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Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients (DIALIVE _ACLF)

Primary Purpose

Acute on Chronic Liver Failure

Status

Completed

Phase

Not Applicable

Locations

International

Study Type

Interventional

Intervention

DIALIVE Liver Dialysis Device

About this trial

This is an interventional device feasibility trial for Acute on Chronic Liver Failure focused on measuring Medical device, Liver dialysis, Haemofilter, ACLF

Eligibility Criteria

18 Years - 81 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

Standard of Care

DIALIVE Liver Dialysis Device treatment arm

Arm Description

For patients with ACLF grade 1 or 2 and 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. They will receive standard of care.

Patients with ACLF grade 1 and ACLF grade 2 on the background of alcoholic cirrhosis randomized to the DIALIVE arm will receive treatment in an intensive care (ICU) or renal dialysis unit setting. They will receive DIALIVE treatment according to a fixed treatment schedule over a period of 10 days post-randomization.

Outcomes

Primary Outcome Measures

Safety of DIALIVE in terms of percentage of ACLF patients experiencing serious adverse events during DIALIVE treatment period.

To evaluate the safety of the DIALIVE device in patients with Acute on Chronic Liver Failure Grades 1 and 2 (ACLF). Outcome measure is: The percentage of subjects who experience at least one (1) serious adverse event (SAE) between Day 1 and Day 10.(DIALIVE arm only). Outcome is measured on day 10 and compared between treatment arms.

Safety of DIALIVE in terms of percentage of ACLF patients who discontinued treatment due to severe adverse event.

The outcome measure is the percentage of subjects who discontinued DIALIVE treatment due to a serious adverse device event (SADE) between Day 1 (first day of treatment) and Day 10.(DIALIVE arm only)

Secondary Outcome Measures

Performance of DIALIVE by assessing removal of endotoxins.

To evaluate the performance of the DIALIVE device in patients with ACLF (DIALIVE arm only). Outcome measure is : - Change in Plasma endotoxin concentrations between end of treatment with DIALIVE and the beginning of treatment with DIALIVE (Day 1). TV: 40% reduction; AV: 20% reduction

Performance of DIALIVE by assessing removal of albumin.

To evaluate the performance of the DIALIVE device in patients with ACLF (DIALIVE arm only). Outcome measure is : - Change in Albumin function (Human non-mercapt albumin -2 (HNA-2) / Human mercapt albumin (HMA ratio) between end of treatment with DIALIVE and the beginning of treatment with DIALIVE (Day 1)

Change in Clinical Parameters by DIALIVE treatment (ACLF grade and score) between treatment arms.

Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in CLIF-C score (Chronic LIver Failure Consortium)

Change in Clinical Parameters by DIALIVE treatment (ACLF grade) between treatment arms.

Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in ACLF Grade

Change in mortality between treatment arms.

The outcome measure is the difference in mortality between the DIALIVE treatment arm and the Standard of Care arm at day 28 post-randomization. During the study, the follow up period was prolonged to 90 days (3 months).

Change in Clinical Parameters by DIALIVE treatment (CLIF-C score) between treatment arms.

Status of ICU and hospital discharge.

Location of patient at day 28 and 90 post randomization, and timing of discharge from hospital.

Length of stay in ICU and in hospital

Evaluation of length of stay of patient in the hospital and on the ICU.

ICU and hospital re-adminssions with another episode of ACLF

Assessment of re-admissions of patients for another episode of ACLF after hospital discharge post-randomization.

Full Information

NCT ID

NCT03065699

First Posted

January 18, 2017

Last Updated

May 26, 2021

Sponsor

Yaqrit Ltd

Collaborators

European Foundation for Chronic Liver Failure, University College, London, Fakkel bvba

1. Study Identification

Unique Protocol Identification Number

NCT03065699

Brief Title

Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients

Acronym

DIALIVE _ACLF

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

2. Study Status

Record Verification Date

May 2021

Overall Recruitment Status

Completed

Study Start Date

July 9, 2017 (Actual)

Primary Completion Date

December 31, 2019 (Actual)

Study Completion Date

January 15, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Yaqrit Ltd

Collaborators

European Foundation for Chronic Liver Failure, University College, London, Fakkel bvba

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute on Chronic Liver Failure

Keywords

Medical device, Liver dialysis, Haemofilter, ACLF

7. Study Design

Primary Purpose

Device Feasibility

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

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.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard of Care

Arm Type

No Intervention

Arm Description

Arm Title

DIALIVE Liver Dialysis Device treatment arm

Arm Type

Active Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

DIALIVE Liver Dialysis Device

Other Intervention Name(s)

YAQ 002

Intervention Description

ACLF patients will receive dialysis treatment for 8-12 hrs/day and on three to five consecutive days over a 10-day time period. Dialysis treatment is performed by using the DIALIVE device provided by YAQRIT Ltd.

Primary Outcome Measure Information:

Title

Safety of DIALIVE in terms of percentage of ACLF patients experiencing serious adverse events during DIALIVE treatment period.

Description

Time Frame

Treatment period is from 1 to 10 days post-randomization.

Title

Safety of DIALIVE in terms of percentage of ACLF patients who discontinued treatment due to severe adverse event.

Description

The outcome measure is the percentage of subjects who discontinued DIALIVE treatment due to a serious adverse device event (SADE) between Day 1 (first day of treatment) and Day 10.(DIALIVE arm only)

Time Frame

Treatment period is from 1 to 10 days post-randomization.

Secondary Outcome Measure Information:

Title

Performance of DIALIVE by assessing removal of endotoxins.

Description

Time Frame

End of DIALIVE treatment (max 10 days after randomization)

Title

Performance of DIALIVE by assessing removal of albumin.

Description

Time Frame

End of DIALIVE treatment (max 10 days after randomization)

Title

Change in Clinical Parameters by DIALIVE treatment (ACLF grade and score) between treatment arms.

Description

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Change in Clinical Parameters by DIALIVE treatment (ACLF grade) between treatment arms.

Description

Evaluate the improvement in clinical parameters between Acute on Chronic Liver Failure (ACLF) patients receiving DIALIVE treatment vs Standard of Care. Outcome measure is: - Change in ACLF Grade

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Change in mortality between treatment arms.

Description

Time Frame

At day 28 post-randomization (for all patients). At day 90 for those patients enrolled under protocol version 6.0.

Title

Change in Clinical Parameters by DIALIVE treatment (CLIF-C score) between treatment arms.

Description

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Status of ICU and hospital discharge.

Description

Location of patient at day 28 and 90 post randomization, and timing of discharge from hospital.

Time Frame

Treatment period is from 1 to 90 days post-randomization.

Title

Length of stay in ICU and in hospital

Description

Evaluation of length of stay of patient in the hospital and on the ICU.

Time Frame

Assessment is done on day 28 and day 90.

Title

ICU and hospital re-adminssions with another episode of ACLF

Description

Assessment of re-admissions of patients for another episode of ACLF after hospital discharge post-randomization.

Time Frame

Assessment is done on day 28 and day 90.

Other Pre-specified Outcome Measures:

Title

Efficacy of the DIALIVE for liver function: changes in MELD score

Description

Outcome measure as compared between SoC and DIALIVE arm is: Liver: Changes in MELD score, plasma/serum cCK18/M30 and flCK18/M65 (markers of liver cell death). Liver: serum bilirubine Model for End-Stage Liver Disease (MELD) Scoring Systems.

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Efficacy of the DIALIVE for kidney function: changes in creatine and NGAL

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Kidney: Changes in serum creatinine and urinary NGAL (Neutrophil gelatinase-associated lipocalin - marker of kidney injury).

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Efficacy of the DIALIVE for brain function: changes in West Haven Criteria

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Brain: West Haven Criteria to assess changes in severity of hepatic encephalopathy.

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Efficacy of the DIALIVE for immune function.

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Immune function: Incidence of Infection. Changes in white cell count and plasma-induced neutrophil function (Phagoburst and Phagotest), serum CRP and cytokines (TNF-α, IL-6, IL-8, IL-10, IL1RA).

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Assessment of coagulation and haemostasis.

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Coagulation: Changes in INR and platelet levels.

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Efficacy of the DIALIVE for pulmonary function.

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Lung: P/F or S/F ratio.

Time Frame

Treatment period is from 1 to 10 days post-randomization

Title

Efficacy of the DIALIVE for the cardiovascular function.

Description

Outcome measure as compared between SoC and DIALIVE arm is: - Cardiovascular system: measurement off the Mean Arterial Pressure.

Time Frame

Treatment period is from 1 to 10 days post-randomization

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

81 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Banwari Agarwal, Dr

Organizational Affiliation

Royal Free Hospital London NHS

Official's Role

Principal Investigator

Facility Information:

Facility Name

university Hospital Graz

City

Graz

Country

Austria

Facility Name

University Hospital Erasmus

City

Brussels

Country

Belgium

Facility Name

University Hospital

City

Aarhus

Country

Denmark

Facility Name

Hôpital Beaujon

City

Clichy

Country

France

Facility Name

Paul Brousse Hospital

City

Villejuif

ZIP/Postal Code

94800

Country

France

Facility Name

University Hospital of Rostock

City

Rostock

ZIP/Postal Code

18051

Country

Germany

Facility Name

Fundeni Clinical Institute

City

Bucharest

Country

Romania

Facility Name

Hospital Clinic Barcelona

City

Barcelona

Country

Spain

Facility Name

University Hospital Gregorio Maragnon

City

Madrid

Country

Spain

Facility Name

Royal Free Hospital London NHS

City

London

State/Province

Hampstead

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

Facility Name

university hospital BASILDON

City

Basildon

Country

United Kingdom

Facility Name

Queens Medical Centre

City

Nottingham

ZIP/Postal Code

NG7 2UH

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Only anonymized clinical data can be shared out of central database according to the H2020 project plan.

Citations:

PubMed Identifier

25937432

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.

Results Reference

background

Links:

URL

http://yaqrit.com

Description

webpage legal responsible partner & spnosor

Available IPD and Supporting Information:

Available IPD/Information Type

Clinical Study Report

Available IPD/Information URL

http://yaqrit.com

Available IPD/Information Identifier

DIALIVE CSR summary 20210319

Available IPD/Information Comments

A summary of the final Clinical Study Report can be obtained through request to: YAQRIT Ltd, attention of Daniel Green, CEO (daniel.green@yaqrit.com) or Carrie Morgan (carrie.morgan@yaqrit.com) FAKKEL bvba, attention of Jaak Minten, CEO (info@fakkel-bvba.com)

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Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients

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Safety and Performance Trial of DIALIVE Liver Dialysis Device in Acute On Chronic Liver Failure Patients (DIALIVE _ACLF)

Acute on Chronic Liver Failure

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial