Clinical trial NCT03065699: Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients
Official title: A Multi-centre, Randomised Controlled Study, to Evaluate the Safety and Performance of The DIALIVE Liver Dialysis Device (LDD) in Patients With Acute on Chronic Liver Failure (ACLF) Versus Standard of Care (SOC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute on Chronic Liver Failure
Keywords: Medical device
Liver dialysis
Haemofilter
ACLF
Lead sponsor: Yaqrit Ltd
Sponsor class: INDUSTRY
Collaborators: name: European Foundation for Chronic Liver Failure
name: University College, London
name: Fakkel bvba
First posted: 2017-02-28
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 81
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The design is a multi-centre, randomised, controlled, study to generate data for the evaluation of safety (as measured by the percentage of subjects who experience at least one serious adverse event (SAE)) and performance (as measured by lowering of the plasma endotoxin concentrations, and improved albumin function) of DIALIVE in 24 evaluable patients with Acute on Chronic Liver Failure (ACLF) versus standard of care (SOC). During the study the sample size was increased to include a total 30 evaluable patients.
Primary purpose: DEVICE_FEASIBILITY

Brief summary: The First-In-Man study is a multi-centre, randomised, controlled, study to generate data for the evaluation of safety and performance of DIALIVE Liver Dialysis Device in 24 evaluable patients with Acute on Chronic Liver Failure (ACLF) versus standard of care (SOC).

Detailed description: The First-In-Man study will evaluate the safety and performance of DIALIVE Liver Dialysis Device in Acute on Chronic Liver Failure (ACLF) patients and will compare the outcome with patients treated under standard of care (SOC).

The hypothesis is that DIALIVE will significantly improve the prognosis of ACLF patients by modulating systemic inflammation.

The target patient population are men and women ≥18 years, ≤81yr. Patients with ACLF grade 1 and ACLF grade 2 on the background of alcoholic cirrhosis. During the study, inclusion criteria were expanded to include also AKI-1 and ACLF 3a patients. Treatment will be undertaken in an intensive care (ICU) or renal dialysis unit setting if the patients are randomised to the DIALIVE treatment arm. For patients randomised to the 'Standard of care' arm, the location of treatment (ICU or general ward) will be determined by their clinical need and will be decided by the site Principal Investigator.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 733057.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects aged ≥18 years ≤81yr who have given informed consent to participate in the study and are able to understand and comply with the requirements of the study (otherwise written informed consent must be obtained on behalf of the subject in accordance with local ethical and legal requirements).
* History indicative of alcohol-related cirrhosis based on clinical, radiological and/or histological evidence.
* History of an acute decompensating event (including but not limited to ascites, gastrointestinal bleeding, hepatic encephalopathy and/or acute bacterial infections), occurring within ≤6 weeks of screening.
* • Subject with :

  * ACLF Grade 1, 2 or 3a defined per the CLIF-C OF scoring system OR
  * single hepatic organ failure for serum bilirubin \> 20 mg/dL (342 µmol/L) at screening and randomization, OR
  * AKI-stage 1b (sCr \> 1.5 mg/dL or 134 µmol/L).
* Where a subject has received corticosteroids for alcohol-induced ACLF, is unresponsive to at least 7 days of treatment (where lack of response defined as Lille score \> 0.45 or steroids stopped before 7 days due to any complication such as infection). This refers to the first course of corticosteroid therapy only.

Exclusion Criteria:

* Co-infection with HIV and AIDS defining illness.
* Subjects with acute or sub-acute liver failure without underlying cirrhosis.
* Subjects with severe thrombocytopaenia, defined by the platelet count of \< 40,000 / mm3 or rapid reduction in platelet count (\> 50% reduction) 24 hrs prior to inclusion.
* Subjects with International Normalised Ratio (INR) \> 3
* ACLF 3b patients, i.e. ACLF with more than 3 organ failures.
* Subjects with cirrhosis who develop decompensation at any time in the post-operative period following partial partial liver resection or major non-liver surgery.
* Subjects with uncontrolled infection. Patients may be entered into the study provided antimicrobials have been administered for at least 48 hours with an appropriate response observed prior to randomization.
* Subjects with respiratory organ failure (as per CLIF-C OF scoring: PaO2/FiO2\< 200 mmHg or 27 kPa or SaO2/FiO2 \< 214).
* Subjects with haemodynamic instability:

  i) persistent hypotension (mean arterial pressure \< 65 mmHg) with evidence of tissue hypoperfusion, not responsive to volume resuscitation and/or low dose vasopressor support; ii) a norepinephrine dose of \> 0.2 µg/kg/min, or a second pressor (terlipressin for variceal haemorrhage and/or hepato-renal syndrome does not count as pressor, unless it is specifically used to treat systemic hypotension) at screening or randomization. Patients can be reconsidered for study inclusion after at least a 24 hour period of norepinephrine requirement \< 0.2 µg/kg/min.
* Subjects not considered appropriate for full active treatment including organ support or those with a Do Not Attempt Cardio-Pulmonary Resuscitation order (DNACPR).
* Subjects with active, or with a history of non hepatic malignancy unless adequately treated or in complete remission for five or more years.
* Patients with HCC outside Milan criteria.
* Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the subject from participating in and completing the study.
* Subject who has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study; concomitant observational studies are allowed.
* Evidence of uncontrolled seizures.
* Subjects diagnosed with Creutzfeldt-Jakob disease.
* In females: known pregnancy or lactating.
* Subjects weighing less than 30 kg (as per contra-indications of oXiris and septeX)
* Where subjectspresent with a known allergy to heparine of have type II thrombocytopaenia caused by heparin (HIT syndrome type II)
* In the opinion of the investigator, it is unsafe for the patient to be considered for the study.

Primary outcomes:
measure: Safety of DIALIVE in terms of percentage of ACLF patients experiencing serious adverse events during DIALIVE treatment period.
timeFrame: Treatment period is from 1 to 10 days post-randomization.
measure: Safety of DIALIVE in terms of percentage of ACLF patients who discontinued treatment due to severe adverse event.
timeFrame: Treatment period is from 1 to 10 days post-randomization.
Secondary outcomes:
measure: Performance of DIALIVE by assessing removal of endotoxins.
timeFrame: End of DIALIVE treatment (max 10 days after randomization)
measure: Performance of DIALIVE by assessing removal of albumin.
timeFrame: End of DIALIVE treatment (max 10 days after randomization)
measure: Change in Clinical Parameters by DIALIVE treatment (ACLF grade and score) between treatment arms.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Change in Clinical Parameters by DIALIVE treatment (ACLF grade) between treatment arms.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Change in mortality between treatment arms.
timeFrame: At day 28 post-randomization (for all patients). At day 90 for those patients enrolled under protocol version 6.0.
measure: Change in Clinical Parameters by DIALIVE treatment (CLIF-C score) between treatment arms.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Status of ICU and hospital discharge.
timeFrame: Treatment period is from 1 to 90 days post-randomization.
measure: Length of stay in ICU and in hospital
timeFrame: Assessment is done on day 28 and day 90.
measure: ICU and hospital re-adminssions with another episode of ACLF
timeFrame: Assessment is done on day 28 and day 90.
Other outcomes:
measure: Efficacy of the DIALIVE for liver function: changes in MELD score
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Efficacy of the DIALIVE for kidney function: changes in creatine and NGAL
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Efficacy of the DIALIVE for brain function: changes in West Haven Criteria
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Efficacy of the DIALIVE for immune function.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Assessment of coagulation and haemostasis.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Efficacy of the DIALIVE for pulmonary function.
timeFrame: Treatment period is from 1 to 10 days post-randomization
measure: Efficacy of the DIALIVE for the cardiovascular function.
timeFrame: Treatment period is from 1 to 10 days post-randomization
Locations:
city: Graz
country: Austria
facility: university Hospital Graz
city: Brussels
country: Belgium
facility: University Hospital Erasmus
city: Aarhus
country: Denmark
facility: University Hospital
city: Clichy
country: France
facility: Hôpital Beaujon
city: Villejuif
country: France
facility: Paul Brousse Hospital
city: Rostock
country: Germany
facility: University Hospital of Rostock
city: Bucharest
country: Romania
facility: Fundeni Clinical Institute
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Madrid
country: Spain
facility: University Hospital Gregorio Maragnon
city: London
country: United Kingdom
facility: Royal Free Hospital London NHS
state: Hampstead
city: Basildon
country: United Kingdom
facility: university hospital BASILDON
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
Study officials:
affiliation: Royal Free Hospital London NHS
name: Banwari Agarwal, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee KC, Baker LA, Stanzani G, Alibhai H, Chang YM, Jimenez Palacios C, Leckie PJ, Giordano P, Priestnall SL, Antoine DJ, Jenkins RE, Goldring CE, Park BK, Andreola F, Agarwal B, Mookerjee RP, Davies NA, Jalan R. Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study. J Hepatol. 2015 Sep;63(3):634-42. doi: 10.1016/j.jhep.2015.04.020. Epub 2015 May 1.