrhosis and septic shock, aimed at evaluating if intravenous low-dose hydrocortisone improves 28-d survival in comparison with standard therapy.

The study started in April 2015 and until the end of 2020 included 94 patients. Ten centres were theoretically active but just two were currently recruiting. A total of 244 were screened, but not included (screening failure). Due to the low recruitment rate, the study was prematurely stopped on December 31, 2020. The next steps are the finalization of online monitoring, cleaning of the database and initiation of the analysis of clinical data and samples. Cortisol metabolism will be analysed in Leuven. The rest of the analysis (inflammation and omics) will be performed by EF Clif investigators.

APACHE Trial. Effects of Plasma Exchange with Human Serum Albumin 5% (PE-A 5%) on Short-term Survival in Subjects with "Acute-On-Chronic Liver Failure" (ACLF) at High Risk of Hospital Mortality.

Randomised Controlled Clinical Trial Javier Fernández (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)
Fin Stolze Larsen (Rigshospitalet. Copenhagen, Denmark)

Promoter: Grifols, SA
Start date: 21/02/2019
End date: 31/12/2022

It is a phase III, multicentre, randomized, open-label trial in 380 patients with ACLF-1b, ACLF grade 2 or ACLF-3a, aimed to determine whether plasma exchange with 5% albumin (from 4 to 9 plasma exchange [PE] sessions) improves 90-day survival, in comparison with standard medical therapy.

The study is being performed in 30 centres, 20 from Europe and 10 from North America. Most hospitals had their site open visit at the end of 2019, or in the first quarter of 2020. Until now, 105 patients have been enrolled. The estimated additional duration of the study is 24 months, considering the problems of recruitment associated with the COVID-19 pandemic.

ALADDIN Study.

Clinical-Translational Research Joan Clària (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)

Promoter: EF Clif
Start date: 01/02/2020
End date: 31/12/2022

The ALADDIN Study is an agnostic investigation aimed to assess the mechanisms of systemic inflammation and ACLF in a large series of patients with and without ACLF. Protein expression, kinomic and genotyping will be determined using high throughput molecular biology techniques, in patients with ACLF from the APACHE study. Since patients included in the APACHE Study will be investigated before, during and after treatment, the study will also assess the mechanism of action of plasma exchange and predictors of response in patients with ACLF. The recruitment of patients for study inclusion is ongoing.

PRECIOSA Study Prevention of Mortality with Long-Term Administration of Human Albumin in Subjects with Decompensated Cirrhosis and Ascites.

Randomized Controlled Clinical Trial Javier Fernández (Hospital Clínic Barcelona-IDIBAPS; EF Clif. Barcelona, Spain)
Paolo Angeli (University of Padova. Padova, Italy)

Funder: Grifols, SA
Start date: 20/04/2018
End date: 31/12/2023

This is a phase IV, multicentre, randomized open-label trial, in 410 patients with decompensated liver cirrhosis with ascites, aimed to determine if long-term albumin administration (1.5 g/kg body weight every 10 days for 12 months) prevents ACLF and improves 1-year transplant-free survival in comparison with standard medical therapy.

The study is being performed in 29 European and 10 North American centres. The first site was opened in April 2018. Until now, 115 subjects have been included. The estimated additional duration of the study is 30 months, given the problems of recruitment caused by the COVID-19 pandemic.

HEPASTEM.

- HEP101-PHASE Multicenter Phase II safety and preliminary efficacy study of 2 dose regimens of HEPASTEM in patients with acute-on-chronic liver failure.

Phase II Randomised Controlled Clinical Trial Frederik Nevens (UZ Leuven. Leuven, Belgium)

Funder: Promethera Biosciences
Start date: 16/12/2016
End date: 21/08/2020

An Interventional, multicentre, open, safety study of 2 dose regimens of HepaStem, given in subsequent cohorts with approximately 24 hospitalized ACLF patients. Its primary objective is to assess the safety administration of different doses of HepaStem up to D28, and the secondary one is to evaluate preliminary efficacy parameters up D28, up to M3 and up to 1 year.

The clinical part of this study has been completed in the period under review. LPLV was on 21August 2020. The CSR is not available at the time of this report. Subject exposure: 24 patients. Safety results: 2 patients with underlying coagulation disturbances/ failure (due to their disease) experienced severe bleeding, caused by severe coagulopathy in the highest dose cohort (5 Mio cells/kg). 21/24 patients treated in the reduced dose cohorts (0.6 to 1.2 single and double doses 1 week apart) did not experience coagulopathy. The coagulation parameters stayed within the set safety limits for fibrinogen and platelets.

- HEP102-RANDOMIZED, placebo controlled, double blind, multi-center PHASE IIB study to evaluate the efficacy and safety of HEPASTEM in patients with acute-on-chronic liver failure (ACLF).

Phase IIB Randomised Controlled Clinical Trial Frederik Nevens (UZ Leuven. Leuven, Belgium)

Funder: Promethera Biosciences
Start date: 21/01/2020
End date: 31/12/2023

Interventional, double blind, randomised (2:1) and placebo-controlled study on one dose regimen of HepaStem. 1-week double-blind treatment period with 2 i.v. infusions of HepaStem at 1.0 x 106 cells/ kg BW or Placebo. The primary objective is to demonstrate the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg (7-day interval) on the overall survival proportion at D90 days.

FPFV: 21 January 2020. Recruitment has been strongly impacted for the COVID-19 situation. 12 Patients were exposed to HepaStem or placebo up to 08-12-20. The randomization ratio is 2:1 Therefore, an estimated number of 8 patients received HepaStem. No safety concerns have been observed in the treated population so far.

Liposomal peritoneal dialysis for the management of hepatic encephalopathy.

Phase I Randomised Controlled Clinical Trial Jonel Trebicka (Goethe University Frankfurt. Frankfurt, Germany; EF Clif. Barcelona, Spain)

Funder: Versantis GmbH
Start date: 01/09/2019
End date: 11/03/2021

Versantis, a clinical-stage company developing novel therapies for orphan liver and paediatric diseases, performs a Phase 1b clinical trial of VS-01 in decompensated liver cirrhosis. VS-01 was tested in a first-in-human, single-ascending and multiple dose study.

The primary objective of the study is to evaluate the safety and tolerability of i.p.-administered VS-01 on top of standard of care in cirrhotic patients with ascites and mild hepatic encephalopathy, following single and multiple intraperitoneal administrations. The secondary objectives are to gather preliminary PK, PD and clinical efficacy data. In total, 12 patients were successfully treated, 9 in the single ascending dose part (3 doses) and 3 in the multiple dose (daily treatment for 4 days) part of the study. The results show that VS-01 was safe and well tolerated, with no dose-limiting toxicities or unexpected safety signals. No serious adverse events (AE) are reported, and no patients discontinued because of an AE. Patients receiving multiple doses of VS-01 show improvements in selected biomarkers and clinical cognitive tests, which support the clinical potential of VS-01 and encourage its further investigation in a Phase 2a study in the target indication of ACLF.