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)
Phase: NA
Conditions: Acute on Chronic Liver Failure
Sponsor: Yaqrit Ltd

 
 
Clinical Investigation Plan 
DOC. No: CIP YAQ-002 
Clinical Investigation Plan 
Version Date:  
10 October 2019 
 
Version No: 
7.0  
 
 
(Yaqrit Ltd Confidential, Not For Release) 
p. 1 of 88 
 
 
  
 
Project is supported in part by a grant of the European Community (ALIVER EU-grant No 733057) 
 
 
Title: 
A multi-centre, randomised controlled study, to evaluate the safety 
and performance of The DIALIVE Liver Dialysis Device (LDD) in 
alcohol related cirrhosis patients with Acute on Chronic Liver Failure 
(ACLF) versus standard of care (SOC).  
Short Title: 
DIALIVE in ACLF 
Clinical Investigation Plan 
Number: 
Final Version v7.0 of 10 October  2019  
EUDAMED Number: 
CIV-16-08-016644 
Revision history: 
UK 5.0  
FR/ES/DE 3.0 
AU/RO/DK/BE: 3.0 
Sponsor: 
Yaqrit Limited 
Coordinating Investigator: 
Dr Banwari Agarwal 
Consultant in Critical Care Medicine 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 2 of 88 
Table of Contents 
1. 
OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION ............................................................................................................. 7 
Inclusion Criteria ......................................................................................................................................................................... 8 
Exclusion Criteria ........................................................................................................................................................................ 9 
2. IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE .......................................................................................... 15 
2.1 
Summary description of the investigational device and its intended purpose. ......................................................................... 15 
2.2 
Definitions. ................................................................................................................................................................................................ 16 
2.3 
Details concerning the manufacturer and traceability of the investigational device. ............................................................... 19 
2.4 
Device materials that will be in contact with tissues or body fluids ............................................................................................. 20 
2.5 
Summary of the necessary training and experience needed to use the investigational device. .......................................... 21 
2.6 
Description of the specific medical or surgical procedures involved in the use of the investigational device. .................. 21 
2.7 
Current Standard of Care and Need for Improvement ................................................................................................................... 21 
2.8 
Rationale for utilising DIALIVE device for ACLF patients .............................................................................................................. 22 
2.9 
Findings of pre clinical work .................................................................................................................................................................. 23 
3 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION ........................................................... 24 
3.1 
Anticipated clinical benefits ................................................................................................................................................................... 24 
3.2 
Anticipated adverse device effects associated with DIALIVE ....................................................................................................... 26 
3.3 
Residual risks associated with participation in the clinical investigation. ................................................................................... 30 
3.4 
Possible interactions with concomitant medical treatments .......................................................................................................... 30 
3.5 
Steps that will be taken to control or mitigate the risks .................................................................................................................. 30 
3.6 
Risk-to-benefit rationale ......................................................................................................................................................................... 31 
4 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION .......................................................................................... 32 
4.1 
Objectives, primary and secondary ..................................................................................................................................................... 32 
4.2 
Hypotheses and claims .......................................................................................................................................................................... 32 
4.3 
Risks and anticipated adverse device effects that are to be assessed ..................................................... 32 
5 
DESIGN OF THE CLINICAL INVESTIGATION .............................................................................................................................. 33 
5.1 
General ...................................................................................................................................................................................................... 33 
5.1.1 
Measures taken to minimize or avoid bias ................................................................................................... 33 
5.1.2 
Primary Endpoints ..................................................................................................................................................... 33 
5.1.3 
Secondary End Points ............................................................................................................................................... 33 
5.1.4 
Exploratory End points ............................................................................................................................................ 34 
5.1.5. 
Methods and timing for assessing, recording, and analysing variables .................................. 35 
5.1.6. 
Equipment to be used for assessing the clinical investigation ..................................................... 35 
5.1.7. 
Replacement of subjects. ................................................................................................................................... 35 
5.2. 
Investigational device exposure ..................................................................................................................................................... 35 
5.3. 
Subjects ............................................................................................................................................................................................... 37 
5.3.1. 
Inclusion criteria .................................................................................................................................................... 37 
5.3.2. 
Exclusion criteria ................................................................................................................................................... 37 
5.3.3. 
Criteria and procedures for subject withdrawal or discontinuation ....................................... 38 
5.3.4. 
Point of enrolment ................................................................................................................................................ 39 
5.3.5. 
Total expected duration of the clinical investigation. ....................................................................... 39 
5.3.6. 
Expected duration of each subject's participation. ............................................................................. 39 
5.3.7. 
Number of subjects included in the clinical investigation. ............................................................. 39 
5.3.8. 
Estimated time needed to select this number (i.e. enrolment/recruitment period). ..... 40 
5.4. 
Procedures .......................................................................................................................................................................................... 40 
5.4.1. 
Additional sponsor representative(s) activities (excluding monitoring). ............................ 47 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 3 of 88 
5.5. 
Monitoring plan ................................................................................................................................................................................... 47 
5.5.1. 
Confidentiality ......................................................................................................................................................... 48 
5.5.2. 
Record keeping and archiving ........................................................................................................................ 48 
6. 
STATISTICAL CONSIDERATIONS ............................................................................................................................................ 48 
7. 
DATA MANAGEMENT ............................................................................................................................................................ 49 
7.1.1. 
Procedures for data review, database cleaning, and issuing and resolving data queries.
 
49 
7.1.2. 
Procedures for verification, validation and securing of electronic clinical data systems
 
50 
7.1.3. 
Data and  biosample retention ....................................................................................................................... 51 
7.1.4. 
Clinical quality assurance ................................................................................................................................. 51 
8. 
AMENDMENTS TO THE CIP ................................................................................................................................................... 51 
9. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ................................................................................................................ 52 
9.1. 
Procedures for recording, reporting and analysing CIP deviations. .............................................. 52 
9.2. 
Notification requirements and time frames. ............................................................................................... 52 
9.3. 
Corrective and preventive actions and principal investigator disqualification criteria. ... 52 
10. 
DEVICE ACCOUNTABILITY ..................................................................................................................................................... 52 
11. 
STATEMENTS OF COMPLIANCE ............................................................................................................................................. 53 
11.1. 
Declaration of Helsinki, International Standards and national regulations ............................. 53 
11.2. 
Approvals ......................................................................................................................................................................... 53 
11.3. 
Insurance ......................................................................................................................................................................... 53 
12 
INFORMED CONSENT PROCESS ............................................................................................................................................. 54 
12. 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES .............................................................................. 55 
12.1. 
The definitions are compliant with ISO 14155 and MEDDEV Guidance 2.7.1 rev 3 ......................................................... 55 
12.2. 
Reporting requirements and timelines .......................................................................................................................................... 56 
12.3. 
Assessments of adverse events .................................................................................................................................................... 57 
12.3.1. 
Severity ......................................................................................................................................................................... 57 
12.3.2. 
Seriousness ................................................................................................................................................................. 57 
12.3.3. 
Causality ....................................................................................................................................................................... 57 
12.3.4. 
Expectedness .............................................................................................................................................................. 59 
12.4. 
Procedures for recording and reporting Adverse Events and Device Deficiencies ........................................................... 59 
12.4.1. 
. Investigator responsibilities: ........................................................................................................................ 59 
12.4.2. 
Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor responsibilities .................... 59 
12.4.3. 
Safety Update Reports ......................................................................................................................................... 60 
12.4.4. 
Progress reports ..................................................................................................................................................... 60 
12.5. 
Foreseeable adverse events and anticipated adverse device effects .................................................................................. 60 
12.6. 
Emergency contact details for reporting serious adverse events, serious adverse device 
effects and device deficiencies. ........................................................................................................................................... 61 
13. 
VULNERABLE POPULATION .................................................................................................................................................. 61 
14. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION ........................................................................ 61 
15. 
LEGAL REPRESENTATIVE ..................................................................................................................................................... 62 
16. 
PUBLICATION POLICY ........................................................................................................................................................... 62 
17. 
SIGNATURES ....................................................................................................................................................................... 62 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 4 of 88 
LIST OF ABBREVIATIONS 
 
ALF 
Acute Liver Failure 
ACLF 
Acute on Chronic Liver Failure 
AD 
Acute Decompensation 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
AV 
Acceptable Value 
BP 
Blood Pressure 
CA 
Competent Authority 
CI 
Chief Investigator 
CIA 
Clinical Investigation Agreement 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
CRO 
Contract Research Organisation 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CVS 
CardioVascular System 
CVVH 
Continuous veno-venous haemofiltration 
CVVHD 
Continuous veno-venous haemodialysis 
CVVHDF 
Continuous ven-venous haemodiafiltration 
CXR 
Chest X-ray 
DCF 
Data Clarification Form 
DD 
Device Deficiency 
DIBD 
Developmental International Birth Date 
DIC 
Disseminated intravascular coagulopathy 
DM 
Data Manager 
DNACPR 
Do Not Attempt Cardio-Pulmonary Rescuscitation 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
EAA 
Endotoxin Activity Assay 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 5 of 88 
EC 
European Commission 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ER 
Essential Requirements 
EU 
European Union 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulations 
GI 
Gastro-Intestinal 
HCC 
Hepatocellular Carcinoma 
HD 
Haemodialysis 
HDF 
Haemodiafiltration 
HDU 
High Dependency Unit 
HE 
Hepatic Encephalopathy 
HF 
Haemofiltration 
HIT 
Heparin Induced Thrombocytopaenia 
HMA 
Human mercaptalbumin 
HNA 
Human non-mercaptalbumin 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
INR 
International Normalised Ratio 
LDD 
Liver Dialysis Device 
LFT 
Liver Function Tests 
MAP 
Mean Arterial Pressure 
MDD 
Medical Devices Directive (93/42/EEC) 
Mg 
milligrams 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mL 
milliliters 
Mm 
millimeters 
mmHG 
millimeters of Mercury 
MRI 
Magnetic Resonance Imaging 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 6 of 88 
NCA 
National Competent Authority 
NHS 
National Health Service 
NHS R&D 
National Health Service Research & Development   
NICE 
National Institute of Clinical Excellence 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PT 
Prothrombin Time 
PTT 
Partial thromboplastin time 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
REC 
Research Ethics Committee 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SBP 
Spontaneous Bacterial Peritonitis 
SDV 
Source Data Verification 
sCr 
Serum Creatinine 
SIV 
Site Initiation Visit 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure  
TMG 
Trial Management Group 
TV 
Target Value 
U&Es 
Urea and Electrolytes 
UADE 
Unanticipated Adverse Device Effect 
UCL 
University College London 
UGIB 
Upper Gastric Intestinal Bleed 
UK 
United Kingdom 
USADE 
Unanticipated Serious Adverse Device Effect 
  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 7 of 88 
1. 
OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION 
 
 
Title  
A multi-centre, randomised controlled study, to evaluate the safety and performance of The 
DIALIVE Liver Dialysis Device (LDD) in alcohol related cirrhosis patients with Acute on 
Chronic Liver Failure (ACLF) versus standard of care (SOC). 
Study Design 
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 the lowering of the 
plasma endotoxin concentrations, and improved albumin function) of the DIALIVE in 30 
evaluable patients with Acute on Chronic Liver Failure (ACLF) on the background of 
alcoholic cirrhosis versus standard of care (SOC).  
Hypothesis 
The hypothesis is that DIALIVE will significantly improve the prognosis of ACLF patients by 
modulating systemic inflammation. 
Target Population 
Men and Women ≥18 years, ≤81yr. Patients with a background of alcoholic cirrhosis who 
have either: 
1. ACLF grade 1, ACLF grade 2 or grade 3a1 as per CLIF-OF scoring system; OR 
2. .Serum bilirubin > 20 mg/dL (342 µmol/L) as single organ failure2; OR 
3. Stage 1b Acute kidney injury3. 
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. 
 
                                                 
1 ACLF grade 3a patients, i.e. with 3 organ failures only, are included based on a favorable safety report by the Data Safety 
Monitoring Board following review of safety data on 12 ACLF grade 1 and 2 patients studied so far. ACLF grade 1 patients 
who have poor prognosis (28 day mortality > 15%) according to the more recent evidence, but were not identified within the 
original CANONIC study. 
2 Rapidly progressive hyperbilirubinaemia with serum bilirubin rising to > 20 mg/dL (342 µmol/L)in ACLF is associated with 
high mortality, equivalent to ACLF 1. 
3 Recent data on Acute Kidney Injury (AKI) in decompensated cirrhotics suggest that even milder degrees of renal dysfunction 
(AKI 1b defined as serum Cr > 1.5 mg/dL or 134 µmol/L) are associated with high mortality. AKI 1b does not constitute ‘kidney 
failure’ in the CLIF-OF scoring system. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 8 of 88 
Inclusion Criteria 
 
Male or female subjects aged ≥18 years ≤81yr 
 
Subject is able to provide informed consent to participate in the study, otherwise written 
informed consent must be obtained on behalf of the subject by next of kin or a legal 
representative 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 decompensation event (including but not limited to ascites, 
gastrointestinal bleeding, hepatic encephalopathy and/or acute bacterial infections), 
occurring within ≤6 weeks of screening. 
 
Subject with  : 
o ACLF Grade 1, 2 or 3a defined per the CLIF-C OF scoring system OR 
o single hepatic organ failure for serum bilirubin > 20 mg/dL (342 µmol/L) at 
screening and randomization, OR 
o AKI-stage 1b (sCr > 1.5 mg/dL or 134 µmol/L). 
 
Where a subject has received corticosteroids as specific therapy for alcohol hepatitis and 
is deemed unresponsive to steroids after 7 days of treatment (lack of response defined as 
Lille score of  > 0.45 or steroids stopped before 7 days due to any complication such as 
infection). This refers to the first course of corticosteorid therapy. Further courses of 
corticosteroids during the course of illness  must not be used to determine steroid 
responsiveness.   

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 9 of 88 
Exclusion Criteria 
 
Co-infection with HIV and AIDS defining illness4 
 
Subjects with acute or sub-acute liver failure without underlying cirrhosis. 
 
Subjects with severe thrombocytopaenia, as defined by the platelet count of <40,000/mm3 
(at screening/randomization) or rapid reduction in platelet count (> 50% reduction) in the 
previous 24 hrs prior to randomisation (day 0)  
 
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 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: 
o i) persistent hypotension (mean arterial pressure < 65 mmHg) with evidence of 
tissue hypoperfusion, not responsive to volume resuscitation and/or low dose 
vasopressor support; 
o 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.  
 
Subjects who have 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 unncontrolled seizures. 
 
Subjects diagnosed with Creutzfeldt-Jakob disease. 
 
In females: known pregnancy or lactating. 
 
Subjects weighing less than 30 kg (as per contra-indication of oXiris and septeX) 
 
Where subjects present with a known allergy to heparin or 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. 
 
 
 
                                                 
4 A patient can be HIV +ve as long as they are clinically stable and not presenting with any AIDS defining illness i.e. 
 
a CD4+ T-cell count below 200 cells/µL 
 
a CD4+ T-cell percentage of total lymphocytes of less than 15% 
 
or one of the defining illnesses such as PCP, Kaposi’s sarcoma, CMV, Candidiasis etc 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 10 of 88 
 
Objectives 
Outcomes Measures 
Primary End 
Point 
To evaluate the safety of the DIALIVE 
in patients with Acute on chronic liver 
failure (ACLF)  
The percentage of subjects who experience at least 
one (1) serious adverse event (SAE) between study 
Day 1 and Day 10; especially the incidence rate of 
SAE in both arms of the study at Day 1 and Day 10. 
The percentage of subjects who discontinued 
DIALIVE due to a serious adverse device event 
(SADE) between Day 1 (first day of treatment) and 
Day 10 (DIALIVE arm only). 
 
Secondary End 
Point(s) 
To evaluate  the impact of biochemical 
performance outlined hereunder 
towards clinical benefit for patients 
receiving DIALIVE treatment plus 
Standard of Care vs Standard of Care 
alone 
 
MortaIity: 28-days and 3 months 
 
Change in ACLF Grade  
 
Change in CLIF-ACLF  score  
 
Improvement in individual organ function: 
brain (HE), kidney (serum creatinine), CVS 
(mean arterial pressure), pulmonary (P/F 
ratio or S/F if arterial blood gas info is not 
available), liver (serum bilirubin) and 
coagulation (INR and platelet levels). 
 
Status of ICU and Hospital Discharge 
(including discharge to a hospice for 
palliative care). 
 
Lengths of stay in ICU and hospital at D28 
and D90. 
 
ICU and hospital re-admissions with another 
episode of ACLF up to 90 days post 
randomization. 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 11 of 88 
Secondary end 
Point(s) 
Objectives 
Outcomes Measures 
To evaluate the performance of the 
DIALIVE in patients with ACLF  
 
 
Change in Plasma endotoxin level 
(endotoxin activity and endotoxin 
concentration) between; 
1. Study D1,D3,  D5 and D10 across SOC arm 
2. Study D1, D3, D5 and D10 across DIALIVE 
arm 
3. Start and end of a treatment session with 
DIALIVE on D1, D2 and D3 
4. Study D1, D3, D5 and D10 between SOC 
and DIALIVE arms for patients  with the 
same grade of ACLF at the time of  inclusion 
in the study  
 
Target-Value (TV): 40% reduction; 
Acceptable-Value (AV): 20% reduction 
Change in Albumin function (Human non-
mercapt albumin -2 (HNA-2) / Human 
marcapt albumin (HMA) ratio: 
5. Study D1, D3, D5 and D10 across SOC arm 
6. Study D1, D3, D5 and D10 across DIALIVE 
arm 
7. Start and end of a treatment session with 
DIALIVE on D1, D2 and D3. 
8. Study D1, D5 and D10 between SOC and 
DIALIVE arms for patients presenting with 
the same grades of ACLF  
 
TV: 40% reduction; AV: 20% reduction 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 12 of 88 
Exploratory end 
points 
 
Objectives 
Outcomes Measures 
To study other exploratory biological 
and clinical effects  of the DIALIVE in 
patients with ACLF compared with the 
Standard of Care group.Some of these 
parameters are centre-specific in line 
with local expertise, research interest 
and the capacity to perform these tests. 
 
Organ Function and Biomarkers 
 
Liver: Changes in MELD score, plasma/serum 
cCK18/M30 and flCK18/M65 (markers of liver 
cell death).  
 
Kidney: Changes in serum creatinine and 
urinary NGAL (marker of kidney injury).  
 
Brain: West Haven Criteria to assess changes 
in severity of hepatic encephalopathy.  
 
Immune function: Incidence of Infection. 
Changes in white cell count, and assessment 
of neutrophil and monocyte function.  
 
Assessment of Coagulation and haemostasis: 
Incidence of thrombotic or bleeding 
complications, assessment of pro- and anti-
coagulant clotting factors and complement 
activation.  
 
 
Screening/ Baseline 
Assessments 
Screening assessments will commence following informed consent. See schedule of 
assessments. 
Additional Study 
Assessments  
(per schedule of 
events) 
The treatment phase will occur within the window period of 10 days to achieve one 
successful treatment cycle with DIALIVE. 
See schedule of assessments. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 13 of 88 
Sample 
size/Statistical 
Analysis 
30 evaluable subjects will be randomized  to receive either standard of care (SOC) or 
treatment with DIALIVE (1:1 randomisation).  
All statistical analyses will be carried out on the safety population, defined as the subset of  
randomized patients who receive at least one treatment5. No imputation of missing values will 
be implemented. Only available data will be analysed. In addition, a sensitivity analysis will be 
carried out to check the main safety results using SAE-data of all evaluable patients 
 
No statistical tests will be performed. All final statistical analyses will be descriptive. The 
categorical variables will be summarised by means of the count and percentages 
corresponding to each variable category, while continuous variable will be summarized  by the 
mean and Standard Deviation of each distribution or the median and min-max values in case 
of those variables non-normally distributed. 
For each treatment arm, treatment-emergent AE’s, SAEs, SADEs, ADEs, USADEs and DDs 
will be summarised  by organ system and treatment causality. The number and percentage of 
patients discontinuing the study due to Aes, SAEs, SADEs or other stopping criteria confirmed 
by the Data Safety Monitoring Board (DSMB) will be  summarized for each arm. Secondary 
and exploratory parameters (changes from baseline at each study visit) will be descriptively 
analysed by treatment arm by means of the appropriate statistics. 
Statistical analyses of safety data will be run when each study cohort is completed and the 
corresponding results will be communicated to the DSMB.  Data extraction at interim time 
points do not serve study analyses. 
Number of Visits 
Patients will undergo the following 
 
Screening assessment (up to 72hrs)6 
Study Day 0-randomisation (DIALIVE treatment may commence on this day if all day 1 
parameters have been met) 
Study Day 1 assessments7  
Study Days 1-10 treatment phase commences and completes  
Study Day 5 assessments  
Study Day 10 assessments 
Study Day 14 assessments 
Study Day 28 assessments 
Study Day 90 assessments 
 
                                                 
5 One treatment will be defined as any duration of exposure to the DIALIVE.  
6 Screening period (post consent) has been set up to 72 hours to allow sufficient time to gather all relevant clinical  information for the subject to be 
eligible to progress to randomisation. However, if this information becomes available sooner, then randomisation can proceed after that time (without 
having to wait for 72 hours). For further clarity, the plan for gathering the most recent and relevant clinical information, yet not delaying the start of the 
study is as follows:  
a. 
Thorough clinical examination of the patient and assessment of FBC, U&E, LFT, Coagulation must be repeated during this period. If 
randomised to the DIALIVE arm FBC, U&E, LFT, Coagulation results from the screening period may be used if performed up to 24 hours prior 
to starting treatment unless patients’ clinical status has changed. 
b. 
Microbiology results from samples sent in and up to the previous 72 hours (at commencement of screening) need not be repeated. On the 
day of screening, if the patient is not septic clinically as determined by the PI, then consent can proceed without having to wait for 
microbiology results. Likewise, if a patient is deemed to be septic based on clinical grounds without positive microbiological cultures, the PI 
will determine if it is safe to continue with consent and randomization, and this will be reviewed daily. 
c. 
Viral serology results from up to 8 weeks before the screening period will be accepted 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 14 of 88 
Per Patient 
Duration/Total 
Trial Duration 
3 months per patient /39  months for completion of the study. Proposed start Feb 2017. 
Proposed finish Dec 2019 
Applicable 
legislation 
National and/or local legislation is application, including the new GDPR regulation, and 
especially in view of the inclusion of patients who might become or are unconscious and on the 
involvement of a legal representatives – if appropriate/allowed. 
Legal 
Represenative 
The Legal Representative, appointed by the sponsor YAQRIT Ltd, is: 
FAKKEL-bvba 
Mr Jaak Minten 
Groenendael 43/001 
3400 Landen 
Belgium 
 
 
    
 
 
                                                                                                                                                                           
d. 
Liver imaging such as liver ultrasound, doppler studies or CT/MRI scan up to 8 weeks prior will be acceptable unless there has been a 
significant change in the clinical status dictating repeat imaging. 
  
*Some or all of the above tests may need to be repeated during the screening period should there be any significant change in the clinical status of the 
patient as assessed by the clinical team. 
7 May concur with study Day 0 if all assessment parameters (as per the schedule of assessments) have been met. DIALIVE treatment must commence before the end of study 
day 1.  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 15 of 88 
2. IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
2.1 Summary description of the investigational device and its intended purpose. 
 
The device under investigation is the DIALIVE Liver Dialysis Device (LDD) comprising of the Baxter (previously Gambro®) 
SepteX™ Hamodialyser, the Gambro® oXiris Haemodialyser. The novelty of the DIALIVE lies in the synergistic effect of 
using commercially available filters on a haemofiltration platform (Prismaflex) to control and monitor the ex-vivo circulation 
of subject blood.  The LDD acts as one unit that removes dysfunctional albumin and endotoxins, infuses fresh functional 
albumin and specifically targets systemic inflammation. The Prismaflex is a standard dialysis pump system with a software 
driven control unit. As per the Instructions for Use of septeX and oXiris, a minimum version 4.0 of the software is to be 
installed8. 
The available current knowledge and the evidence of the role of albumin and of endotoxins in the pathophysiology of liver 
failure have led to the formulation of a hypothesis that albumin removal and replacement, in conjunction with endotoxin 
removal may be beneficial in the treatment of subjects with liver failure.  
It is predicted that DIALIVE will reduce the death rate of hospitalised ACLF patients, allow intensive care ACLF patients to 
return to the ward and home and reduce readmission rates to ICU and the hospital. In those patients that do not recover, 
DIALIVE will bridge them to liver transplantation. Thus DIALIVE will improve both mortality and quality of life (QOL). 
All components of the system are commercially available and individually CE Marked for haemofiltration applications.  The 
filters will be purchased directly from Baxter.  
Replacement human serum albumin is administered  during each treatment session at a rate of 5 g/hr of dialysis.  The 
amount of replacement albumin to match the amount removed by the DIALIVE is extrapolated through results from 
previous animal studies and the in-vitro study of albumin clearance by the device. This equates to albumin replacement of 
40 grams for an 8-hour and 60 grams for a 12- hour completed treatment session. The aim is to maintain post-treatment 
serum albumin level as close to the baseline as possible. The re-infused fresh albumin will be administered through the 
HepalbinTM filter (Albutec GmbH). Albumin for other indications should occur as per standard practice in both SOC and 
DIALIVE arms. 
The HepalbinTM-Adsorbent is a nano-structured carbon filter that removes up to 95% of the industrial stabilisers octonoic 
acid (caprylate) and N-acetyltryptophanate from commercially available pharmaceutical albumin preparations. These 
stabilisers are associated with the binding sites of albumin, thus reducing albumin functionality and binding capacity. While 
in healthy individuals, these stabilisers are metabolized by the liver and have a very short half-life, this  is significantly 
prolonged in liver disease potentially causing accumulation of these materials.  The use of HepalbinTM-Adsorbent for 
albumin transfusion indicated that there may be clinical benefit to stabilizer removal in patients with decompensated liver 
disease in a small controlled study [16 ]. 
 
 
                                                 
8 In the majority of hospitals most recent versions of both Prismaflex and software are available. In Austria the Model ref: 60 
23014700 can be in used in Graz; the software version installed is version 8.1  
SepteX and oXiris filters are the brandnames of the filters and have no further model specification. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 16 of 88 
2.2 Definitions. 
 
Screen failures: 
1. The patient does not meet one or more criteria, which are assessed after the patient (and/or consultee if 
applicable) signed the Informed Consent; patient can re-enter the study later if at that moment all inclusion criteria 
and no exclusion criteria are met. Patient informed consent remains valid until end of the study or until withdrawal 
from the study. 
2. Patient who did not start dialysis before the end of DAY 1 if randomized to the DIALIVE treatment arm, is 
considered a screen failure; such a patient does not have to resign a consent form, but can re-enter the study via 
de novo demonstration of compliance with the in- and exclusion criteria. 
Patient withdrawal: a patient (or the consultee if applicable) can withdraw consent at any time. No further clinical data 
can be collected as of that moment; the data collected prior to that moment, remain part of the clinical study. 
Patient exclusion: a patient is considered excluded from the study (and from re-entering into the study): 
1. Upon demonstration of more than 2 interuptions of more than 24 hrs between subsequent dialysis sessions 
and within the first 10 day time period after randomization (DIALIVE arm); 
2. If the clinical condition of a patient meets one or more study stopping criteria. 
 
Patients considered to be a ‘screen failure’ or ‘excluded’ will remain in study for a minimum follow up period of 28 days. 
Standard definitions: definitions for DIALIVE organ failure and ACLF grading per the CLIF-C OF scoring system, Lille 
score, and others, are given in Appendix 1-2. 
Hepatic Encephalopathy (HE) : determination of HE as part of ACLF grading will be based upon clinical assessment 
and graded as per the West Haven criteria. However, if there is ambiguity or observer variability, an EEG may be 
sought by the PI for supportive evidence.  This is particularly relevant for grade 1 HE which may not be consistenly 
reproducible using the West Haven criteria, and as such is now included as part of the covert HE spectrum along with 
minimal HE often requiring psychometric tests or EEG for diagnosis    
 
Specific therapy such as corticosteroids for alcoholic hepatitis can be used if a patient is already within the study and 
these have not been trialed previously and as long as clinical justification and rationale is clearly documented.This 
applies to patients in both SOC and the DIALIVE arm. For other indications of steroid use such as potential relative 
adrenal insufficiency, it should precede a short synacthen test, particularly in patients who are haemodynamically 
stable, to establish this diagnosis. 
 
Standard of Care (SOC) is defined as the standard medical and nursing management of patients with ACLF Grades 1 
and 2 as per local practices. Medical intervention is to be guided by the treating physician taking into account the 
overall clinical picture, precipitating event, and the nature and severity of organ dysfunction. The interventions may 
include (but not limited to) the supportive management with fluid therapy, including albumin therapy where indicated, 
antibiotics for suspected or confirmed infections, nutrition, bowel management, thromboprohylaxis, and organ system 
support including the use of terlipressin as splanchnic vasopressor and for cardiovascular support where indicated, 
oxygen and non-invasive respiratory support, laxatives and non-absorbable antibiotics for hepatic encephalopathy, and 
dialytic therapy for renal failure. SOC may also include urgent liver transplantation as per local practices.  
Patients presenting with, or developing during the study period, severe actue renal failure requiring renal support, will 
receive continuous renal replacement therapy (CRRT) as per standard local practices. This would apply to subjects in 
both SOC and DIALIVE arms. For those in the DIALIVE arm, the same vascular catheter which is used for DIALIVE 
treatment may be used for CRRT following the completion of the DIALIVE treatment session. It is however envisaged 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 17 of 88 
that increased intensity of dialysis component in the DIALIVE system (from 1lit/hr to 1.5lit/hr) and allowance for fluid 
removal in the new protocol may delay or remove altogether the need for CRRTin these situations. The decision for 
additional CRRT would depend on clinical situation and will be taken by the site PI. 
DIALIVE arm  consists of standard of care (defined above), plus DIALIVE treatment.  
A DIALIVE treatment session denotes treatment for the day, whereas A DIALIVE treatment cycle refers to the total 
number of treatment days.  
A DIALIVE treatment session = A minimum, cumulative duration of 8 to 10 hrs (+ 30 min) of the DIALIVE treatment, 
thus allowing for breaks which may be planned (for example patients needing to go for imaging) or unplanned (device 
clotting, issues with vascular access or other any other unplanned reasons). A break within a treatment session 
(consisting of a cumulative time longer than 4hrs), or a cumulative duration of less than 8 hrs of dialysis during one day 
constitutes a session failure for that day. A session failure will require to restart the dialysis session within 24 hrs after 
the end of the previous session and will reset the start of the dialysis cycle. 
A DIALIVE treatment cycle= Consists of 3 consecutive days of 8-10 hrs of DIALIVE treatment sessions on each day 
within the 10 day window period. A break of more than 24hrs between each treatment session will require a new 
baseline (i.e. a new treatment cycle commenced). A second failed treatment session within the 10 day window period 
would result in patient exlusion.The patient must have completed one successful treatment cycle within the 10 day 
window period to be considered evaluable.    
Day of randomization constitutes study Day 0.  
The first treatment session (DIALIVE arm only) must commence before the end of study Day 1. As such, dialysis might 
also start on the day of randomization which might created confusion as ‘the first day of dialysis’ then concurs with 
DAY 0 of the study schedule. 
Commencement of DIALIVE treatment session i.e. connection of patient to the Prismaflex machine = time point 0, can 
occur at any time before the end of study Day 1 subject to availability of all relevant information required for treatment 
to commence.   All blood samples should be measured from this time point. Any pre samples required should be taken 
just before connection.  
Nuts and bolts of DIALIVE Treatment: a ready reference 
 
-Before starting treatment  
The patient to be moved to an intensive care unit or similar once randomised to DIALIVE. 
 Appropriate monitoring needs to be instituted including the following:  
 
 
Insertion of an arterial line for continuous invasive blood pressure monitoring and blood sampling 
 
Insertion of a vascular catheter for DIALIVE treatment 
 
Insertion of a central venous catheter for prompt treatment with vasopressors if required 
(Lines should be inserted under USS guidance. Correction of clotting abnormalities, if any, should follow local 
protocols. The line positions should be confirmed through appropriate means; e.g. CXR for neck lines). 
* NB: Majority of ACLF grade 3 patients are likely to be already in the ICU with the above monitoring in situ. 
 
Additional tests (Baseline samples for FBC, U/E, LFT, coagulation, septic screen will already have been 
collected to check eligibility) prior to commencing DIALIVE therapy will be done: 
 
 
Arterial blood gas analysis 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 18 of 88 
 
Haemolysis screen (FBC including reticulocyte count, blood film, unconjugated and conjugated 
bilirubin, LDH, haptoglobin, urinary free haemoglobin) – to be perfomed only on D1, before and after 
therapy   
 
DIC screen, if clinically indicated 
 
And, Endotoxin Activity Assay (EAA) analysis (start of day 1, 2 and 3) 
 
Blood to be collected as part of biobank samples.(start of day 1, 2 and 3) 
 
Fluid pre-loading of up to 500mls over 1-2 hours is implemented, the volume and speed of fluid therapy to be 
determined on a clinical basis, and the choice of fluid would preferably be albumin (4.5 or 5% solution as per 
local availability).   
 
- during dialysis session  
 
 
Anticoagulation with unfractionated heparin and/or prostacycline analogues (the dose as per local protocols) 
 
 
Blood flow rates on DIALIVE device to be started at 50 mls/min and increased gradually over 1-2 hours to up 
to a maximum of 250 mls/min 
 
 
Replacement fluid (pre-dilution solution) to start at a rate of 1000 ml/hr and increased gradually to up to 3500 
mls/hr (50mls/kg/hr for a 75 kg person) subject to haemodynamic stability. Concomitant dialysis component to 
run at 1500 mls/hr (25 ml/kg/hr for a 75 kg person). 
 
 
Albumin is exchanged simultaneously with DIALIVE treatment. Infusion of fresh albumin will be through the 
HepAlbin filter at a rate of 5 g/hr (to replace albumin removed by the device). This equates to an infusion of 
20% human albumin solution at a rate of 25mls/hr.  
 
 
Mean arterial pressure is to be continuously monitored, and MAP is maintained at 90% or higher of pre-
treatment MAP or above 65 mmHg, whichever is higher. 
 
 
2-hourly blood gas analysis (including lactate), and 4 hourly other bloods (FBC, U/E, LFT, coagulation) at 0, 4 
and 8-12 hrs (end of treatment) should be performed. 
 
 
A senior staff member will closely supervise the dialysis procedure during the first few hours of treatment, with 
a clear internatl escalation plan available, and discuss with study CI where necessary 
 
 
Effluent of dialysis fluid from the effluent line AND waste collection bag to be collected a 0-1, 4, 8-10 hrs (end 
of treatment) as part of biobank samples. 
 
 
- Following completion of  treatment session :  
 
Blood within the circuit is to be returned back to the patient, unless the filter is clotted. 
 
 
Repeat Haemolysis screen (at end of session of D1 only) 
 
 
EAA-analysis ( end of days 1, 2 and 3) 
 
 
Ensure treatment data is stored in the device and retrieved at a later date 
 
 
Blood to be collected as part of biobank samples. (end of days 1, 2, 3) 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 19 of 88 
 
 
2.3 Details concerning the manufacturer and traceability of the investigational device. 
 
Membrane9: 
 
septeX™ Haemofilter 
 
oXiris® Haemofilter 
Manufacturer: 
 
Baxter, USA 
 
 
Baxter, USA 
 
Indications: 
 
Continuous renal 
replacement therapy for 
subjects with acute renal 
failure 
 
For subjects who have acute 
renal failure, fluid overload or 
both. 
Intended use: 
 
Continuous veno-venous 
haemodialysis (CVVHD) in 
conditions where the 
removal of plasma 
components with molecular 
weights up to a value of 45 
kDa, such as substances 
that mediate inflammation, 
is indicated 
 
Veno-venous therapies: slow 
continuous ultrafiltration (SCUF); 
continuous veno-venous 
haemofiltration (CVVH); 
continuous veno-venous 
haemodialysis (CVVHD); 
continuous veno-venous 
haemodiafiltration (CVVHDF) 
Contraindications: 
 
There are no 
contraindications to 
CVVHD with high cut-off 
membrane 
 
Where subjects present with a 
known allergy to heparin or have 
type II thrombocytopaenia caused 
by heparin (HIT syndrome type II) 
MDD Classification: 
 
IIb 
 
III ( incorporates heparin) 
 
 
                                                 
9 Both the septeX and oXiris filters are brandnames from Gambro; products are not further specified with model number and 
are distributed by Baxter as commercial devices to support dialysis in kidney failure.  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 20 of 88 
 
2.4 Device materials that will be in contact with tissues or body fluids  
 
 
Membrane 
 
septeX™ Haemofilter 
 
oXiris® Haemofilter 
Housing 
 
 
Polycarbonate 
 
 
Polycarbonate 
 
Potting compound 
 
 
Polyurethane 
 
 
Polyurethane 
 
Tubing 
 
 
Plasticized polyvinyl 
chloride 
 
 
Plasticized PVC 
 
Cartridge plate 
 
 
Polyethylene terephthalate 
glycol-modified (PETG) 
 
PETG 
 
 
 
 
Fig 1. DIALIVE Liver Dialysis Device (LDD) as incorporated into the extracorporeal circuit. 
       Filter set 1 + 2 + interconnecting tubing constitutes the DIALIVE unit, rest is 
       standard dialysis equipment 
 
DIALIVE 
2
1
3
4
5
6
7
8
9
10
11
12
Extracorporeal 
Support Equipment  
Regulatory 
Status
Prismaflex Monitor
CE 0086
Extension Tubing
CE 0086
Accessories
CE 0086
1.
Gambro Septex – Albumin 
Removal (Allocated 
“FILTER SET 1”)
2.
Gambro oXiris– Bacterial 
Endotoxin Removal 
(Allocated “FILTER SET 2”)
3.
Heparin Syringe pump
4.
Blood pump
5.
Bubble trap
6.
Pre-Diluter Solution bag
7.
Effluent bag
8.
Dialysate bag
9.
Safety valve
10.
Pump
11.
Pressure sensor
12.
Sampling site
Albumin replacement 
during  DIALIVE session via 
the HepalbinTM filter 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 21 of 88 
 
2.5 Summary of the necessary training and experience needed to use the investigational device.  
 
The main end users of the LDD are expected to be the Hepatologists, Intensive care physicians, Renal physicians and the 
Liver transplant surgeons, all of whom have extensive experience in using dialysis and haemofiltration equipment. Training 
on the DIALIVE device set up will be provided to each site by Yaqrit (sponsor) who has experience in the DIALIVE 
delivery. The set up and Instructions For Use (IFU) are outlined in the Investigator’s Brochure and a separate IFU and will 
be provided to each site.  
 
2.6 Description of the specific medical or surgical procedures involved in the use of the 
investigational device. 
 
Patients randomised to receive DIALIVE liver dialysis treatment will be treated in a high dependency setting (HDU), or 
Intensive Care Unit (ICU) to ensure provision of expertise in the use of the Liver Dialysis Device and provision of 
continuous monitoring whilst the patient is receiving DIALIVE liver dialysis treatment. Please see § 2.2. Definitions.  
 
2.7 Current Standard of Care and Need for Improvement 
 
Two-hundred and sixty epidemiological studies from 8 different European countries between 2008 and 2013 [1] estimated 
that liver cirrhosis affected 0.1% of the total EU population with an incidence of 14- 26 new cases per 100,000 inhabitants 
and about 170,000 deaths per year [1]. Although the overall mortality rate for liver cirrhosis slightly declined in Europe (as 
well as in USA) from 1980 to 2010 due to better management and control of liver diseases and alcohol consumption; it 
increased in Eastern European countries, the United Kingdom and Ireland [2]. The only available treatment for cirrhosis 
and liver failure patients is liver transplantation, and with the shortage of donors world-wide about 1 million patients die 
from liver failure each year.  
The number of liver transplants performed each year is limited by organ availability and over the past 15 years, the 
number of transplants in Europe has plateaued at about 6000/year (European Liver Transplant registry; ELTR.org). A 
recent analysis of the Eurotransplant data of over 16,000 patients listed for liver transplantation in Europe, 27.8% died 
while waiting for a suitable organ for transplantation become available [3]. Consequently, there is a clear need to find 
regimes which can be used to maintain and improve the condition of such patients requiring transplant [4].  
Liver transplantation is the only treatment for patients with liver failure and an alternative to this remains an unmet need. In 
Acute Liver Failure (ALF), the ideal LDD would replace the functions of the failing liver in order to permit spontaneous 
recovery as the liver’s powerful regenerative potential obviates the need for transplantation. In patients with Acute on 
Chronic Liver Failure (ACLF), an LDD would ideally support hepatic function during a period of acute deterioration until 
spontaneous recovery from the episode of decompensation. It would allow time for drugs to address the precipitating 
event or the underlying the liver disease. In patients with decompensated cirrhosis, a LDD could support hepatic function 
until liver transplantation. In addition, LDDs may have potential to treat the multi-organ failure that accompanies liver 
failure including hepatic encephalopathy, renal failure and immune dysfunction. 
Acute decompensation (AD) or cirrhosis complicated with organ failure (ACLF) has a mortality rate of 30-40% and death is 
mostly related to multiple organ dysfunction [5]. The condition is widespread, affecting about 30% of all hospitalised 
cirrhotic patients and has a 28-day mortality of about 30% [ 6, 7]. Furthermore, ACLF occurs in young patients (mean age 
52 years) and about 50% have no knowledge of their underlying cirrhosis. Indeed, in about 40% patients, no precipitating 
event can be identified. A prospective observational study of hospitalized patients with cirrhosis in 2013 by the European 
Association for the Study of the Liver-Chronic liver failure (EASL-CLIF) Consortium, the EASL-CLIF Acute-on-Chronic 
Liver Failure in Cirrhosis (CANONIC), the largest and most comprehensive registry on ACLF to date, showed a 28 day 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 22 of 88 
mortality of 22%, 32% and 78% for ACLF grades 1, 2 and 3, respectively. [6]. The diagnosis of ACLF is made using the 
CLIF Consortium organ failure scores (CLIF-C OFs), the prognosis of these patients using the CLIF Consortium ACLF 
score (CLIF- C  ACLF), and ACLF severity grades defined using the CLIF-OF organ failure score [8], In the CANONIC 
study two organs, the kidneys and the brain, were found to be of particular significance in determining short term mortality. 
More recent studies suggest that even milder degrees of renal impairment in cirrhosis, not in the ‘failure’ range of the 
CLIF-OF scoring system, may be associated with development of ACLF and significant mortality. This refers to the 
subgroup(1b) of stage 1 AKI defined by a serum Creatinine (sCr) at presentation of above 1.5 mg/dL [9]. As for brain 
dysfunction, mild hepatic encephalopathy (HE) particularly grade 1 HE may not be consistently reproducible using the 
West Haven criteria, and as such is now included as part of the covert HE spectrum along with minimal HE [10] often 
requiring psychometric tests or EEG for diagnosis. 
Additioally, post-hoc analysis of CANONIC data has identified rapidly progressive hyperbilirubinaemia with a serum 
bilirubin level greater than 20 mg/dL at the time of presentation as a single hepatic organ failure being associated with 
poor prognosis. This criterion was also  used in the RELIEF study, the only randomized controlled trial to date of MARS 
therapy in ACLF [11]. 
 
 
2.8 Rationale for utilising DIALIVE device for ACLF patients 
 
The novelty of DIALIVE is that it incorporates albumin removal (and replacement) and endotoxin removal, which has not 
been applied before into one device. DIALIVE has powerful and selective toxin elimination (using an endotoxin-specific 
filter adsorber, oXiris®, and replacement of defective albumin (SepTex™ filter plus fresh albumin reinfusion) functions 
while preserving other important plasma proteins. The two filters used are already CE-marked and have been on the 
market since 2010 to treat sepsis, Acute Kidney Injury (AKI) and Continuous Renal Replacement Therapy (CRRT).  
The currently available Liver Dialysis Devices (LDDs) are based on the principal of removal of protein bound and water 
soluble substances (blood purification) by albumin dialysis, by plasma separation and filtration or by therapeutic plasma 
exchange. Devices based solely on the removal of water soluble substances (blood detoxification) have not shown any 
benefit in survival, possibly because of the limited, non-specific absorptive capacity of chemical adsorbents. Recent 
clinical trials of MARS [11] and Prometheus [12], devices based on the principles of albumin dialysis, in patients with 
ACLF failed to demonstrate a survival benefit compared to standard medical treatment. In these clinical trials the 
oxidized fractions of human mercaptalbumin (HMA, non-oxidized), human nonmercaptalbumin-1 (HNA1, reversibly 
oxidized) and human nonmercaptalbumin- 2 (HNA2, irreversibly oxidized), were markedly increased. Both MARS and 
Prometheus treatments resulted in a shift of HNA1 to HMA while HNA2 was not significantly affected. This shift in 
albumin fraction was transient and disappeared within 24 hours after treatment. There were no significant differences 
between MARS and Prometheus treatments with respect to the redox state of albumin.  
 
From the pathophysiological perspective, ACLF is characterised by systemic inflammation and endotoxaemia. The 
severity of neutrophil dysfunction has also been shown to correlate with the risk of death of ACLF patients [13]. The 
mechanism of this immune failure is unclear but studies have clearly demonstrated that the defects in neutrophil function 
can be reversed if the patient’s neutrophil is incubated with normal plasma. In addition, incubation of normal neutrophils 
with patient plasma makes them dysfunctional, assuming the patient phenotype [13, 14]. These observations suggest that
 the plasma can transmit the neutrophil functional defect. Further studies showed that this substance in plasma was an 
‘endotoxin- like substance’ suggesting that removing this from the plasma could prevent immune failure and possibly 
consequent infection in ACLF patients. This rapidly evolving cycle of inflammation / hepatocyte cell death / immune failure 
/ exacerbation of liver failure is referred to as the ACLF spiral. The data support the hypothesis that targeting inflammation 
may prevent cell death, and endotoxin removal may prevent immune failure thereby reducing the risk of infection and 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 23 of 88 
mortality.  
DIALIVE targets the ACLF spiral with a combination of albumin removal and replacement and, endotoxin removal; 
thereby reducing systemic inflammation. The results of these studies led to the hypothesis that a combination of albumin 
removal and replacement and, endotoxin removal may be useful to treat patients with liver failure. In both cases, 
achieving an improvement by 20% would result in improved survival. 
 
Importantly, all current LDDs have limited effect on inflammation and do not restore albumin function. DIALIVE 
addresses these deficiencies and replaces irreversibly destroyed albumin and removes endotoxin. 
 
The success of the DIALIVE observed in animal models is related to its ability to efficiently remove endotoxin and 
irreversibly oxidized albumin (human non-mercapt albumin-2; HNA-A2). Thus the combination of endotoxin and 
damaged-albumin removal followed by fresh albumin infusion improved liver function and mostly importantly markedly 
increased the survival of pigs. 
2.9 Findings of pre clinical work 
Pre-clinical data (animal)  
Two animal studies were performed (n=29 pigs); 13 in study 1 and 16 in study 2 in clinically-relevant, fully monitored pigs 
with paracetamol-induced acute liver failure that were managed in an intensive care unit setting with full supportive 
therapy to generate proof of concept data. This model was chosen because it exhibits the key pathophysiological 
features of ACLF [15]  
a. Multiorgan dysfunction manifested by severe encephalopathy, renal failure and consequent mortality. 
b. Biochemical evidence of liver injury, coagulopathy and lactatemia. 
c. The classical pathophysiological factors the DIALIVE device is designed to address and is found in patients with liver 
failure: 
    (i) albumin dysfunction 
    (ii) endotoxemia and consequent neutrophil dysfunction 
 
Animal Study 1: [Funded by DoH, HTD-420]: Performed in Tubingen, Germany. N=13 pigs were randomised to standard 
of care or device treatment, using an early version of DIALIVE (using non-CE marked filters). The results showed safety 
and biocompatibility of the device with significant improvement in the key variables such as the severity of endotoxemia, 
albumin and neutrophil dysfunction. Difference in survival between the two groups using a log-rank test was, p=0.02. The 
hazard ratio (Control:Device) was 5.45 (95% CI 1.1-26.4). This device however, will not be CE marked and it was 
thought that the results were too variable for translation into man. Therefore, additional studies were performed using an 
improved device design, which can be directly translated into man (Animal Study 2, see below). 
 
Animal Study 2: [Funded by MRC-DPFS G09221]: Was performed using the current version of the device to be CE 
marked. In the first part, the data showed that an improved biological and clinical effect with the use of both filters together, 
producing a synergistic benefit. In the second part, n=16 pigs were studied in a randomised, blinded clinical trial to receive 
standard of care or treatment with DIALIVE [5].  
 
Briefly, the results showed: 
a. Safety, biocompatibility and ease of use with a set up time of less than 2 hours. 
b. Difference in survival between the two groups using a log-rank test was, p=0.02. The hazard ratio (Control:Device) was 
3.81 (95% CI 1.2-12.4). 
c. Improved clinical condition: The animals required significantly less fluid support and had better respiratory function in the 
DIALIVE group. 
d. The severity of endotoxemia, neutrophil and albumin dysfunction was attenuated in the DIALIVE animals. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 24 of 88 
 
The optimized DIALIVE used in animal study 2 was easy to use with a set-up time of 1.6-2 hours. No device failures 
were observed, and circuit clotting requiring change of filter was also not observed. Device related complications such as 
embolism, bleeding or DIC were not observed in any of the animals studied. The vascular catheters used were the same 
as that used in humans for haemofiltration, and no device related issues were observed.  
 
The results of the above animal studies demonstrated that DIALIVE was safe and increased survival of the pigs treated 
with the device compared with untreated controls.  
 
Pre-clinical data (in-vitro study)  
  
 
A further laboratory based study was devised to investigate and quantify the removal of a range of biological markers, 
including endotoxin, from whole blood in vitro and when using the DIALIVE system as configured in the clinical trial, i.e. 
oXirs plus septeX plus connecting tubing mounted onto the Prismaflex. This preliminary data will be used to support the 
continuing European multi-center, first into man, clinical investigation, which is currently underway.  The methods, results 
and conclusions are listed in the IB v 3.0. The main results and conclusions from the in vitro tests are: 
 
The system demonstrated effective clearance of small molecules as expected; 
 
The progressive removal over time of albumin  across the filters was demonstrated: total albumin removal 
amounted to 6.5g/L, or the equivalent of 1.1g/L/hr. 
 
Consistent removal of endotoxin was demonstrated using the chromogenic LAL assay. 
We feel the results seen from the previous animal studies and the results obtained from the recent in vitro study, continues 
to support the hypothesis for the ongoing first into man clinical investigation which is currently underway.  
 
 
3 RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION 
3.1 Anticipated clinical benefits 
 
 It is anticipated and hypothesised that a clinically effective Liver Dialysis Device (LDD) could reduce deaths from liver 
failure, allow earlier discharge from intensive care and in a proportion of patients, prolong survival without transplantation.  
 Patient groups that could benefit from the device include:  
 
Patients with ALF and ACLF: preventing need for transplantation or serve as a bridge to transplantation in 
ALF, and aiding recovery to pre-event level of liver function in ACLF;  
 
Patients with decompensated cirrhosis who are waiting for a transplant: preventing clinical deterioration while 
on a waiting list thereby reducing mortality;  
 
Patients with decompensated cirrhosis not considered suitable for transplantation: long term dialysis to 
improve survival;  
 
Patients with intractable pruritus and/or fatigue: improve quality of life and prevent need for transplantation.  
 The following patients may also benefit:  
 
Multiple organ dysfunction in intensive care – almost all patients with critical illness have endotoxemia which 
contributes to inflammation;  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 25 of 88 
 
Alzheimer’s disease and stroke – albumin is dysfunctional in these conditions where plasmapheresis has 
been found to be beneficial;  
 
Intoxication from protein bound substances – protein bound toxins such as drugs and biological weapons may 
be treatable with albumin exchange;  
 
Cholestatic syndromes: such as porphyria, in-born errors of metabolism, drug related cholestasis and graft 
versus host disease;  
 
Severe iron accumulation – treatment of heart failure due to iron overload as albumin can bind iron.  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 26 of 88 
3.2 Anticipated adverse device effects associated with DIALIVE  
 
The procedural and device risks associated with the indicated use of the septeX™ and oXiris® filters in summary are: 
Risk 
Mitigation 
Blood loss, e.g. leading to organ failure 
 exsanguination from extracorporeal blood circuit 
 exsanguination via haemofilter to dialysing fluid circuit 
 coagulopathy associated with extracorporeal therapies 
 
- 
CVVHD/HF/HDF via CVC is long 
established  
- 
septeX™ sets are indicated for CVVHD, and 
cytokine removal  
- 
oXiris® sets are indicated for CVVHDF, and 
endotoxin adsorption and cytokine 
adsorption 
- 
UCL studies of LDD in a porcine PALF 
model (series septeX™ and oXiris® using 
Prismaflex platform) showed experimental 
arrangement to be compatible, 
biocompatible and safe 
- 
CIP specifies ICU/HDU monitoring 
particularly monitoring: 
-liver function 
-cardiovascular function 
-cerebral function  
-renal function 
-pulmonary function 
-albumin and immune function 
 
Air embolism, eg leading to ischaemia, congestion, metabolic 
dysfunction, reperfusion injury et sequelae: 
 air introduced via extracorporeal blood circuit 
 air introduced via haemofilter membrane from dialysing fluid 
circuit 
 air introduced via anticoagulant infusion 
Prismaflex control unit, indicated for CVVHD, HF and 
CVVHDF, controls and monitors extracorporeal 
circuit: 
o physiological flow rates  
o air ingress  
o blood loss  
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 27 of 88 
Thromboembolism, e.g. leading to congestion and organ failure: 
 particulates 
 degradation products 
Prismaflex control unit, indicated for CVVHD, HF and 
CVVHDF, controls and monitors extracorporeal circuit: 
o physiological flow rates  
o air ingress  
o blood loss  
 
septeX™ and oXiris® sets MDD CE’d for CRRT 
applications 
 
Haematological risks: 
 haemolysis (mechanical and chemical lysis) 
 anaemia 
 leucopenia 
 
thrombocytopenia 
 altered function of cells 
 hypoalbuminemia 
 thrombosis 
 platelet activation 
 complement system activation (inflammation) 
septeX™ , oXiris® sets and extension tube are: 
o assured compatibility with blood (ISO 
10993-4)  
o CE marked (93/42/EEC)  
o Complaints data do not identify issue  
 
Material medicated toxaemia, including those arising from 
leachables, particulate, degradation products and incompatibility 
with packaging: 
 cytotoxicity 
 hypersensitisation 
 irritation 
 systemic toxicity 
 genotoxicity 
 carcinogenicity 
 immunotoxicity 
 reproductive/developmental toxicity 
 pyrogenic fever 
 septeX™ and oXiris® sets MDD CE’d for CRRT 
applications 
 
Contamination – production, transport and storage  induced 
infection (transmissible agents may include bacteria (and 
endo/exo toxins), mould, yeast, parasites and unclassified 
pathogens: 
 fever 
 septicaemia 
 lupus 
 organ failure 
 septeX™ , oXiris® sets and extension tube are:  
- 
terminally sterilized EtO (ISO11135-1)  
- 
validated primary packaging  
- 
CE marked (93/42/EEC) 
unadulterated   
- 
single-use only  
 
 interconnection and priming uses aseptic technique  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 28 of 88 
Performance degradation 
 adsorption of plasma proteins, lipids, calcium 
 adhesion of platelets, leukocytes or erythrocytes 
 potential mechanical haemolysis 
 
 
Misuse of the LDD by clinical staff not qualified to deal with; 
 
- 
adverse events 
- 
exsanguination  
- 
thromboembolism 
- 
clotting  
- 
exacerbation of symptoms and complications of liver failure 
death 
 
resulting from delivery of liver dialysis support 
The DIALIVE is only available: 
- 
to the named investigator  
- 
exclusively for clinical investigation  
- 
under approved CIP (SAFETY Clinical 
Investigation) 
  
 potential future benefits outweigh CIP risks  
  
Set-up and Priming 
 
septeX™ barcode removed so that 
treatment parameters can be set manually  
 
septeX™ set loaded as normal  
 
oXiris® dialyzer aseptically connected using 
extension  tube  
 
septeX™ and oXiris® set primed in series 
(auto prime  followed by manual prime)  
 
oXiris® blood return line substituted on 
Prismaflex for  septeXTM blood return line  
 
air removal of oXiris® dialyser finished by 
hand  
 
complete by clamping off oXiris® dialysing 
fluid-effluent  circuit  
Operation 
 Prismaflex control, monitoring and safety 
features all engaged  
 CVVHDF proceeds as indicated except blood 
path series connection of septeX™ and 
oXiris®  
 ICU/HD monitoring per CIP and institutional 
standard of care  
 Restitution of all extracorporeal blood during 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 29 of 88 
and at end of session, except in case of filter 
clothing. 
Circumventing of Prismaflex monitoring and control features: 
- 
LDD adverse events  
- 
exanguination  
- 
thromboembolism  
- 
clotting  
- 
exacerbation of symptoms and complications of liver failure 
- 
death  
 
 Functional compatibility of Prismaflex, septeX™ 
set + oXiris® set verified in porcine model  
 Prismaflex pre-programmed sequential 
procedures mostly eliminate slips, lapses and 
mistakes  
 Prismaflex control, monitoring and safety features 
engaged  
 Prismaflex CE marked for CVVHDF  
 Investigator familiarity with CVVHDF  
Use is restricted to qualified investigator and 
supervised qualified support familiar with aseptic 
technique and liver failure patients 
 
Blood loss due to venous cannulation 
 - Undertaken by experienced staff trained in the 
procedure 
 - Standard clinical procedures are followed 
 - Coagulation results reviewed prior to cannulation 
- CIP specifies ICU/HDU monitoring particularly 
monitoring: 
- 
liver function  
- 
cardiovascular function 
- 
renal function  
 
Hypotension induced by DIALIVE, especially in patients who may be 
intravascularly depleted because of fluid restriction, diuretic therapy, 
inadequate oral intake and anemia, or those with evidence of 
vasoplegia. 
 - perform fluid preloading 
 - simultaneous replacement of lost albumin 
 - stepwise increase of blood flow rate through the 
DIALIVE 
 - stepwise increase of replacement fluid 
 - closely monitor the patient 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 30 of 88 
 
3.3 Residual risks associated with participation in the clinical investigation.  
 
The risks associated with intermittent haemodialysis (HD) and continuous haemodiafiltration (HF) are well established and 
understood.  Similarly the risks associated with intravenous albumin delivery for replacement of blood loss are well known.  
Both procedures constitute normal SOC. Risks associated with the use of an extracorporeal circulation, known as the “first 
use syndrome”, is not specifically related to the DIALIVE but rather a risk associated with any type of extracorporeal 
circulation exposure. Well established protocols exist to adjust the condition by experienced medical staff. 
 
3.4 Possible interactions with concomitant medical treatments 
 
Heparin and/or Epoprostenol will be administered to keep the circuit open and the amount used will be dependent upon 
the clotting profile of the patient determined by their platelet count, prothrombin time, partial thromboplastin time and 
fibrinogen. Clotting may be corrected by the administration of clotting products as required prior to insertion of the central 
line and will be decided on a case by case basis.  
 
There is a potential for elimination of albumin bound and water soluble drugs, but there are well established protocols for 
dose adjustments during haemofiltration particularly for drugs such as antibiotics. 
 
Terlipressin: Should only be administered in patients diagnosed with hepatorenal syndrome according to the ICA 
guidelines. In case a patient has a variceal bleed, terlipressin can be administered as per protocol. The use of terlipressin 
for these indications are for splanchnic vasoconstriction and not as a pressor for systemic hypotension. 
 
Lactulose and Rifaximin: Should only be commenced in patients if they have clinical evidence of hepatic encephalopathy. 
They may be continued on Lactulose and Rifaximin if they were receiving it at the time of randomization. 
 
Albumin: The use of albumin should be restricted for evidence-based indications. These include: a diagnosis of 
spontaneous bacterial peritonitis, hepatorenal syndrome and large volume paracentesis (>2 litres). Risks associated with 
albumin administration are well known and appropriately taken care of by medical staff. 
 
Beta-blockers: A). Should be continued in patients receiving it at the time of randomization unless the patients is 
hypotensive in which case the dose either be reduced or the drug stopped If this is stopped completely, alternative 
medications such as octreotide may be used per local policies. B) should not be started if the patient is not receiving it at 
the time of screening.  
 
 
3.5 Steps that will be taken to control or mitigate the risks 
 
All hazards associated with the intended use of DIALIVE including single fault conditions where applicable, have been 
identified and evaluated.  The process of risk reduction has not introduced any new risks that have not been overlooked 
and further risk control measures are judged to be unnecessary.   
 
On the basis of the risk management report, the technological solutions and organisational measures for qualifying and 
monitoring subjects implemented in the proposed protocol, including compliance with relevant safety, performance and 
clinical care standards, any residual risk are judged to be very low or as low as reasonably practicable and acceptable 
when weighed against the anticipated patient benefits as elicited from the clinical investigation. 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 31 of 88 
Regular safety review and recommendations will be performed by individual expert investigators and by the members of 
the TMG and DSMB to mitigate any potential risks associated with DIALIVE therapy. New recommendations will be 
implemented at appropriate iterations of the protocol versions.  
 
 
3.6 Risk-to-benefit rationale 
The series connection of the septeX™ and oXiris® dialyser sets extends the risks addressed in section 3.2 without the 
introduction of new risks in respect of: 
- 
infection; 
- 
blood loss;  
- 
air ingress.  
 
The risk analysis, risk-to-benefit assessment and risk control is described in detail in the Investigator’s Brochure (IB). After 
risk mitigation, no hazards remain with an unacceptable risk level.  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 32 of 88 
4 OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
4.1 Objectives, primary and secondary 
 
Primary Objective 
 
To evaluate the safety of the DIALIVE in patients with alcohol related cirrhosis with Acute on Chronic Liver Failure 
Grades 1, 2 and 3a (ACLF) compared with the group treated with standard of care. 
 
 
Secondary Objective 
 
To evaluate the performance of the DIALIVE in the above mentioned patient group. To evaluate clinical benefit in patients 
receiving DIALIVE treatment plus Standard of Care (SOC) versus SOC alone. 
 
4.2 Hypotheses and claims 
 
 The underlying hypothesis is that DIALIVE will significantly improve the prognosis of patients with ACLF by i) exchanging 
irreversibly damaged native albumin, which accumulates during this disease process and is ineffective in its function, with 
fresh albumin, and ii) removal of endotoxins, inflammation and endotoxaemia being the central pathogenetic feature of this 
illness. 
This is a first into man study of a novel Liver Dialysis Device. No specific hypothesis is to be statistically assessed in 
this first feasibility study. Randomization of patients is implemented to obtain unbiased clinical data appropriately 
balanced between SoC and DIALIVE treated  patients to provide fundamental learning data on the outcome of 
treatment in both study arms, in line with the recommendations of the DSMB (see appendix 7). To this end, safety 
data, are regularly reviewed (i.e. after each cohort of patient enrollment) but also other clinical parameters are 
reviewed, to learn and adjust study design when necessary and as appropriate. 
 
Based on this perspective it is the goal to obtain an adequate number of observations in each study arm, with 
emphasis on the learning from DIALIVE treatment. Future trials will be defined to assess the efficacy of DIALIVE 
treatment to the appropriate extend. 
 
 
 
4.3  Risks and anticipated adverse device effects that are to be assessed 
 
The oXiris® and septeX™ dialysers are going to be clinically assessed for their safety and performance in relation to the 
intended goal of removing oxidized albumin and endotoxins in a combined method. For this, the described system will be 
applied in a specific patient population, i.e. Acute-On-Chronic Liver Failure patients.  
The following elements are addressed in the clinical Investigation to mitigate the risk of use: 
 
  
-  The system is only used by a few, selected, qualified and trained investigators already familiar with the 
haemodialysers and with the Prismaflex;  
 
  
-  The CIP specifies further ICU/HDU monitoring requirements: liver function, haematology, coagulation factors, platelet 
count, cardiovascular function, cerebral function, renal function, pulmonary function; albumin function, immune function;  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 33 of 88 
 
  
-  The IB and IFU provides further set-up and priming instructions for the DIALIVE system and additional information 
will be provided to the investigators as clinical experience will demonstrate to optimize the patient’s treatment;  
 
  
-  The CIP is designed to minimize risk of exacerbating symptoms and in line with standard of care, i.e. there are no 
specific clinical trial procedures to be applied other than haemodialysis while there are multiple health checks build in to 
monitor the patient’s condition;  
 
  
-  The CIP provides organisation control for the patient, i.e. patient treatment on the HDU or /ICUunit per local standard 
medical practice but with adequate monitoring capabilities.  
 
 
5 DESIGN OF THE CLINICAL INVESTIGATION  
5.1 General 
 
This is a European, 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 plasma endotoxin concentrations and albumin function) of the DIALIVE in 30 evaluable patients with Acute on Chronic 
Liver Failure (ACLF) versus standard of care (SOC). The study will therefore be open label. The design is appropriate for 
the study as the primary outcome is to assess safety of the device on a small group of patients. 
 
5.1.1 
Measures taken to minimize or avoid bias 
 
The trial is being conducted by investigators who have no direct association with the inventor or the sponsor to ensure no bias 
is introduced.   
5.1.2 
Primary Endpoints 
 
The goal is to evaluate the percentage of subjects who experience at least one (1) serious adverse event (SAE) between study 
Day 1 and Day 10; especially the incidence rate of SAE between the study groups occurring in the period of Day 1 to Day 10. 
The percentage of subjects who discontinued DIALIVE due to a serious adverse device event (SADE) between Day 1 (first day 
of treatment) and Day 10 (DIALIVE arm only)10. 
5.1.3 
Secondary End Points 
To evaluate the performance of the DIALIVE in patients with ACLF. This is measured by; 
 
 
Change in Plasma endotoxin level (endotoxin activity and concentration) between; 
 
D1, D3, D5 and D10 across SOC arm 
D1, D3, D5 and D10 across DIALIVE arm 
                                                 
10 In case a patient’s treatment is discontinued, the follow up period will remain 28 days from the moment of randomization. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 34 of 88 
Start and end of a treatment session (on D1, D2 and D3) with DIALIVE 
D1,D3,  D5 and D10 between SOC and DIALIVE arms for patients presenting with the same grades of ACLF (i.e. 
Grade 1 ALCF compared with Grade 1 ACLF) 
 
Target-Value (TV): 40% reduction; Acceptable-Value (AV): 20% reduction at end of treatment cycle. 
 
 
Change in Albumin function (Human non-mercapt albumin -2 (HNA-2) / Human marcapt albumin (HMA) ratio: 
D1, D3, D5 and D10 across SOC arm 
D1,D3,  D5 and D10 across DIALIVE arm 
Start and end of a treatment session (on D1, D2, D3) with DIALIVE 
D1,D3, D5 and D10 between SOC and DIALIVE arms for patients presenting with the same grades of ACLF (i.e. 
Grade 1 ALCF compared with Grade 1 ACLF) 
 
TV: 40% reduction; AV: 20% reduction at end of treatment cycle. 
 
MortaIity: 28-days and 90 days 
 
Change in ACLF Grade  
 
Change in CLIF-ACLF  score 
 
Improvement in individual organ function: Brain (HE), Kidney (creatinine), CVS (mean arterial pressure), Pulmonary 
(P/F ratio, or S/F if patient is not intubated), Liver (serum bilirubin) and coagulation (INR and platelets). 
 
Status at ICU and Hospital Discharge (including discharge to a hospice for palliative care). 
 
Lengths of stay in ICU and Hospital  at D28 and D90 
 
ICU and Hospital re-admissions with another episode of ACLF up to 3 months after randomisation. 
 
5.1.4 
Exploratory End points 
 
 
To study other exploratory biological and clinical effects  of the DIALIVE in patients with ACLF compared with the 
Standard of Care group.Some of these parameters are centre-specific in line with local expertise, research interest and 
the capacity to perform these tests.  Liver: Changes in MELD score, plasma/serum cCK18/M30 and flCK18/M65 
(markers of liver cell death).  
 
Kidney: Changes in serum creatinine and urinary NGAL (marker of kidney injury).  
 
Brain: West Haven Criteria to assess changes in severity of hepatic encephalopathy.  
 
Immune function: Incidence of Infection, changes in white cell count, CRP and assessment of neutrophil and monocyte 
function. .  
 
Assessment of Coagulation and haemostasis: Incidence of thrombotic or bleeding complications, assessment of pro- 
and anti-coagulant clotting factors and complement activation.  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 35 of 88 
5.1.5. 
Methods and timing for assessing, recording, and analysing variables 
 
All data will be recorded real-time in the subject source documents and entered into an electronic Case Report Form 
(eCRF) by the investigator and/or his/her delegates within a reasonable period following the study visit. The 
Sponsor/appointed DM centre will manage and maintain the study database throughout the Investigation. At the 
conclusion of the Investigation, the database will then be locked and analysed. A final copy of the database will be 
provided to the study site. Where data is transferred electronically, this will be in accordance with EU data protection 
Directive (Directive 95/46/EC) and applicable national legislation requirements. There will be a documented record of 
data transfer and measures in place for the recovery of original information after transfer. 
 
Statistics: A qualified statistician will conduct data analyses, and this will be done independently of data entry. Given 
the small sample size in this safety study, analyses will be primarily descriptive in nature and will include analyses of 
both the primary and secondary outcomes and hypothesis. All treated subjects entered into the study will be included 
in the analyses. A sensitivity analysis will be conducted including all evaluable patients. All serious adverse events will 
be reported in full detail. Please refer to the Statistical Analysis Plan (SAP) for further details.  
 
5.1.6. 
Equipment to be used for assessing the clinical investigation  
 
All equipment except for the DIALIVE device, the EAA luminometer for endotoxin analysis, and the Primsmaflex 
platform11 will be the property of the Investigator(s) and/or institutions and maintained and calibrated according to 
institutional guidelines. Records of maintenance and calibration will be made available at the Sponsor’s request.  
 
5.1.7. 
Replacement of subjects. 
 
30 evaluable patients will be recruited across all sites to receive either treatment using the DIALIVE or SOC. Screen 
failures will be replaced to achieve an even balance in each cohort. The patient numbers will be increased and 
replaced if there are dropouts during the treatment period to allow 30 evaluable patients to be included. 
Dropouts can be i) patients who withdraw their consent, ii) patients who are considered ‘not evaluable’ because of an 
incomplete dialysis cycle (for DIALIVE patients) or iii)  if a patient dies in the 10-day period following randomization to 
the SOC-arm, or iv) patients who are excluded based on a stopping rule. 
A dropout rate of 17% is anticipated on the basis of observations made during execution of this study in the first 2 
cohorts of patients. Patients who drop-out for reasons of an incomplete dialysis cycle are followed up for a duration of 
28 days post-randomization. 
 
 
5.2. Investigational device exposure 
 
For the randomization an Interactive Wireless Randomization System (IWRS) is used, which is linked to the study data 
base. Randomization is automatically assigned through the IWRS system. Patients are randomised to either the DIALIVE 
or SOC arm in a 1:1 ratio.  
                                                 
11 The prismaflex platform will be provided by Yaqrit to those sites that do not have access to such haemofiltration machines. The machine will remain the property of Yaqrit Ltd 
during and after the study. A mainenance agreement in such circumstances will be established with each institution.  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 36 of 88 
 
Patients will be assigned into five (5) Cohorts. Each cohort will consist of six (6) patients (3 DIALIVE: 3 SOC). If there are 
dropouts in any of the following cohorts during the study period, patients will be replaced in each of the cohorts described 
below to reach the appropriate number of 6 evaluable patients in each cohort. 
 
 
Cohort 1: including 3 control and 3 DIALIVE treated patients.  
Cohort 2: including 3 control and 3 DIALIVE treated patients.  
Cohort 3: including 3 control and 3 DIALIVE treated patients.  
Cohort 4: including 3 control and 3 DIALIVE treated patients. 
Cohort 5: including 3 control and 3 DIALIVE treated patients.  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 37 of 88 
 
5.3. Subjects 
5.3.1. 
Inclusion criteria 
 
 
Male or female subjects aged ≥18 years ≤81yr 
 
Subject is able to provide informed consent to participate in the study, otherwise written informed consent must be 
obtained on behalf of the subject by next of kin or a legal representative 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 decompensation event (including but not limited to ascites, gastrointestinal bleeding, hepatic 
encephalopathy and/or acute bacterial infections), occurring within ≤6 weeks of screening. 
 
Subject with : 
o ACLF Grade 1, 2 or 3a defined per the CLIF-C OF score system OR 
o single hepatic organ failure for serum bilirubin > 20 mg/dL (342 µmol/L)  at screening and randomization, OR 
o AKI-stage 1b (sCr > 1.5 mg/dL or 134 µmol/L)12. 
 
Where a subject has received corticosteroids for alcohol hepatitis and is deemed unresponsive to steroids after 7 days 
of treatment (lack of response defined as Lille score13 of > 0.45 or steroids stopped before 7 days due to any 
complication such as infection). This refers to the first course of corticosteorid therapy. Further courses of 
corticosteroids during the course of illness  must not be used to determine steroid responsiveness.   
 
 
5.3.2. 
Exclusion criteria  
 
 
Co-infection with HIV and AIDS defining illness14 
 
Subjects with acute or sub-acute liver failure without underlying cirrhosis. 
 
Subjects with severe thrombocytopaenia, as defined by the platelet count of <40,000/mm3 (at screening) or rapid 
reduction in platelet count (> 50% reduction) in the previous 24 hrs prior to randomisation (day 0)  
 
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 
hepatectomy or major 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: 
o i) persistent hypotension (mean arterial pressure < 65 mmHg) with evidence of tissue hypoperfusion, not 
responsive to volume resuscitation and/or low dose vasopressor support; 
                                                 
12 See appendix 2 for further definitions and justification. 
13 See appendix 2 for further definitions. 
14 A patient can be HIV +ve as long as they are clinically stable and not presenting with any AIDS defining illness i.e. 
 
a CD4+ T-cell count below 200 cells/µL 
 
a CD4+ T-cell percentage of total lymphocytes of less than 15% 
 
or one of the defining illnesses such as PCP, Kaposi’s sarcoma, CMV, Candidiasis etc 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 38 of 88 
o 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 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.  
 
Any 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-indication of oXiris and septeX) 
 
Where subjects present with a known allergy to heparin or 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. 
 
5.3.3. 
Criteria and procedures for subject withdrawal or discontinuation 
 
Other than those required for liver dialysis, no additional Investigation or interventions are expected over and above 
the routine SOC, which the patient will continue to receive. It is anticipated, therefore, that all subjects will continue to 
be highly compliant with the CIP study procedures. Non-compliance with the CIP study procedures will be documented 
by the investigator and reported to the Sponsor as agreed. Persistent non-compliance may lead to be withdrawn of the 
patient from the study.  
 
The participant may, however, voluntarily choose to withdraw from the study at any time for any reason. This will not in 
any way affect their routine care. If the participant loses capacity during the study, the legal representative (if 
appointed)  also has the right to withdraw the participant in this instance, acting on the presumed wishes of the 
participant.  
 
The investigator also has the right to withdraw a patient at any time due to failure to follow CIP, administrative, safety 
or other reason. Stopping rules (for the study and for the DIALIVE treatment) have been developed as follows: 
 
A) Rules for discontinuing DIALIVE therapy during a treatment session, based on safety grounds   
a. Persistent shock (MAP < 65mmHg or < 90% pre-treatment value, whichever is higher) for > 2 hrs with 
features of tissue hypoperfusion, unresposive to volume resuscitation and/or low dose noradrenaline 
(0.1µg/kg/min). Treatment can be restarted once haemodynamic stability is restored. 
b. Deteriorating respiratory failure as defined by worsening PaO2/FiO2 to < 200 mmHg (27 kPa) and 
SaO2/FiO2 to < 214. Treatment can be recommenced following a 12 hour recovery period. 
c. Disseminated Intravascular Coagulation (DIC). Thrombocytopenia alone (to below exclusion criterion 
threshold) without evidence of DIC is not a stopping rule. Platelet treatment should be considered in this 
case. 
d. Progression to more than 3 organ failures 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 39 of 88 
e. In the opinion of the PI, the treatment is unsafe to continue 
 
B) Study stopping rules for  patients randomized to either the SOC or the DIALIVE arm  
a. Withdrawal of patient consent by the patient (or if applicable the appointed respresentative, where the 
patient were to lose capacity during this process). 
b. Following review of safety data by the DSMB if  they wish to stop the study on safety grounds 
 
 
 
The reasons for screen failure or withdrawal shall be documented in the eCRFs and in the patient notes. If a 
withdrawal is on the grounds of safety the Investigator will seek permission from the patient, or legal representative as 
appropriate, to follow up his/her status outside of the Investigation, but at least until resolution or full clarification of the 
adverse event. 
 
5.3.4. 
Point of enrolment  
 
Patients will be recruited through in-patient wards across multiple European centres. Approximately one (1) patient every 
four (4) months per centre will be recruited with an estimated three (3) patients per centre in total, although competitive 
recruitment will be utilised. This recruitment strategy is based upon the data accumulated during the performance of the 
CANONIC study [5].  
Following consent and confirmation of eligibility, patients will be randomised electronically via the eCRF . The site will be 
issued with the subject ID number and informed of their treatment arm. Patients will be deemed enrolled at the point of 
randomization (Day 0). 
 
5.3.5. 
Total expected duration of the clinical investigation.  
 
The total duration of the study will be approximately 39 months.  
 
5.3.6. 
Expected duration of each subject's participation.  
 
After signing the Informed Consent, the patient can be screened for compliance with the in/exclusion criteria for up to 3 
days. Patients from cohort 1, 2  and 3 are followed for 28 days, those from cohort 4 and 5 for 90 days. 
 
Patients will be randomized on study day 0 followed by a maximum treatment window period of 10 days (DIALIVE arm). All 
patients will be  intensively followed during the initial 28 days post-randomization and complete the study after completion 
of study day 28 (cohort 1, 2 and 3) or day 90 (cohort 4 and 5)..    
 
5.3.7. 
Number of subjects included in the clinical investigation.  
 
30 evaluable subjects will be randomised to receive either standard of care (SOC) or treatment with DIALIVE (1:1 
randomisation). 
As this is a first-in-man trial, and no hypothesis is to be tested, the sample size is arbitrarily set to obtain adequate 
information in a small patient population. This reduces the total number of patients exposed to potential study related risks 
while allowing the investigators to learn maximally from this potential treatment for ACLF-patients for which no alternative 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 40 of 88 
treatment exists and the Data Safety Monitoring Board to make appropriate decisions on study (dis)continuation by 
comparing occurrence of adverse events between control and treatment arms in each of the 5 cohorts of patients.  
 
 
5.3.8. 
Estimated time needed to select this number (i.e. enrolment/recruitment period). 
 
There is an estimated 39 months recruitment period that has been assigned. Start was on February 2017 and patient 
recruitment is anticipated to run till December 2019. 
 
 
5.4. Procedures 
See Schedule of assessments below for Standard of Care and DIALIVE Patients:  
 
 
 
 
 
 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 41 of 88 
 
 
                                                 
 
 
15 Informed consent must occur before ANY study specific procedures commence.  Thorough clinical examination and assessment of FBC, U&Es, LFTs, Coagulation must be repeatedn if the test have been undertaken > 24 hours 
before randomization. Microbiology results obtained within the previous 72 hrs prior to screening may be used and samples not repeated. Viral serology results obtained within 8 weeks prior to screening maybe used and samples not 
repeated.  Liver imaging results obtained 6 weeks prior to screening maybe used and tests not repeated unless there has been a significant change in clinical status 
16 Confirmation only. Document in medical notes. 
17 Tests performed: HBsAg, anti-HCV, and anti-HIV. Viral serology results obtained within 8 weeks prior to screening maybe used and samples not repeated.   
18 Standard haematology and biochemistry as per local practice (Including CRP). 
19 Tests performed: Platelets, PT, INR, PTT, Fibrinogen 
20 Survival data only via a telephone call. 
SOC Patients 
Prior Screening 
Screening 
 
Study Days 
 
Study Procedures 
 
0-72hrs  
Day 0 
 
Day 1 
Day 3 
Day 5 
Day 10 
Day 14 
+/- 2 days 
Day 28 
+/- 5 days 
Day 90 
+/- 5 days 
Informed consent15 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X16 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Complete physical examination 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Weight (kg) and height (cm) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
X 
 
X 
 
 
 
 
 
 
Viral screen (local laboratory)17  
 
X 
 
 
 
 
 
 
 
 
Clinical laboratory (local laboratory)18 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Full infection screen (local laboratory) 
 
X 
 
X 
 
X 
X 
 
 
 
Pregnancy test (women only) 
 
X 
 
 
 
 
 
 
 
 
Coagulation (local laboratory)19 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
AE assessments 
 
 
 
X 
X 
X 
X 
X 
X 
X20 
Concomitant medications 
 
 
 
X 
X 
X 
X 
X 
X 
 
CLIF-C OF Score, CLIF-C ACLF score, ACLF grade 
 
X 
 
X 
X 
X 
X 
X 
X 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 42 of 88 
 
 
                                                 
21 Blood Biomarker tests : cCK18/M30, flCK18/M65, Caspase 3, Caspase 7, IL-18, soluble CD163, cytokines (TNF-α, IL-6, IL-8, IL-10), chemokines  (CX3CL1, CXCL3, CCL2, CCL5) 
11 Includes blood for Human non-mercapt albumin -2 (HNA-2) and Endotoxin Plasma Concentration (LAL Assay). 
22 Urine Biomarker tests: NGAL, TLR4, IL-18 
23 Peripheral blood mononuclear cells (PBMC) Royal Free Hospital, London only.  
SOC Patients 
Screening 
Study Days 
 
Study Procedures 
0-72hrs  
Day 0 
 
Day 1 
Day 3 
Day 5 
Day 10 
Day 14 
+/- 2 days 
Day 28 
+/- 5 
days 
Day 90 
+/- 5 days 
MELD, MELD-Na 
X 
 
X 
X 
X 
X 
X 
X 
 
Pugh and Lille Scores 
X 
 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
 
X 
X 
X 
X 
X 
X 
 
West Haven grade 
X 
 
X 
X 
X 
X 
X 
X 
 
Blood sample for biomarkers including Albumin (HNA2) and Endotoxin Plasma 
Concentration (initial processing locally, samples are transferred to Biobank Royal 
Free Hospital for analysis)21 
 
 
X 
X 
X 
X 
 
 
 
Urine sample for biomarkers (initial processing locally, samples are transferred to 
Biobank Royal Free Hospital for analysis)22 
 
 
X 
X 
X 
X 
 
 
 
PBMCs ( initial processing locally, samples are transferred to Biobank Royal Free 
Hospital for analysis )23   
 
 
X 
X 
X 
X 
 
 
 
Endotoxin Activity Assay (local processing and analysis) 
 
 
X 
X 
X 
X 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 43 of 88 
 
 
 
                                                 
24 DIALIVE treatment must commence before end of day 1. DIALIVE treatment may commence on day 0 at the discretion of the investigator. If DIALIVE treatment commences on Day 0, then Day 1 tests must be perfomed before 
treatment commences on Day 0 and therefore does not need repeating again on Day 1. 
25 Informed consent must occur before ANY study specific procedures commence.  Thorough clinical examination and assessment of FBC, U&Es, LFTs, Coagulation must be repeated if the test have been undertaken > 24 hours before 
randomization. Microbiology results obtained within the previous 72 hrs prior to screening may be used and samples not repeated. Viral serology results obtained within 8 weeks prior to screening maybe used and samples not repeated.  
Liver imaging results obtained 6 weeks prior to screening maybe used and tests not repeated unless there has been a significant change in clinical status. s 
26 Confirmation only. Record in medical notes. 
27 Blood pressure (supine), respiratory rate, body temperature will be recorded throughout DIALIVE treatment (as per Standard of Care) 
28 Tests performed: HBsAg, anti-HCV, and anti-HIV. Viral serology results obtained within 8 weeks prior to screening maybe used and samples not repeated 
29 Standard haematology and biochemistry as per local practice (including CRP). Performed throughout DIALIVE treatment as per local practices. 
30 Tests performed: Platelets, PT, INR, PTT, Fibrinogen. Performed throughout DIALIVE treatment as per local practices. 
DIALIVE Patients 
Pre-screening Screening 
Treatment Period 
 
Study Procedures 
 
0-72hrs 
Day 0 
 
Day 124 
Day 2 
Day 3 
Day 5 
Day 10 
Day 14 
+/- 2 days 
Day 28 
+/- 5 days 
Day 90 
+/- 5 days 
Informed consent25 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
X26 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Weight (kg) and height (cm) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs27 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
X 
 
X 
 
 
 
 
 
 
 
Viral screen (local laboratory)28  
 
X 
 
 
 
 
 
 
 
 
 
Clinical laboratory (local laboratory)29 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Full infection screen (local laboratory) 
 
X 
 
X 
 
 
X 
X 
 
 
 
Pregnancy test (women only) 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation (local laboratory)30 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 44 of 88 
                                                 
31 DIALIVE treatment must commence before end of day 1. DIALIVE treatment may commence at day 0 at the discretion of the investigator. If DIALIVE treatment commences on Day 0, then Day 1 tests must be perfomed before 
treatment commences on Day 0 and therefore does not need repeating on Day 1. 
32 Survival only via telephone call 
DIALIVE Patients 
Screening 
Treatment period 
 
Study Procedures 
0-72hrs 
Day 0 
 
Day 131 
Day 2 
Day 3 
Day 5 
Day 10 
Day 14 
+/- 2 days 
Day 28 
+/- 5 days 
Day 90 
+/- 5 days 
 
 
 
 
 
 
 
 
 
 
 
AE assessments 
 
 
X 
X 
X 
X 
X 
X 
X 
X32 
Concomitant medications 
 
 
X 
X 
X 
X 
X 
X 
X 
 
CLIF-C OF Score,  CLIF-C ACLF score, ACLF grade 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
CLIF-AD Score (if relevant) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
MELD, MELD-Na 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Pugh and Lille Scores 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
West Haven grade 
X 
 
X 
X 
X 
X 
X 
X 
X 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 45 of 88 
 
 
 
                                                 
33 DIALIVE treatment must commence before end of day 1. DIALIVE treatment may commence at day 0 at the discretion of the investigator. If DIALIVE treatment commences 
on Day 0, then pre treatment cycle bloods as indicated for Day 1 must be collected in line with the patients treatment cycle days. 
34 Peripheral blood mononuclear cells (PBMC) Royal Free Hospital, London only.  
35 Blood Biomarker tests : cCK18/M30, flCK18/M65, Caspase 3, Caspase 7, IL-18, soluble CD163, cytokines (TNF-α, IL-6, IL-8, IL-10), chemokines  (CX3CL1, CXCL3, CCL2, 
CCL5)  
24 Includes bloods for  Human non-mercapt albumin -2 (HNA-2) and Endotoxin Plasma Concentration (LAL) 
36 Pre-treatment is prior to initiating DIALIVE treatment. Post-treatment is within one hour after ending a DIALIVE treatment session) 
37 Urine Biomarker tests: NGAL, TLR4, IL-18 
38 Effluent is collected from the effluent line and from the waste collection bags. 
39 Haemolysis screen: FBC including reticulocyte count, blood film, unconjugated and conjugated bilirubin, LDH, haptoglobin and urinary free haemoglobin only at end of DAY 
1. 
Study Procedures 
0-72hrs 
Screening 
Day 033 
Randomisation 
 
Day 1 – day 10 
Treatment Period 
Day 14 
+/- 2 days 
Day 28 
+/- 2 days 
PBMCs ( initial processing locally, samples are 
transferred to Biobank Royal Free Hospital for 
analysis )34  
 
 
Pre-treatment sample and post-
treatment  session sample 
 
 
Endotoxin blood sample (local processing for 
endotoxin activity analysis EAA) 
 
 
Pre-treatment sample and post-
treatment session sample. If patient 
not receiving DIALIVE treatment on 
study  day 5 or study day 10 please 
collect a sample on these days and 
process 
 
 
Blood sample for biomarkers to include 
Albumin HNA2 and Endotoxin plasma 
concentration  (initial processing locally, 
samples are transferred to Biobank Royal Free 
Hospital)35 
 
 
Pre-treatment sample and post-
treatment session sample36  If patient 
not receiving DIALIVE treatment on  
day 5 or study day 10 please collect a 
sample on these days and process 
 
 
Urine sample for biomarkers (initial processing 
locally, samples are transferred to Biobank 
Royal Free Hospital)37 
 
 
Pre-treatment sample and post-
treatment  sessione sample If patient 
not receiving DIALIVE treatment on 
study  day 5 or study day 10 please 
collect a sample on these days and 
process 
 
 
Dialysate Fluid (initial processing locally, 
samples are transferred to Biobank Royal Free 
Hospital) 
 
 
One sample to be collected prior to 
commencement of the first  DIALIVE 
treatment session only, from the 
Dialysate bag 
 
 
Ultrafiltrate/Effluent fluid (initial processing 
locally, samples are transferred to Biobank 
Royal Free Hospital)38 
 
 
On every DIALIVE treatment day: 
collect samples after 1hr, 4hrs, and  8-
10hrs  during treatment. 
 
 
Preparation and monitoring of patient per 
DSMB recomendations 
 
 
Treatment on ICU, pre-loading fluid, 
appropriate arterial/venous lines, 
arterial blood gas analyses every 2 
hrs, haemolysis screen39, DIC screen 
if clinically indicated. 
 
 
DIALIVE Patients-During Treatment 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 46 of 88 
 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 47 of 88 
5.4.1. 
Additional sponsor representative(s) activities (excluding monitoring). 
 
Sponsor representatives will be available to assist sites in the device set up. 
 
5.5. Monitoring plan 
 
A contract research organisation (CRO) will be utilised by the Sponsor, Yaqrit, to undertake the management and delivery 
of the clinical investigation. A project plan will be agreed and implemented to ensure effective conduct. Each site will be 
evaluated and the qualifications of the PIs verified and documented in a site selection report. There will be an agreement 
between the Sponsor, CRO and the sites to define responsibilities for study conduct between all parties.  
 
Monitoring will verify that the rights and well-being of the subjects are protected and that the clinical investigation is 
conducted according to ethical and Good Clinical Practices (GCP), Declaration of Helsinki, Data Protection regulations 
and the overarching ISO 14155, as well as any regional or national regulations, as appropriate. 
 
The monitor will conduct a Site Initiation Visit (SIV) at each study centre prior to patient recruitment activity. A delegation 
log will be completed identifying key personnel involved in the study, signatures, functions and designated authorisations.  
 
The monitor will conduct on-site routine monitoring visits in accordance with the agreed monitoring plan during the study, 
to ensure adherence to the CIP, accurate data recording in the electronic Case Report Form (eCRF) and to monitor 
recruitment rates and adherence to follow up schedules. The Investigator(s) shall permit and assist the monitor to carry out 
verification of completed CRFs against data in the source documents.  
 
The frequency of monitoring will be in accordance with the risk of the study. Whilst the study utilises two CE marked 
devices (filters), the study team has deemed the risk of the study to be High Risk. This is a first into man clinical 
investigation with a un-CE marked device (combination of two CE marked filters in new disease indication).  
 
A SIV will be conducted at each site after all applicable approvals have been received. The monitor will ensure that each 
principal investigator has received and understood the requirements and content of the CIP, IB, the informed consent 
form, CRFs and Instructions for use of DIALIVE. Verification of site training on the set up and use of DIALIVE will also be 
undertaken.   
 
 
At each visit the monitor shall ensure; 
 
 
Compliance with the CIP (and any amendments), ISO 14155 and other applicable regulatory requirements for medical 
devices 
 
The device is being used in accordance with the CIP and instructions for use 
 
Informed consent of patients has been obtained before any clinical investigation-related procedures are undertaken 
 
Traceability of the devices is appropriately maintained and device stored appropriately 
 
Source documents are accurate, complete, up-to-date and maintained appropriately.  
 
Verify that investigator repeatedly attempted to retrieve clinical information from patients considered lost-to-follow up. 
 
CRFs and queries are complete, recorded in a timely manner and consistent with source 
 
Adverse events are recorded and reported without unjustified delay 
 
Investigator study documentation (Investigator Site File) contains all required documents 
 
A monitoring report will be generated and sent to the Sponsor after each visit. Additional site monitoring visits will be 
agreed between the Sponsor and CRO if any significant site issues are identified after a routine visit.  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 48 of 88 
 
The level of Source Data Verification (SDV) will be agreed between the Sponsor and CRO. It is 100% for the patient 
informed consent forms, regulatory and ethical approvals and all study reported serious adverse events.  
 
 
A close-out visit will be conducted at each site to ensure that the PI records are complete, all documents needed for the 
Sponsor are retrieved and all previously identified issues have been resolved. Arrangements for archiving will be made at 
this visit. 
 
Additional detail regarding Monitoring aspects can be found in the associated Yaqrit risk based Monitoring Plan.  
 
5.5.1. 
Confidentiality 
All data will be handled in accordance with the EU Data Protection Directive (95/46/EC) and applicable national 
requirements. The CRFs will not contain the subject’s name or other personal identifiable data. The subject’s initials, 
date of birth and trial identification number, will be used for identification. Subjects will be assigned a trial identification 
number upon enrolment into the study. The study site will maintain a master subject identification Log.  
If national authorities require specific information to be included in the local/national Informed Consent, then this will be 
implemented, especially with reference to GDPR. To this end, also the information obtained from the medical staff of 
the investigational centers will be treated by sponsor and CRO in a confidential manner and only used for the purposes 
of the study – as is most often already outlined in the specific Investigator Agreements. 
 
 
5.5.2. 
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report. Investigators are 
responsible for the secure archiving of essential trial documents as per their institutional policy. All essential 
documents will be archived for 5 years after completion of trial. Destruction of essential documents will require 
authorisation from the Sponsor.   
 
6. 
STATISTICAL CONSIDERATIONS 
 
An independent statistician will be responsible for all statistical aspects of the investigation. 
 
All statistical analyses will be carried out on the safety population, defined as the subset of randomised patients who 
receive at least one treatment. No imputation of missing values will be implemented. Only available data will be analysed. 
In addition, a sensitivity analysis will be carried out to check the main safety results using SAE-data of all evaluable 
patients, defined as all those patients who received standard of care or those who received the correct dialysis treatment 
cycle. 
 
Due to the nature of the study all statistical analyses will be descriptive. The categorical variables will be summarised by 
means of the count and percentages corresponding to each variable category, while continuous variable will be 
summarised by the mean and Standard Deviation of each distribution or the median and min-max values in case of those 
variables non-normally distributed. 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 49 of 88 
For each treatment arm, treatment-emergent AEs, SAEs, SADEs, ADEs, USADEs and DDs will be summarised by organ 
system and treatment causality.  The number and percentage of patients discontinuing the study due to AEs, SAEs, 
SADEs or other stopping criteria confirmed by the DSMB (withdrawal of patient consent; development of septic shock; 
progression to ACLF Grade 3b or more; disseminated Intravascular coagulation; unanticipated serious adverse device 
effects, device deficiencies, or in the opinion of the PI, the treatment is unsafe to continue) will be summarised by 
treatment arm.   
 
Secondary and exploratory parameters (changes from baseline at each study visit) will be descriptively analysed by 
treatment arm by means of the appropriate statistics. 
 
Statistical analyses of safety data will be run when each study cohort is completed (minimally one week FU) and the 
corresponding results will be communicated to the DSMB.  
 
Special interim data extraction required to comply with the EU ALIVER program. 
 
Access to the ALIVER safety clinical trial data by IBM, one of the Partners of the ALIVER-Consortium,  is required to 
determine if the ALIVER dataset has the same variable set of patient characteristics with those which were included in 
the CANONIC dataset [5]. This availability is critical to ensure compatibility of the predictive models which IBM is 
building for ALIVER with the safety clinical trial as input data. Also critical, is an assessment and subsequent  potential 
adjustment of the model to allow for inconsistencies between the CANONIC and the safety clinical trial data e.g. 
specifications for names, types, and codes of patient characteristics.  Access to the clinical data is required at regular 
interim time points to implement this in two main steps. Initially a process will be executed to filter out patient 
characteristics that are not considered critically useful in the prediction of mortality rates of ACLF patients. The filtering 
will be carried out applying statistical criteria using a multivariate feature selection analysis based on the Mutual 
Information.  The filtering will also be carried out using criteria provided by clinicians to determine the usefulness of 
patient characteristics gathered using exploratory and non-exploratory based laboratory approaches. The second step 
will be to manage any missing values that could be absent from the safety clinical data provided by  considering 
statistical information extracted from the variables available in the data. If the performance of the CANONIC predictive 
machine learning models decreases significantly when tested, using the safety clinical data provided, then alternative 
analytics approaches will be considered and determined.  
 
The techniques which are envisaged for application tor the ALIVER safety data are:  
- Standard descriptive statistics to determine the overall structure of the data.  
- Data missing values replacement – statistical approach. 
- Filtering/Selection of groups of patient characteristics according to previously stated usefulness analyses.  
- Machine Learning models such as Logistic Regression,  XGBoost and, for future work, Deep Neural Networks. 
 
The results obtained from this research work will be made available in a report form not before the clinical trial is 
completed to guarantee confidentiality and to avoid any bias. No study end-points are assessed by this activity. 
 
 
7. 
DATA MANAGEMENT 
7.1.1. 
Procedures for data review, database cleaning, and issuing and resolving data queries.  
 
All clinical investigators will have current Good Clinical Practice (GCP) training, specifically ISO 14155 standards for 
conducting a clinical Investigation. 
 
Responsibilities 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 50 of 88 
 
Data Management will be the responsibility of the Sponsor/designee. All documents and data shall be produced and 
maintained in a way that assures control and traceability. All documents, and subsequent versions, related to a clinical 
investigation shall be identifiable, traceable and appropriately stored to provide a complete history of the clinical 
investigation. Only authorised individuals will have access to the electronic system after appropriate training has been 
provided.  
 
Data Collection 
All collected patient data will be treated confidentially and identified only by a unique patient identification number. Medical 
records relating to clinical investigation, including those that are electronically maintained and those that may contain 
information that would identify an individual patient will remain confidential, but may be reviewed by, released, and/or 
transmitted to representatives of the hospital, regulatory authorities, or its agents when reasonable and appropriate for the 
conduct of the study. 
 
An electronic Case Report Form (eCRF) will be used in the study and completed for every patient who is enrolled for 
participation. The eCRF will be developed and held by the data management centre of European Foundation for Chronic 
liver Failure (EF-CLIF), Barcelona, Spain. Data entered in the eCRF must be consistent with the source documents 
(medical and nursing notes, laboratory reports, ECGs, echocardiogram). Data must be entered by the site in a timely 
manner and be consistent with the source. The PI (or designee) will be responsible for the ensuring the eCRFs are signed. 
Any changes to the initial data recorded must be signed for to ensure an appropriate audit trail is maintained. The Trial 
Monitor(s) will carry out on-site monitoring during the study and at the end of the study to ensure accuracy and quality of 
data (Source Data Verification). Site investigators will ensure the Monitor’s access to patients’ medical records, laboratory 
reports, imaging reports, and other patients’ records needed. Site Investigators will cooperate with the Trial Monitor to 
ensure that any problems detected in the course of these monitoring activities are resolved.  
 
Avoidance of confusion. 
The procol allows for a start of DIALIVE dialysis on the day of randomization (DAY 0). As this constitutes the first day of 
treatment in the DIALIVE-arm, it might be confused with “DAY 1” of the study scheme. The currently available electronic 
data base (eCRF) also does not provide data entry options for “DAY 0” data collection, other than directly related to the 
randomization assignment. If dialysis is performed on DAY 0, then clinical data are required to be entered on the eCRF 
indicated as “DAY 1”. The date of treatment will allow, however, to retrospectively reconstruct the exact timing of dialysis 
sessions and to identify the ‘eligible dialysis cycle’ to be considered for the end-point analysis. 
 
 
7.1.2. 
Procedures for verification, validation and securing of electronic clinical data systems 
 
 
 
The study database will be located at the above data management centre. The database will be aligned with the case 
report forms so that the data captured are complete, accurate, reliable and consistent. Database design will be 
documented at each stage of development, including (but not limited to) test runs, training exercises, security checks, 
periodic reviews to confirm data integrity and compliance with operational specification. Once completed, the system will 
be validated to ensure that it is fit for purpose for the trial. 
 
Appropriate software will be used in developing/designing a database to ensure:  
 
 Ease of use with appropriately controlled access  
 Prevention of duplicate entries  
 Field validations, where appropriate  

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 51 of 88 
 Consistent data coding (e.g. MedDRA coding or other convention which is developed at the start of the study)  
 Consistent and accurate downloads for analyses  
 Full audit trail possible of data entered and any changes made.  
 Regular back-ups  
 
 
Prior to database lock, the entire database will be verified to ensure that there are no outstanding errors or unjustified 
missing data. When all queries have been resolved the database will be locked.  
 
Statistical review of the Database  
 
There will be a requirement to ensure that all the trial data have been received, verified, fully coded and cleaned for 
analysis with all queries resolved before locking the database for analysis. Unlocking of the database will only be 
undertaken in a strictly controlled environment and rationale for doing so will be fully documented.  
 
The designated statistician will receive the full and dated download of the database with a complete and accurate dataset 
used for analysis. This will be retained separately from the live database to allow reproducible analyses (database-lock).  
 
A final copy of the database will be provided to the study site. Where data is transferred electronically, this will be in 
accordance with applicable Data Protection regulations. There will be a documented record of data transfer and 
measures in place for the recovery of original information after transfer. 
 
7.1.3. 
Data and  biosample retention  
 
Archiving will be authorised by the Sponsor following submission of the end of study report. Investigators are 
responsible for the secure archiving of essential trial documents and the trial database as per their trust policy. All 
essential documents will be archived for 5 years after completion of trial. Destruction of essential documents will 
require authorisation from the Sponsor.   
 
Biosamples will be used for data analysis as specified and destroyed no later than 5 years after study closure, unless 
local national regulations specifically allow longer retention times (e.g. UK). 
 
 
7.1.4. 
Clinical quality assurance 
 
The trial management group (TMG), consisting of the coordinating investigator, site investigators and experts from 
relevant specialties (if required) will meet routinely in accordance with the TMG terms of reference, to discuss and address 
any concerns regarding the conduct of the study. The TMG will be consulted for appropriate review and adjudication of 
adverse events.  Please refer to the TMG Charter for further details. 
8. 
AMENDMENTS TO THE CIP 
 
Amendments to this CIP may be necessary to protect the safety of the patients and integrity of the data. In 
collaboration with the Investigator(s), the CIP amendments will be documented and submitted for ethical and 
regulatory approval prior to implementation. All changes will be evaluated for impact per Sponsor SOPs. Amendments 
will be considered implemented after all ethical and regulatory approvals are received and all key sponsor and site 
staff has been trained. This process does not affect the individual clinician’s responsibility to take immediate action if 
thought necessary to protect the health and interest of individual patients. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 52 of 88 
The Prismaflex utilizes certain software to appropriately run the pumps according to specific settings. Per the user 
manual of oXiris and septeX a software version 4.0 or higher is to be used. For the DIALIVE study, in Austria a 
software version 8.1 only will be allowed. 
 
9. 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
 
A deviation is either a violation of the conditions and principles of GCP in connection with that trial; or the CIP relating 
to that trial, as amended from time to time.  
 
The Investigator shall not deviate from this CIP except in situations that affect the subject’s rights, safety and well-
being, or the scientific integrity of the clinical investigation.  
 
9.1. Procedures for recording, reporting and analysing CIP deviations.  
Any deviations form the CIP that occur must be documented on the deviation log and maintained by the study site 
throughout the duration of the Investigation. Deviations will be submitted to Data Management so they maybe included 
in the analysis.  
 
9.2.  Notification requirements and time frames.  
 
Requests for deviations by the investigator will be responded to by the Sponsor within 48 hours of receipt.  
 
9.3.  Corrective and preventive actions and principal investigator disqualification criteria. 
 
Refer to the Yaqrit Risk-based Monitoring Plan, for corrective and preventative actions and principal investigator 
disqualification criteria.  
 
 
10. DEVICE ACCOUNTABILITY 
 
The DIALIVE system has been assessed against the Medical Devices Directive 93/42/EEC (MDDs) Essential 
Requirement (ERs) aspects as listed in Annex I of the IB. It is concluded that DIALIVE complies with the MDD ERs except 
for those aspects that are the subject of this investigation: 
Essential Requirements 1 and 3 relating to patient safety and 6 relating to determination of side effects 
The quality of the haemofilters used in DIALIVE is assured by design and production certified compliant with MDD Annex II 
(Full Quality Assurance System) and ISO 13485 Quality Management Systems for Medical Devices – System 
requirements for regulatory purposes.  
The same applies for the inter-dialyser connection tubing.  
The commercially available filters and connecting tube (Device) will be purchased directly from the suppliers and re-
packaged by Yaqrit Ltd into a box labeled “exclusively for clinical investigation”. The sterility of all component parts will 
not be altered in any way. Yaqrit Ltd will release and distribute the required number of devices to the sites ready for 
use. Each device will be assigned a unique device code to ensure full traceability once sent to sites. The sponsor will 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 53 of 88 
maintain a master list of all devices. The device shall be stored according to the storage conditions listed in the 
approved IB. 
 
Access to the DIALIVE device shall be controlled and the device shall only be used in the clinical investigation 
according to this CIP.  The Sponsor will maintain records to document the physical location of all devices from 
shipment to sites to destruction. The instructions for use are detailed in the IB. DIALIVE treatment will be delivered by 
either (a) Trained study specific staff provided by Yaqrit Limited or (b) Site specific staff that have been specifically 
trained in the use of DIALIVE and signed training logs will be maintained in the Trial Master file. 
 
Each site will maintain accountability records from receipt of the devices through to its use on a per patient basis and 
destruction following each treatment to ensure a full audit trail is maintained. This shall include the following 
information; 
 
 a) the date of receipt,  
 b)  identification of each investigational device (batch number/serial number or unique code),  
 c)  the expiry date, if applicable,  
 d)  the date or dates of use,  
 e)  subject identification,  
 f)  date on which the investigational device was returned/explanted from subject, if applicable, and  
 g)  the date of return of unused, expired or malfunctioning investigational devices, if applicable.  
 
11. STATEMENTS OF COMPLIANCE 
11.1. Declaration of Helsinki, International Standards and national regulations  
 
The clinical investigation shall be conducted in accordance with the ethical principles of the Declaration of Helsinki, 
MDD 93/42/EEC, ISO 14155:2011 and all other applicable national regulations.  
 
11.2.  Approvals 
The clinical investigation shall not commence at the site until ethics and regulatory approval and any institutional 
approval (as applicable) is received. All additional requirements imposed by the ethics committees and/or regulatory 
authority will be followed. No device will be release to site until all applicable approvals have been verified and the site 
initiation has been undertaken/scheduled.  
11.3.  Insurance 
The Sponsor will maintain appropriate trial insurance for the clinical investigation as detailed in the Clinical 
Investigation Agreement(s).  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 54 of 88 
 
12 INFORMED CONSENT PROCESS 
 
Fully informed consent will be obtained at the initial screening visit. It will be the responsibility of the Investigator, or 
designee (on the delegation log) to obtain written informed consent from each subject prior to participation in the trial, 
following adequate explanation of the aims, methods, anticipated benefits and potential hazards of the study  
The inclusion of patients with reduced capacity or who are unconscious (HE grade 3 or 4)  is restricted to the approval 
based on local and / or national legislation. In different European countries, different rules apply. The applicable 
approach will be documented and applied according to the  local or national Ethics Committee guidelines, 
recommendations or obligations. 
 
Two approaches need to be considered.  
A. Patient is conscious at start of enrollment process but might be at jeopardy to lose capacity as decided by the 
treating investigator. To provide additional protection of subjects, each subject will be offered the option – in line 
with local and national regulations – to nominate a consultee/representative at the point of consent who, should 
the patient loose capacity during the study, will act under their presumed wishes and ensure any study 
intervention conducted will have the consent of the consultee/representative. If a consultee/representative is 
appointed, he/she must have agreed to act in this capacity before the patient is randomized (i.e. during the 
screening phase) and this must be documented in the medical notes by site. Where verbal agreement has been 
initially sought, the site must ensure the Patient Informed Consent Form is co-signed and filed in the site file as 
soon as is practicable but not later than patient discharge from hospital.  Where a patient does not have a 
consultee/representative (family member, legal representative) and in case he/she would prefer to have one 
appointed, a professional consultee/representative (independent of the study) will be offered to the patient. The 
consultee/representative will not undertake any decision making on behalf of the patient unless they are deemed 
to have lost capacity based on medical assessment.  
B. Patient is unconscious at start of enrollment process. As this constitutes a ‘vulnerable patient’ per the definition 
of the ISO 14155, special care is to be provided that all local and national regulations are implemented. Inclusion 
of this kind of vulnerable patients might be prohibited, while in other countries or centers tolerated under specific 
conditions. These conditions might be linked, but are not restricted to the optimal treatment of the patient by the 
investigator and/or to the release of the clinical data which need to be approved at study end by either the 
patient’s or the legal representative’s consent, OR the upfront written consent by a legal representative, identified 
and approved per the local/national regulations 
 
“Adequate time” will be given for consideration by the patient before taking part. The investigator, or designee, will 
record when the Informed Consent documents has been given to the patient. The Investigator or designee will explain 
the patients are under no obligation to enter the trial and that they can withdraw at any time during the trial, without 
having to give a reason. The patient will be given the opportunity to ask questions prior to signing the consent. No 
clinical trial procedures will be conducted prior to obtaining appropriate consent. A copy of the signed Informed 
Consent Form (ICF) will be given to the participant. The original signed form will be retained at the study site and a 
copy placed in the medical notes. If new safety information results in significant changes in the risk/benefit 
assessment, the consent form will be reviewed and updated if necessary and subjects will be re-consented as 
appropriate within the time limits of the study. 
 
As this is not an emergency treatment, no patients shall be enrolled into the study without full informed consent 
following the local/national legislation. Once a patient provided appropriate consent, this consent remains valid until 
study completion, withdrawal or exclusion.  
 
Each Investigator will maintain a log of all subjects enrolled into the trial, to ensure assigned trial codes and names can 
be linked. This will be retained at each site.  
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 55 of 88 
12. ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
12.1.  The definitions are compliant with ISO 14155 and MEDDEV Guidance 2.7.1 rev 3 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical 
device or the comparator 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events 
related to investigational medical devices 
Adverse Device Effect 
(ADE) 
Adverse Event related to the use of an investigational device.  
Note 1: This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational device 
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device 
Serious Adverse Event 
(SAE) 
Any adverse event that: 
• 
Led to death, injury or permanent impairment to a body structure or a 
body function 
• 
Led to serious deterioration in the health of the subject, that either 
resulted in  
- 
a life-threatening illness or injury, or 
- 
a permanent impairment of a body structure or a body function, or 
- 
in-patient or prolonged hospitialization, or 
- 
in medical or surgical intervention to prevent life-threatening illness  
• 
Led to foetal distress, foetal death or a congenital anomaly or birth defect 
 
Planned hospitalization for a pre-existing condition or a procedure required by 
the CIP, without a serious deterioration in health is NOT considered a SAE. 
Serious Adverse 
Device Effect (SADE) 
An ADE that has resulted in any of the consequences characteristic of an SAE 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
An SADE, which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report.  
 
Device Deficiency (DD) 
Inadequately of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. 
Note 1: this includes malfunctions, use errors, and inadequate labeling 
 
An adverse event does not include: 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 56 of 88 
 Medical or surgical procedures; the condition that leads to the procedure is an adverse event. 
 Pre-existing disease, conditions, or laboratory abnormalities present at the start of the study that do not 
worsen in frequency or intensity. 
 Situations where an untoward medical occurrence has not occurred (e.g., hospitalizations for cosmetic or 
elective surgery or social/convenience admissions); 
 The disease being studied or signs/symptoms associated with the disease unless more severe than 
expected for the subject’s condition. 
 Expected post-operative course (see section 3) 
12.2. Reporting requirements and timelines 
 
 
 
The SAE reporting form in appendix 1 of the MEDDEV guidance will be used unless national/local requirements specify a 
different reporting requirement.  
 
In line with MEDDEV guidance 2.7/3 rev 3 May 2015 and Annex X section 2.3.5 of the MDD40 
Term 
Reporter 
Reported to 
Reporting Timeline from awareness of 
the event 
Adverse Event (AE) 
Investigator 
Sponsor/CRO 
As soon as reasonably possible 
Adverse Device 
Effect (ADE) 
Investigator 
Sponsor/CRO 
As soon as reasonably possible 
Device Deficiency 
(DD) 
Investigator 
Sponsor/CRO 
Immediately, not later than 3 calendar days 
after site awareness of event 
Sponsor/CRO 
CA/Ethics 
Committee  
Immediately but no later than 2 calendar 
days if the event may have led to an SAE if; 
 
suitable action had not taken 
 
intervention had not been made 
 
if circumstances had been less 
fortunate  
 
Serious Adverse 
Event (SAE), Serious 
Adverse Device 
Effect (SADE), 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
Investigator 
Sponsor/CRO 
Immediately, not later than 3 calendar days 
after site awareness of event 
Sponsor/CRO 
CA/Ethics 
Committee 
Immediately but not later than 2 calendar 
days of sponsor becoming aware of event 
if event indicates an imminent risk of death, 
serious injury, or serious illness and that 
requires prompt remedial action for other 
patients, users or persons, or a new finding 
to it 
For all other events Immediately but not later 
than 7 calendar days of sponsor becoming 
aware of event 
New findings/updates 
in relation to already 
reported events 
Sponsor/CRO 
CA/Ethics 
Committee 
Immediately but not later than 7 calendar 
days of sponsor becoming aware of event 
 
 
                                                 
40 Special national requirements might apply and will be implemented 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 57 of 88 
12.3.  Assessments of adverse events 
 
Each adverse event will be assessed by the PI for the following criteria: 
12.3.1. Severity  
 
Category 
Definition 
Mild 
The adverse event does not interfere with the volunteer’s daily routine, and does not require 
intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the volunteer’s routine, or requires 
intervention, but is not damaging to health; it causes moderate discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly damaging to health 
Note: A severity rating of severe does not necessarily categorise the event as an SAE. 
 
12.3.2. Seriousness 
Seriousness as defined for an SAE in section 13.1.  
12.3.3.  Causality 
The relationship between the use of DIALIVE treatment and the occurrence of each adverse event shall be assessed and 
categorised. During causality assessment activity, clinical judgment shall be used and the relevant documents, (IB and the 
CIP) shall be consulted, as all the foreseeable serious adverse device effects (SADE) and the potential risks are listed and 
assessed there. The presence of confounding factors, such as concomitant medication/treatment, the natural history of the 
underlying disease, other concurrent illness or risk factors shall also be considered. For the purposes of this investigation 
the device related expected events will be outlined in the IB, The CIP will outline the disease expected events and cross 
refer to the IB.  
 
The above considerations apply also to the serious adverse effects (SAEs) occurring in the comparison group.  
 
For the purpose of harmonising reports, each SAE will be classified according to five different levels of causality. The 
Sponsor and the investigators will use the following criteria to assess the relationship of the serious adverse event to the 
investigational medical device or procedures. 
 
Not related 
Relationship to the device or procedures can be excluded when: 
 
 
the event is not a known side effect of the product category the device  belongs to or of similar 
devices and procedures;  
 
the event has no temporal relationship with the use of the  investigational device or the 
procedures;  
 
the serious event does not follow a known response pattern to the  medical device (if the 
response pattern is previously   known) and is  biologically implausible;  
 
the discontinuation of medical device application or the reduction of the  level of 
activation/exposure - when clinically  feasible - and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event;  
 
the event involves a body-site or an organ not expected to be affected by the device or 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 58 of 88 
procedure;  
 
the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors);  
 
the event does not depend on a false result given by the investigational device used for 
diagnosis when applicable;  
 
harms to the subject are not clearly due to use error;  
 
In order to establish the non-relatedness, not all the criteria listed above  might be met at the 
same time, depending on the type of  device/procedures and the serious event.  
 
Unlikely 
The relationship with the use of the device seems not relevant and/or  the event can be reasonably 
explained by another cause, but additional  information may be obtained. 
Possible 
The relationship with the use of the investigational device is weak but  cannot be ruled out completely. 
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible.  
 
Probable 
The relationship with the use of the investigational device seems relevant and/or the event cannot 
reasonably explained by another cause, but additional information may be obtained.  
 
Causal 
relationship 
The serious event is associated with the investigational device or with procedures beyond reasonable 
doubt when: 
 
the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;  
 
the event has a temporal relationship with investigational device use/application or procedures;  
 
the event involves a body-site or organ that o the investigational device or procedures are 
applied to; o the investigational device or procedures have an effect on;  
 
the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known);  
 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
 
other possible causes (e.g. an underlying or concurrent illness/ clinical  condition or/and an 
effect of another device, drug or treatment) have  been adequately ruled out;  
 
harm to the subject is due to error in use;  
 
the event depends on a false result given by the investigational device  used for diagnosis when 
applicable;  
 
In order to establish the relatedness, not all the criteria listed above  might be met at the same 
time, depending on the type of device/procedures and the serious event.  
 
 
 
The sponsor and the investigators will distinguish between the Serious Adverse Device Effects (SADEs) related to 
DIALIVE treatment and those related to investigation procedures (any procedure specific to the clinical investigation). An 
adverse event can be related both to procedures (inherent in the study) and the investigational device. Complications of 
procedures are considered not related if the said procedures would have been applied to the patients also in the absence 
of investigational device use/application. 
 
 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse (device) events 
(USADEs). The occurrence of unanticipated events related to the use of DIALIVE could suggest that the clinical 
investigation places subjects at increased risk of harm than was to be expected beforehand. The DSMB will review all 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 59 of 88 
safety data at specific time points throughout the study as outlined in the DSMB charter. 
 
12.3.4. Expectedness 
Category 
Definition 
Expected 
An adverse event that is consistent with the information about DIALIVE listed in the 
Investigator Brochure (IB) and CIP 
Unexpected 
An adverse event that is not consistent with the information about DIALIVE listed in 
the Investigator Brochure (IB) and CIP 
 
The reference document to be used to assess expectedness against the intervention is the IB.  
The CIP will be used as the reference document to assess disease related and/or procedural expected events.  
12.4. Procedures for recording and reporting Adverse Events and Device Deficiencies 
12.4.1. . Investigator responsibilities:  
The site Investigator shall report any SAE, SADE, USADE and DDs which occur in a subject to the Sponsor/CRO 
immediately but no later than 3 calendar days after site awareness of the event. The immediate report for all events 
may be made orally or in writing (using the Sponsor’s/CRO SAE form or DD form, as applicable) and shall be followed 
by a detailed written report on the event.  
 
The PI will respond to any queries raised by the Sponsor/CRO as soon as possible.  
 
The Sponsor/CRO will report any SAE or DD to the REC and/or Competent Authority according to national guidelines.  
 
All deaths of a patient during their participation in the study will be reported as a SAE irrespective of whether the death 
is related to trial participation or an unrelated event. 
 
Where the event reported consists of, or results in the death of a subject, the investigator shall supply the 
Sponsor/CRO with any additional information requested by the Sponsor/CRO. Where the death has been reported to 
the relevant ethics committee, the investigator shall supply any additional information requested by that committee. All 
serious adverse events will be recorded in the hospital notes, the eCRF and a SAE form. 
 
The investigator shall keep detailed records of all adverse events and device deficiencies relating to the clinical 
investigation, which are reported to them, by trial participants or users. The investigator shall document all relevant 
information on Sponsor/CRO provided AE logs, SAE forms and DD forms.  
12.4.2.  Reporting of all Adverse Events and Device Deficiencies: Investigator and Sponsor 
responsibilities 
 
Investigator responsibilities shall be as per section 13.4. The sponsor shall keep detailed records of all adverse events 
and device deficiencies relating to the clinical trial, which are reported to them by the trial investigators. The 
Sponsor/CRO shall ensure that all relevant information about a reportable event, which occurs during the course of 
this clinical investigation, is reported as soon as possible to the competent authority and relevant ethics committees 
per their reporting requirements and according to the timelines in section 13.2. Any additional relevant information 
should be sent within the same time frame as the initial report. The Sponsor/CRO is responsible for informing the 
appropriate regulatory authorities, ethics committees and other investigators of any reportable events that have 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 60 of 88 
occurred with the study device in any clinical investigation according to the guidelines set forth by either the ethics 
committees of record or regulatory authority in the country where the clinical investigation is taking place.  
12.4.3. Safety Update Reports 
These will be undertaken in accordance with national requirements. 
12.4.4. Progress reports 
Progress reports will be submitted to the ethics committees yearly as per national requirements. The Sponsor/CRO will 
prepare and submit the progress reports. 
 
12.5.  Foreseeable adverse events and anticipated adverse device effects 
 
Listed below are known complications associated with liver disease 
 
 
Gastrointestinal bleeding 
 
Spontaneous Bacterial Peritonitis (SBP) 
 
Hepatic Encephalopathy (HE) 
 
Hypotension 
 
Septic shock 
 
Respiratory failure 
 
Cardiovascular failure 
 
Renal insufficiency 
 
Hepatorenal syndrome 
 
Death 
 
Any existing condition will be recorded at baseline during screening. Further events relating to an existing condition will not 
be recorded as an AE unless in the opinion of the PI, the condition has worsened since baseline. All AEs will be recorded 
from the point of consent and reported to the Sponsor in accordance with section 13.2.  
 
During initial human dialysis sessions, and subsequent DSMB reviews, the following (potential) device related SAEs were 
observed; these were incorporated in the latest version of the Investigator Brochure: 
 
Hypotension: this resulted in a series of recommendations to follow during the DIALIVE treatment (see §3.2 of CIP) 
 
Higher then expected albumin drop during dialysis led to additional in vitro tests supporting the need to administer 
5 g albumin every hour of dialysis (see §3.4 of CIP and §8.1 of IB) 
 
Anemia was observed  in one patient, requiring blood cell pack administration to restore the hemoglobin level. (see 
page §3.2 of CIP and §9.1, 11.2 and 12.3i of IB) 
Reference is made to section 3.2 of this document, where also the anticipated events related to extracorporeal circulation 
and to kidney dialysis are summarized 
 
 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 61 of 88 
12.6. Emergency contact details for reporting serious adverse events, serious adverse device effects and 
device deficiencies.  
 
All SAEs and USADEs will be reported to the CRO via the eCRF. In the event access to the eCRF is not available, 
paper SAE forms will be completed by the site and emailed to: 
 
DIALIVE.safetyandperformance@fakkel-bvba.com 
 
or via fax (+32 1137 5327). 
 
Please refer to Appendix 6 for Country Specific Safety Reporting. 
 
13. VULNERABLE POPULATION 
 
Many subjects able to consent for themselves will be enrolled in the investigation. To provide additional protection of 
subjects, each subject will nominate a consultee at the point of consent who, should the patient loose capacity during the 
study, can act under their presumed wishes of the subject and ensure any study intervention conducted will have the 
consent of the consultee.  If the patient does not have a consultee then they may be offered a professional consultee 
(independent of the study). In all instanties, the treating physician is required to adhere to Good Clnical Practices, i.e. to 
offer the best care at all times to the patient, irrespective of his/her study participation and health condition. 
Only if the national and/or local Ethics Committee does have legislation to allow the inclusion of unconscious patients, then 
these patients fulfilling all other in/exclusion criteria can be considered for study participation. All applicable regulations will 
need to be implemented prior study inclusion of this kind of vulnerable patient; if regulations cannot be fully complied with 
then the patient will not be considered for study inclusion. The possibility to include these vulnerable patients will be 
assessed and documented upfront prior first study patient enrollment in a given center. 
 
 
14. SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION 
 
The Sponsor may suspend or prematurely terminate either the clinical investigation in an individual investigation site or the 
entire clinical investigation for significant and documented reasons. 
The PI, ethics committee, or regulatory authority may suspend or prematurely terminate participation in a clinical 
investigation at the investigation sites for which they are responsible. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, the Sponsor will suspend the clinical 
investigation while the risk is assessed. All information will be sent to the Data Safety Monitoring Board (DSMB) for review. 
The Sponsor shall; 
a) Terminate the clinical investigation if an unacceptable risk is confirmed by the DSMB. All other Investigators will be 
informed or 
b) If following review the DSMB concludes appropriate corrective actions have been undertaken and are acceptable 
and decides to lift the temporary suspension, the Sponsor will obtain all the necessary approvals for re-instating the 
trial and will inform all Principal Investigators.  
The reports of the DSMB outcome will be forwarded to the national Competent Authority. The outcome will be 
implemented as a protocol amendment after the 1st and 2nd DSMB review. These DSMB outcome reports and 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 62 of 88 
amendment(s) must be re-approved by the requiring National Competent Authority (Germany) prior to study 
continuation and patient enrollment in Germany if the next cohort is allowed. 
 
If, for any reason, the sponsor suspends or prematurely terminates the investigation at an individual investigation site, the 
sponsor shall inform the responsible regulatory authority as appropriate and ensure that the ethics committee is notified,  
If suspension or premature termination occurs, the Sponsor shall remain responsible for providing resources to fulfil the 
obligations from the CIP and existing agreements for following up the subjects enrolled in the clinical investigation, and the 
PI or authorized designee shall promptly inform the enrolled subjects at his/her investigation site, if appropriate. The 
method and the timing of this communication will depend on the circumstances and the perceived risks. 
 
15. LEGAL REPRESENTATIVE 
 
The clinical trial started in 2016 in UK and was broadened to include different European study centers as of 2017.  In 
the event of UK leaving the European Community (Brexit), the Medical Device Regulation requires non-EU based 
manufacturers to be represented in a member state. YAQRIT Ltd, sponsor of the DIALIVE trial,  has appointed the 
CRO FAKKEL as the legal representative for the duration of the study. 
 
Contact details:   
 
 
FAKKEL-bvba 
Groenendael 43/001 
3400 Landen, Belgium 
Contact person : Jaak Minten 
Telephone: +32-475-923-149 
Fax: +32-11-37-53-27 
16. PUBLICATION POLICY 
 
 After the study has been officially closed, a report on the evaluation will be completed. The clinical investigation report 
shall take into account the data from each investigation site and for all subjects. No subject shall be identifiable either from 
the clinical investigation report or the published results. The clinical investigation report will be made available to the all PIs 
for review and comment. The Sponsor will maintain records confirming that the clinical investigation report has been 
provided for review. The final, signed report will be submitted to the authorities in accordance with national requirements. 
The results of this clinical investigation will be made available for publication according to sponsor SOPs and per the 
Clinical Investigation Agreement (CIA).  
 
 
17. SIGNATURES 
 
The Investigators agree to comply with the responsibilities of the Principal Investigator as defined in ISO 14155:2011 
as well as EU GCP and other applicable national legislation, the EU Data Protection Directive (95/46/EC) and 
applicable national legislation, local Information Governance Policies, the Sponsor’s SOPs, Study Specific SOPs and 
other regulatory requirements as amended. 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 63 of 88 
The Sponsor substantiates that this CIP is in accordance with ISO 14155:2011 and the Medical Devices Directives 
93/42/EEC (MDD). The Sponsor agrees to comply with the responsibilities of the Sponsor as defined in ISO 
14155:2011 as well as EU GCP and other national Regulations, the EU Data Protection Directive (95/46/EC) and 
applicable national legislation, local Information Governance Policies, the Sponsor’s SOPs, Study Specific SOPs and 
other regulatory requirements as amended. 
 
 
 
SIGNATURES TO FOLLOW 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 64 of 88 
CO-ORDINATING INVESTIGATOR AND SPONSOR SIGNATURES 
I have read CIP number YAQ-002 V7.0.0 dated 10 October 2019. I agree to conduct the study as detailed in this CIP 
and in compliance with the Declaration of Helsinki, Good Clinical Practice (GCP) and all applicable regulatory 
requirements and guidelines 
 
 
Coordinating Investigator 
 
 
 
Dr Banwari Agarwal 
 
Signature
 
Date 
11 October 2019 
 
 
 
Sponsor Representative 
 
 
 
Daniel Green 
 
 
 
 
 
Signature 
 
 
Date 
 
 
11 October 2019 
Principal investigator 
 
 
 
……………………………………………. 
 
 
 
 
 
Signature 
Date 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 65 of 88 
18  BIBLIOGRAPHY 
 
 1.   
Blachier, M., et al., The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol, 2013. 
58(3): p. 593-608.  
 2.  
 
Mokdad, A.A., et al., Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. 
BMC Med, 2014. 12: p. 145.  
 3.  
 
Gyori, G.P., et al., Impact of dynamic changes in meld score on survival after liver transplantation - a 
eurotransplant registry analysis. Liver Int, 2016.  
 4.   
Lozano, R., et al., Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a 
systematic analysis for the Global Burden of Disease Study 2010. Lancet, 2012. 380(9859): p. 2095-128.  
 5. 
  
 
Lee, K.C., et al., Extracorporeal liver assist device to exchange albumin and remove endotoxin in 
acute liver failure: Results of a pivotal pre-clinical study. J Hepatol, 2015. 63(3): p. 634-42. 
 6;  
Moreau, R., et al., Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute 
 decompensation of cirrhosis. Gastroenterology, 2013. 144(7): p. 1426-37, 1437 e1-9.  
 7. 
  
Jalan, R., et al., Toward an improved definition of acute-on-chronic liver failure. Gastroenterology, 2014. 
147(1):  p. 4-10.  
      8. 
Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gines P, et al. Development and validation of a prognostic score to  
  
predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014;61: 1038–1047. 
  
  
     9;  
Huelin P, Piano S, Sola E, Stanco M, Sole C, Moreira R, et al. Validation of a staging system for acute kidney injury in  
  
patients with cirrhosis and association with acute-on-chronic liver failure. Clin Gastroenterol Hepatol 2017;15:438–445  
  
  
Jalan, R., et al., Acute-on chronic liver failure. J Hepatol, 2012. 57(6): p. 1336-48.  
 10; 
Bajaj J.S. Hepatic Encephalopathy: classification and treatment. J. Hepatol, 2018, 68 (4): 838-839. .  
 11.  Banares, R., et al., Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute- on-
chronic liver failure: the RELIEF trial. Hepatology, 2013. 57(3): p. 1153-62.  
12.  Kribben et al. Effects of fractionated plasma separation and adsorption on survival in patients with Acute-on-chronic   
  
liver failure. Gastroenterology 2012;142(4):782-789. 
 13.  Mookerjee, R.P., et al., Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and 
 predicts the outcome. Hepatology, 2007. 46(3): p. 831-40.  
 14.  Stadlbauer, V., et al., Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic  hepatitis. 
Am J Physiol Gastrointest Liver Physiol, 2009. 296(1): p. G15-22.  
 15.  Lee, K.C., et al., A reproducible, clinically relevant, intensively managed, pig model of acute liver failure for  testing of 
therapies aimed to prolong survival. Liver Int, 2013. 33(4): p. 544-51.  
16.  Stange et al. Industrial Stabilizers Caprylate and N-Acetyltryptophan Reduce the Efficacy of Albumin in Liver Patients.  
  
Liver Transplantation, 2011, 17: p. 705-709.  
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 66 of 88 
Appendix 1a- Acute-on-Chronic Liver Failure Grading Scheme per CLIF-OF scoring system. 
 
 
Grade  
Subgroups  
 ACLF grade equivalent (for DIALIVE study) 
No ACLF*  
• Patients with no organ failure 
• Patients with a single hepatic, coagulation, 
circulation or respiratory failure, no AKI and no 
HE 
• serum creatinine <1.5mg/dL and no hepatic 
encephalopathy (HE) 
• Patients with single cerebral failure and serum 
creatinine <1.5mg/dL  
 
Grade 1  
• Patients with renal failure (sCr > 2 mg/dL) 
• Patients with other single failure organ failure with 
serum creatinine ≥1.5 and <2 mg/dl and/or HE 
grade 1-2 
• 
Patients with serum bilirubin > 20 
mg/dL (364 µmol/L) 
• 
AKI stage 1b (sCr > 1.5 mg/dL or 134 
mol/L)  
Grade 2  
• Patients with 2 organ failures  
 
Grade 3 a 
• Patients with 3 organ failures 
 
Grade 3 b 
• Patisents with more than 3 organ failure 
 
 
 From: Moreau, R., et al., Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute  
decompensation of cirrhosis. Gastroenterology, 2013. 144(7): p. 1426-37, 1437 e1-9.  
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 67 of 88 
Appendix 1b:Chronic Liver Failure Consortium (CLIF-C) Scoring Systems 
 
CLIF-C Organ Failure (CLIF-C OF) Scoring System 
 
Organ System 
Score = 1 
Score = 2 
 
Score = 3 
Liver (mg/dl) 
Bilirubin < 6 
6 ≤ Bilirubin ≤ 12 
Bilirubin >12 
Kidney (mg/dl) 
Creatinine <2 
Creatinine ≥2 <3.5 
Creatinine ≥3.5 or renal replacement 
Brain (West-Haven) 
Grade 0 
Grade 1-2 
Grade 3-4 
Coagulation 
INR < 2.0 
2.0 ≤ INR < 2.5 
INR ≥ 2.5 
Circulation 
MAP ≥70 mm/Hg 
MAP <70 mm/Hg 
MAP < 65 mmHg; Vasopressors 
Respiratory: PaO2/FiO2 
or SpO2/FiO2 
>300 >357 
≤300 - > 200 >214- ≤357 
 
≤200 ≤214 
The shaded areas represent ‘Organ Failures’ 
From: Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gines P, et al. Development and validation of a prognostic score to 
predict mortality in patients with acute-on-chronic liver failure. Journal of Hepatology 2014; 61: 1038–1047 
 
 
CLIF-C Acute Decompensation (CLIF-C AD) Formula 
 
10*0.03*Age + 0.66*Ln Creatinine + 1.71*Ln INR + 0.88*Ln WBC +-0.05*Sodium + 8  
 
From: Jalan R, Pavesi M, Saliba F, Amoros A, Fernandez J, Holland-Fischer P, et al. The CLIF Consortium Acute 
Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-onchronic liver failure. 
Journal of Hepatology 2015; 62: 831–840 
 
 
CLIF-C Acute-on-Chronic Liver Failure (CLIF-C ACLF) Formula 
 
10*[0.33*CLIF-OFs + 0.04*Age + 0.63*Ln WCC – 2] 
  
From: Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gines P, et al. Development and validation of a prognostic score to 
predict mortality in patients with acute-on-chronic liver failure. Journal of Hepatology 2014: 61: 1038–1047 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 68 of 88 
Appendix 2: a) AKI criteria for decompensated cirrhosis  
                      b) Lille score. 
 
a. AKI criteria 
 
The definitions of Acute Kidney Injury (AKI) grading are: 
o AKI stage 1A:  acute rise in serum creatinine (sCr) of > 0.3 g/dl (27 µmol/L) in < 48 hrs, or 
  
      sCr > 1.5 – 2 times the baseline sCr in 7 days (but absolute sCr value < 1.5 mg/dL 
AKI stage 1B: sCr > 1.5 mg/dL (134 µmol/L) 
. 
o AKI stage 2: sCr > 2.1 – 3 times the baseline sCr in 7 days 
 
o AKI stage 3:  3.1 – 4 times baseline sCr in 7 days, or 
  
       sCr > 4 mg/L (354 µmol/L) with evidence of acute rise of > 0.3 g/dl (27 µmol/L) in < 48 hs 
 
AKI stage 1B denotes significant kidney injury in the context of decompensated cirrhosis and equates to single renal 
organ failure or ACLF 1. AKI stages 2 and 3 should be used as per CLIF-OF score. 
 
From: Huelin P, Piano S, Sola E, Stanco M, Sole C, Moreira R, et al. Validation of a staging system for acute kidney 
injury in patients with cirrhosis and association with acute-on-chronic liver failure. Clin Gastroenterol Hepatol 
2017;15:438–445 
 
b. Lille score. 
 
INSTRUCTIONS 
The Lille Model risk stratifies patients already receiving steroids for alcoholic hepatitis treatment for 7 days to predict 
which will not improve and should be considered for other management strategies. All values besides 7-day bilirubin 
are taken from admission 
 
Day 0 
29 / 
10 / 
2018  (dd/mm/yyyy) 
Date of Birth 
/ 
/ 
 (dd/mm/yyyy) 
   
   
Bilirubin 
µmol/L (at Day 0) 
Bilirubine 
µmol/L (at Day 7) 
Creatinine 
µmol/L (at Day 0) 
Albumin* 
g/L (at Day 0) 
Patient's prothrombin time 
sec (at Day 0) 
 
 
* In patients who have been treated with albumin infusions, in order to avoid the use of an artificial value, it is recommended 
to use the available albumin value before infusion of albumin 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 69 of 88 
Lille Model Score = (exp(-R))/(1 + exp(-R))  
 
Where R = 3.19 - (0.101 X age) + (0.147 X baseline albumin) + (0.0165 X change in bilirubin 
level) - (0.206 X creatinine) - (0.0065 X baseline bilirubin) - (0.0096 X prothrombin time) 
 
From: Louvet A., Naveau S., Abdelnour M., et al.         The Lille Model: a new tool for Therapeutic Strategy in patients with 
severe alcoholic hepatitis treated with steroids. HEPATOLOGY, Vol. 45, No. 6, 2007: 1348-1354. 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 70 of 88 
Appendix 3: Model for End-Stage Liver Disease (MELD) Scoring Systems 
 
 
MELD Formula 
3.8*In Bilirubin (mg/dl) +11.2* in INR + 9.6* In Creatinine (mg/dl) + 6.4 
 
 
From: Kamath P., Wiesner R.H., Malinchoc M. et al. A model to predict survival in patients with end-stage liver disease. 
Hepatology 2001; 33: 464-470 
 
 
MELD-Sodium Formula 
3.8*In Bilirubin (mg/dl) +11.2* in INR + 9.6* In Creatinine (mg/dl) + 1.59 (135-Na (meq/l) + 6.4 
 
 
 
From: Biggins S.W., Kim W.R., Terrault NA. et al. Evidence-based incorporation of serum sodium concentration into MELD. 
Gastroenterology 2006; 130: 1652–1660 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 71 of 88 
Appendix 4: West Haven Criteria for Semi-quantitative Grading of 
Mental State 
 
 
 
From: Ferenci P., Lockwood A., Mullen K. et al. Hepatic encephalopathy – definition, nomenclature, diagnosis, and 
quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 
2002; 35: 716 –721 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 72 of 88 
Appendix 5: Definitions of acute decompensation: 
Acute development of large ascites was defined by the development of grade 2 to 3 ascites, according to the International 
Ascites Club Classification, 1 within less than 2 weeks; it could be a first episode of ascites or a new episode. Patients with 
chronic refractory ascites who were admitted to the hospital frequently for therapeutic paracentesis due to rapid reaccumulation 
of large ascites were not included in this definition. 
Acute hepatic encephalopathy was defined by the acute development of a change in mental status in a patient with previous 
normal consciousness and no evidence of an acute neurologic disease.2 It could be the first episode of hepatic encephalopathy 
or a new episode. Patients with chronic hepatic encephalopathy were not included in this definition. 
Acute gastrointestinal hemorrhage was defined by the development of an upper and/or lower gastrointestinal bleeding of any 
etiology.3 
Although bacterial infections are not specific complications of cirrhosis, they were considered as such because of their high 
prevalence and association to abnormalities related to cirrhosis, including bacterial translocation and impaired leukocyte 
functions.4, 5 Spontaneous bacterial peritonitis, spontaneous bacteremia, urinary tract infection, pneumonia, and cellulitis, the 
most frequent infections in cirrhosis,5 as well as any other type of acute bacterial infection were included in this definition. 
1. Moore et al. Hepatology. 2003; 38: 258–266 
2. Blei et al. Am J Gastroenterol. 2001; 96: 1968–1976 
3. Garcia-Tsao et al. N Engl J Med. 2010; 362: 823–832 
4. Arviniti et al. Gastroenterology. 2010; 139: 1246–1256 
5. Gustot et al. Hepatology. 2009; 50: 2022–2033 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 73 of 88 
Appendix 6: Country Specific Safety reporting requirements 
Member State 
Ethics Committee Requirements 
Competent Authority Requirements 
Comments 
 
United Kingdom 
SAEs: Only reports of related and unexpected within 
15 days of the chief investigator becoming aware of 
the event. 
 
Use REC specific template for reporting non-clinical 
trial of investigational medicinal product events.  
 
There is no requirement for annual safety reports in 
addition to the information provided through the annual 
progress report. 
MHRA 
 
When reporting SAEs please include the total 
number of patients treated in the UK at the time of 
reporting. 
 
This includes events occurring outside the UK, 
where the investigation is also being conducted in 
the UK. 
 
When submitting the MEDDEV 2.7/3 reporting 
Excel spreadsheet please email this to 
aic@mhra.gsi.gov.uk quoting CI/2016/0032 
(MHRA's reference number)  
 
Summary reports   
 Reports of all serious adverse events must 
be made on a 3 monthly basis in tabular format 
broken down by event type. To include; 
 number of serious adverse events  
 number of participants affected by those events  
 percentage of the total number of enrolled 
participants affected by those events  
 
Include a summary analysis of the serious events 
together with the manufacturer's/sponsor 
conclusions  
UK utilizes MEDDEV 
2.7/3 requirements for 
CA submissions. 
 
Health Research 
Authority requirements 
included in REC 
submissions. 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 74 of 88 
Member State 
Ethics Committee Requirements 
Competent Authority Requirements 
Comments 
 
Germany 
As per MEDDEV requirements 
BfARM 
SAEs: A causal relationship between the SAE and the 
investigational medical device, a comparator device, 
diagnostic or therapeutic procedures performed as part 
of the clinical trial or other conditions of the trial conduct 
cannot be excluded-RELATED 
Immediately but not later than 2 calendar days 
 
SAEs: A causal relationship between the SAE and the 
investigational medical device, a comparator device, 
diagnostic or therapeutic procedures performed as part 
of the clinical trial or other conditions of the trial conduct 
can be excluded-UNRELATED 
Immediately but not later than 7 calendar days 
SAE summary evaluation 
Use German SAE report 
form for single cases in 
Germany.  
If event occurs outside 
Germany use MEDDEV 
2.7.3 
 
On quarterly basis using 
MEDDEV excel file. Sheets 
to be separated into two 
sheets for those events 
occurring inside Germany 
and those occurring 
outside of Germany. 
 
On quarterly basis using 
the SAE summary 
evaluation report.  
France 
SAEs: No SAE reporting to CPP required.  
Annual report to be submitted.  
As per MEDDEV requirements.   
Other safety data requiring immediate notification within 
15 days of sponsor awareness: any new element that 
could significantly modify the evaluation of the risk-
benefit ratio of the investigational medical device  
An annual safety report required. 
Use ANSM template for 
reporting to CA. 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 75 of 88 
Spain 
SAE: only if country related: immediately but not later 
than 15 days after awareness.  
 
Unexpected SAE that led or could have led to death: 
only if site related: immediately but not later than 7 
days after awareness.  
 
 
At least once a year the annual safety report. 
As per MEDDEV 2 
 
At least once a year the annual safety report. 
 
Denmark 
An annual safety report is required. 
SUSAR: suspected unexpected serious adverse 
reactions should be reported immediately. 
 
Annually and throughout the year the sponsor or 
investigator must submit reports on SA(D)E and 
USA(D)Es. In addition, a safety assessment on trial 
subject’s safety should be presented. 
 
Reports must be forwarded in pdf format. 
An annual safety report is required. 
SUSAR: suspected unexpected serious adverse 
reactions should be reported immediately. 
 
The investigator and/or sponsor must indicate if 
the adverse event is associated with the 
investigational device (SADE), that the event is 
serious and that the event is unexpected 
(USA(D)E). 
An e-form to be 
completed on the 
DKMA webpage. 
Italy 
According to timelines specified in MEDDEV 2.7/3 
December 2010 
According to MEDDEV 
An annual report must be submitted 
No Specific template to 
be used 
Austria 
  
 BASG: According to MEDDEV 2.7 rev 3 
All SAEs if related immediately and 
 
-SAES as strong breach of the public safety: not 
later than 2 days 
-Death and unexpected SAEs: not later than 10 
calendar days 
-Other SAES (not Death _Non unexpected SAE): : 
not later than 30 calendar days 
 
 
 MEDDEV 2.7/3 SAE 
Report Table v2 (XLS) 
And  Notification form 
(Word) 
 
 
Romania 
According to timelines specified in MEDDEV 
2.12/1 rev 8 from January 2013 
According to timelines specified in MEDDEV 
2.7 rev 3 
Ro utilizes MEDDEV 
2.7/3 requirements for 
CA submissions. 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 76 of 88 
Belgium  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Annual report required 
 
 
 
FAGG  
 
- Each SAE 
- Each Device deficiency 
- Each AE that could have been a SAE, but was 
prevented by correct handling  of the responsible 
persons 
 
SAEs occurring in patients treated in Belgium and 
outside of Belgium. 
 
Notification as fast as possible, SAEs immediately  
 
Annual Safety Report required.  
Safety reporting to  
AFMPS/FAGG by using 
MEDDEV 2.7/3 
reporting Excel 
spreadsheet 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 77 of 88 
Appendix 7: Summary report of the DSMB outcome  
A) upon review of the safety aspects observed in cohort 1 of the study. 
 
Upon completion of patient enrollment in cohort 1of the study, the 7 SAEs observed were reviewed by the DSMB on the 19th 
April 2018. The following recommendations were formulated by the DSMB: 
 
1. DSMB unanimously recommended the continuation of the DIALIVE study and approved enrollment of another 6 patients 
(i.e. the completion of enrollment in the second cohort of the study). 
2. A question was raised on the possibility of standardising anticoagulation regime across centres. It was acknowledged by 
all that this is a complex area and that there is no straightforward answer to this. Our current knowledge of what should 
be an optimal anticoagulation strategy for this device is limited. More information is required before a definitive 
standardized anticoagulation regime can be recommended. The current study protocol addresses this issue by 
incorporating detailed assessment of coagulation and haemostasis as part of the study. This would then hopefully 
provide better insight into this matter to then help formulate an informed anticoagulation regime. But until then we would 
continue with local policies used for standard CRRT therapy. 
3. It was recommended to provide adequate guidance within the protocol to avoid inclusion of severely ill patients. The 
specificity of the ACLF grading in determining the expected mortality in an individual patient can sometimes be 
challenging. It is possible that an ACLF grade 2 is clinically sicker than a stable ACLF grade 3. Efforts will be made to 
address this issue in the next iteration of the study protocol, possibly by introducing more stringent exclusion criteria. It 
was also discussed that Point-of-Care measurements may be suboptimal as compared to central laboratory blood 
chemistry values. The co-ordinating PI, Banwari Agarwal, confirmed that it is the current recommendation to all 
investigators to rely only on central laboratory results for medical judgements. 
There is no need to adjust the protocol prior to proceeding with the study. It is important that additional information is accrued 
on more study patients to better understand the optimal treatment of the ACLF-patient. The number of currently enrolled 
patients is too small to make appropriate conclusions. Therefore, additional study patients are required. 
 
B) upon review of the safety aspects observed in cohort 2 of the study. 
 
14 subjects have been enrolled to the study so far; 8 DIALIVE and 6 SOC, 2 of 8 DIALIVE patients were non-evaluable as per 
the study protocol since they failed to complete the minimum treatment required for analysis. Overall, with the exception of the 2 
non-evaluable DIALIVE patients, the intervention seems to be safe and is well tolerated with some expected adverse events 
such as a degree of hypotension, mild platelet consumption and potential complications related to the lines being used to 
deliver the treatment. The two deaths in the DIALIVE arm, both occuring within 24-36 hours of treatment having been 
commenced, appear to be multifactorial including progression of the disease itself and the learning curve of the sites using such 
treatment for the first time thus sometime not realising the nuances of such treatment. Following the recommendations made at 
the interim DSMB meeting whereby a standard document was created to capture these nuances for ready reference to the site 
teams, the three DIALIVE patients treated since then had a very stable treatment course.  
We therefore, based on the evidence provided to us by the central study team and the sponsor, feel reasonably confident that 
the study should continue to the next cohort as and when practical.        
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 78 of 88 
 
 
Appendix 8: Illustrations of clinical procedures. 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 79 of 88 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 80 of 88 
 
 
 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 81 of 88 
Appendix 9 Amendment History- Country Specific 
 
Amendment 
No. 
CIP version no. 
Author(s) of 
changes 
Details of changes made 
1 (Substantial) 
UK Only 
4.0 dated 8th 
December 2016 
Yvanne Enever 
P1-Company logo amended, addition of DIALIVE in title and 
addition of EUDAMED number.  
P2- Principal Investigator amended to Coordinating Investigator  
P3-Addition of additional EU Sites (Germany, France, Spain) 
P8- Overall Synopsis amended; 
 
addition of DIALIVE 
 
Primary End Point outcome measure amended from 
Days 1-7 to Days 1-10  
 
Amendment to % of subjects discontinuing due to 
“SADE between days 1-10 in DIALIVE arm only” 
P9-Amended secondary objective to “DIALIVE arm only” 
P10-Exploratory end points now include additional wording  
 
“compared with SOC group” 
 
 “serum” creatinine 
 
 “plasma induced” neutrophils and additional test IL1RA 
P11-Addition of SAE and number of visits altered to clarify the 
following; 
 
Day 0=Randomisation 
 
Day 5 assessments now replaces day 7 (both arms) 
 
Day 10 assessment for safety (both arms) 
 
Day 21 removed 
Removal of wording “after last treatment” 
Trial dates amended to reflect additional approval requirements 
P15-Additiona of IB as reference for DIALIVE set up 
P24-Addition of “compared with SOC” added to Primary 
objective 
Addition of wording “to evaluate improvement in clinical 
parameters between patients receiving DILAIV treatment vs 
SOC” 
P25-Addition of European requirements in section 5.1 
 
EU data protection Directive (5.1 section c) 
 
Addition of footnote re supply of Prismaflex platform 
(section 5.1 d) 
 
Clarification that 24 evaluable patients are required and 
drop outs will be replaced (section 5.1 e) 
P26-Additional comment re drop outs (section 5.2) and 
additional wording “by the patient or their appointed consultee…. 
during this process” (section 5.1 c) 
P27-Increase in number of sites from 4 to 7, clarification of 3 
patients/site, clarification re randomization=day 0 and criteria for 
screening failures (section 5.2 d), clarification of screening 
phase, treatment phase (DIALIVE) and that all patients will 
complete study after completion of day 28 visit (section 5.1 f), 
the word evaluable added (section 5.2 g), recruitment period 
extended to 18 months (section 5.2 h) 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 82 of 88 
Amendment 
No. 
CIP version no. 
Author(s) of 
changes 
Details of changes made 
1 (Substantial) 
cont… 
4.0 dated 8th 
December 2016 
Yvanne Enever 
P29-30 Schedule of assessment amended to align both groups; 
 
Screening period day-3 to day 0 
 
Day 1 (first day of treatment DIALIVE arm) 
 
Day 5 assessments 
 
Day 10 assessments (safety) 
 
Day 14 window period added 
 
Day 21 removed 
 
Day 28 window period added 
 
Clarification of samples taken locally vs centrally 
 
Clarification of timings for Biomarkers, endotoxin and 
albumin samples 
P31-Addition of Fig 1 Schedule and Amendment of Fig 2 to alter 
timings of assessments 
P33-insertion of word monitor and electronic, removal of 
monitoring schedule specifics as will be added to monitoring 
plan 
P34-EU data protection provision added (section 5.5 a), SAE 
added (section 6 
P36-Clinicians amended to Site investigators 
P37-Clarification regarding release of device and addition of 
unique device code for accountability purposes (section 10), 
addition of Ethics approval and removal of HRA approval and 
addition of wording “no device will be released to 
site…undertaken/scheduled” (section 11 b) 
P38-EU data protection provisions added 
P45 addition of “safety update reports will be in accordance with 
national provisions” (section 13.5 a), amendment of safety 
reporting numbers for SAEs and USADEs (section 13.6) 
P47-signatures amended to account for additional investigators 
P48 addition of PI declaration of compliance 
P49-Additonal PI signatures 
P56-58 Addition of Appendix 5 –EU country specific safety 
reporting requirements 
P59-60-Addtion of Appendix 6-Amendment History 
  
2 (Non 
Substantial) 
UK Only 
CIP v4.1 dated 
27th January 
2017 
Yvanne Enever 
P1 Addition of wording “Project is supported in part by a grant of 
the European Community (ALIVER EU-grant No 733057)” as 
required by the European commission grant conditions. 
P 12 and 14-Clarification of filter name to be used during 
albumin replacement in the DIALIVE arm  
P 12-to correct the serum albumin level to be achieved as this 
stated in error that a level of of >30 g/L should be achieved 
rather than establishing the level of baseline for the patient.  
P45-corrected the safety email address of the CRO  
P48 Amended version of CIP in compliance statement. 
 
 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 83 of 88 
Amendment 
No. 
CIP version 
no. 
Author(s) of 
changes 
Details of changes made 
3. Substantial 
Amendment 
UK  only 
 
Substantial 
Amendment 
Number 1 
France, 
Germany and 
Spain 
 
 
 
CIP v5.0 dated 
16th October 
2017 
Banwari 
Agarwal/Jaak 
Minten/Yvanne 
Enever 
To align all versions of CIP across EU member states following EC and CA 
approvals in Germany, France and Spain.  
P1 Version and date change. 
P2-3 All site details removed and a separate master list will be maintained by 
the CRO. Only the Coordinating Investigator is now identified. Removal of 
Edinburgh as a site and replacement of Basildon Hospital (UK). 
P6-7 Updates to abbreviations. 
P8 Additions of definitions of SOC and DIALIVE treatment to ensure it is 
explicit for site staff. This does not change change the original study concept. 
P10 To clarify in the secondary end points DIALIVE + SOC vs SOC alone. The 
secondary outcomes have not changed. To add in the requirements for 
plasma endotoxin and albumin measurements to ensure explicit requirements 
outlined across both arms. To provide greater clarity of when the 
measurements will be taken from. 
P11 To outline that some exploratory end points will be centre specific 
according to local capabilities. The addition of assessment of coagulation and 
haemostasis as a result of the 2 device related SAEs seen in subject 001. 
P12-Greater clarity provided to ensure sites understand the DIALIVE 
treatment session vs DIALIVE treatment cycle requirements. This does not 
alter the original study concept. Additional wording to outline the statistical 
analysis requirements ensuring that all patients will be evaluated for SAEs in 
line with the primary end point for the study. 
P13 Clarity regarding screening assessment requirements and 
commencement of DIALIVE treatment prior to end of Day 1. This allows 
DIALIVE patients who meet the Day 1 requirements at randomization (Day 0) 
to commence treatment. Further clarification has been provided regarding the 
use of test results obtained prior to screening to ensure tests are not 
unnecessarily repeated. 
P14 Further clarification has been provided to outline the rationale and use of 
the Hepalbin filter for replacement albumin and to amend the levels of albumin 
replacement for DIALIVE patients based on the exposure of patient 001 to the 
DIALIVE and additional in vitro testing conducted.   
P17 Clarification provided to ensure patients requiring CRRT will undergo this 
after their DIALIVE a treatment. 
P20 Additional pre clinical results (invitro data) has been added. No study 
adaptations are required as a result of these data. The IB has been updated 
accordingly. 
 
P 23/24 Risks-hypoalbuminemia and potential mechanical haemolysis added 
and aligned with update of the IB 
P28 The full primary and secondary end points for the study have been added 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 84 of 88 
based on feedback from the German Competent Authority. Assessment of 
coagulation and haemostasis added to further explore the findings seen in 
patient 001. 
P31 Additional wording has been included to clarify the use of corticosteroids 
and to outline the determination of HE assessment. 
P32 The additional exclusion to include known allergies to heparin has been 
included based on the recommendation of the German Competent Authority. 
Additional wording included to reflect the requirement of a patient loosing 
capacity as per the original approval for the study. Clarification of patient 
withdrawal criteria included to outline the re-inclusion of patients following 
response to antibiotic therapy after 24-48hrs.  
P35 Additional wording to again clarify the commencement of DIALIVE 
treatment before the end of Day 1 and that screening failure patients (due to 
the inability to commence DIALIVE treatment before end of Day 1) maybe re-
consented and re-screened. Additional wording to further describe the 
statistical requirements of the study. 
P 34-P39 Separation of Assessment Schedules per arm. Additional 
clarification on test requirements and parameters for taking samples which are 
in line with the newly developed Laboratory Manual. The test requirements 
have not changed from the original study concept.  
P42 Additional wording to clarify the statistical considerations. 
P45 Reference made to the TMG Charter. 
P46 Update to ensure compliance with national regulations rather than UK 
only regulations 
P47 Additional wording to further clarify the requirements of the consultee.  
P53 The DIALIVE safety email address corrected 
P54 Requirement to send the outcome reports of the DSMB to the Competent 
Authority as required by the German Competent Authority and the requirement 
to implement the outcome as an amendment requiring approval. 
P56 Removal of PI signatures to have one signature page per site to allow 
ease of signature collection. 
P63-65 Update to Appendix 6 to be in line with National requirements 
P66-69 Inclusion of Amendment history per Member State 
4. Substantial 
amendment 
for AUSTRIA 
CIP v 5.1 
dated 31 May 
2018 with 
Amendment 1 
dated 10th 
December 
2018 
Jaak Minten 
§2.1 Model number of Prismaflex (Model Ref: 60 23014700) and applied 
software version (version 8.1) is added. 
§2.3 A footnote is added to refer to the absence of model numbers for both the 
septeX and oXiris filters as this is the brandname given by Gambro/Baxter. 
§ 3.3. The “first use syndrome”, which is not specifically related to the DIALIVE 
but rather a risk associated with any type of extracorporeal circulation 
exposure, is added in the section. 
 § 3.4, Risk associated with the administration of albumin have been added to 
the bullet “albumin” and the use of telepressin is indicated. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 85 of 88 
§ 6.3.2. In/exclusion criteria. Per the user manual of oXiris and setpeX the 
body weight of the treated patient should be above 30 kg. Patient lighter than 
30 kg will not be allowed to be enrolled in the study 
§9 Amendments to the CIP. The Prismaflex utilizes certain software to 
appropriately run the pumps according to specific settings. Per the user 
manual of oXiris and septeX a software vesion 4.0 or higher is to be used. For 
the DIALIVE study, in Austria a software version 8.1 only will be allowed. 
 
5. Substantial 
amendment 
for Denmark 
CIP v 5.1 
dated 31 May 
2018 with 
Amendment 1 
dated  
November 
2018 
Jaak Minten 
§6.1.7. Expected dropout rate is specified and 28 days of FU for patients 
dropping out early is added. 
§ 6.1.7.. The follow up procedure for patients that have not completed a 
treatment cycle is specified to be 28 days. 
§6.3.3. It is specified that patients who experience a serious adverse device or 
procedure related event and subsequently withdraw from the study will be 
followed until the reported issue is solved/clarified. 
§6.5. In case a subject is lost to follow-up, it is specified that the monitor will 
check the appropriateness of the investigational site’s attempts to contact the 
subject and/or his contact person. 
§ 6.5. It is specified that the Informed Cosnent Forms, letters of authority (EC 
and CA) and all serious adverse events are for 100% monitored. 
§8.1.3. Biomarker sample retention time specified (limited to 5 yrs). 
 
6. Substantial 
amendment 
for Belgium 
CIP v 5.1 
dated 31 May 
2018 with 
amendment v 
5.2 BE dated  
December 
2018 
Jaak Minten 
Title: the title was adjusted to include the underlying disease of ACLF, i.e. 
“alcohol related cirrhosis”. 
7Substantial 
amendment. 
CIP v 6.0 
All countries 
Jaak Minten 
Version 6.0 attempts to make the CIP uniform for all countries where the study 
is executed. It includes the modifications that are addressed in  version 5.1 (for 
countries Romania, Austria, Belgium and Denmark – listed above) and in 
addition: 
- 
Implementation of the DIALIVE treatment recommendations as 
specified by the DSMB following their safety review of 3rd July 2018 
- 
Implementation of more clarification and specification for the 
appropriate selection criteria of ACLF patients based on 1, 2 or 3 
organs failing (grade 1, 2 and grade 3a) 
- 
Implementation of the need to obtain more clinical evidence of the 
treatment aspects of the DIALIVE dialisys as recommended by the 
investigators / DSMB and by increasing the number of observations, 
but without jeopardizing the safety review as established by the 
DSMB charter 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 86 of 88 
These changes resulted in the specific modifications of following elements: 
Title: includes reference to “alcoholic cirrhosis”. 
Summary: 
- 
Target patient population is adjusted to include AKI 1b, ACLF 3a and 
patients with sole high bilirubine levels 
- 
 includes in/exclusion criteria, omitted section of Definitions. 
- 
Timing and frequency of biomarker sampling adjusted to increase 
accuracy of parameter changes induced by treatment 
- 
Added 3 month follow up for patients of cohort 4-5 to assess survival 
- 
Added clnical benefit endpoints on clinical and economical aspects. 
- 
Adjusted statistical analysis section towards ‘unblinded’ analysis and 
interim data extractions to comply with ALIVER European research 
program 
- 
Added footnote ‘6’ to guide investigators during screening 
- 
Referenced the national legislation on GDPR and vulnerable patient 
population. 
Table of contents is corrected. 
List of abbreviations: list completed with additional abbreviations. 
§2.2. Included section on Definitions (from previous Summary): screen failures 
and use of corticosteroids is clarified; ‘nuts and bolts’ of DIALIVE treatment 
section added; adjusted treatment cycle to 3 sessions of 8-10 hrs. 
§2.4. Corrected Figure 1 to specify that DIALIVE is sub-part of total 
extracorporeal circulation circuit. 
§ 2.6. Moved description to §2.2. Definition. 
§ 2.7. and §2.8. Literature section is updated to include info on CANONIC 
study, on ACLF treatment and referring to recent literature, providing 
additional rationale for EAA analysis and endotoxin removal. 
§3.2.Risk of hypotension added; completed mitigation action in case of 
misuse. 
§3.5. Specification added that outcome of review by TMG & DSMB is 
implemented to mitigate additional observed risks. 
§ 4.1 Adjusted primary objective towards the appropriate target population. 
Reworded the secondary objective. 
§ 4.2. Elaborated on the underlying reason for conducting the study, keeping 
the hypothesis as specified. 
§5. Specified that DIALIVE treatment is to be done in ICU or HDU environment 
with adequate monitoring capabilities. 
§6.1 and 6.1.7 Sample size adjusted from 24 to 30. 
§6.1.2 & 6.1.3. Formulated end-points more precisely. 
§6.1.3. Adjusted biomarker sampling to include D2 (DIA) and D3 (SoC), and 
start and end of each dialysis session; added D90 follow up; added clnical and 
economical outcome endpoints. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 87 of 88 
§ 6.1.6. Added ‘luminometer’ as sponsor’s property. 
§6.1.7. Adjusted sample size from 24 to 30. Added dropout rate of 17% and 28 
days FU for patients dropping out early. 
§6.2. specified use of IWRS and 5 instead of 4 cohorts of patients to reflect 
new sample size. 
§6.3.1. Inclusion criteria. Inclusion of ACLF3a, AKI 1b and sole severe liver 
failure patients.  Specified “consultee” or “legal representative” as defined by 
national/local legislation. Defined better patients under corticosteroids and 
omitted ‘uncontrolled infected’ patients (as is exclusion criterion). 
§6.3.2. Exclusion criteria. Specified better “haemodynamical instability”, 
“respiratory organ failure”, added “ACLF 3b”, and “INR > 3 as exclusion 
criteria. 
§6.3.3. Added/modified rules of therapy discontinuation and study stop. 
§6.3.4. Removed definition on start time of DIALIVE treatment. 
§6.3.5. Adjusted study duration. 
§6.3.6. Adjusted duration of patient participation in study. 
§6.3.7. Adjusted sample size of 24 to 30. 
§6.3.8. Adjusted study duration. 
§6.4. Procedures.Implemented schemes to illustrate the study design, 
adjusted scheme on different study cohorts, adjusted tables to reflect actions 
on D3 and D90 for SoC and D2/3 and D90 for DIALIVE patients, and added 
action to be implemented in DIALIVE patients on D1-10 per recommendations 
of DSMB. Removed irrelevant measures. 
§6.5.a. Added that modifications requested by EC/CA will be implemented per 
local/national regulations, and that GDPR is adhered too. 
§7. Specfied the unblinded nature of statistical safety analysis and the need 
for interim data extractions per the ALIVER program requirements from the 
EU. 
§13. Adjusted the Informed Consent Procedure to comply with multi-national 
and local regulatory/ethical considerations to  allow or disapprove inclusion of 
patients  who have reduced capacity or are unconscious, with or without 
additional consent from a consultee, legal representative, next of kin or other 
appointed person. Consent must be obtained per local/national regulations 
and consent remains valid until study completion, withdrawal or exclusion. 
§14.6 Added information on risks observed during dialysis in patients from the 
first 2 cohorts: hypotension, albumin depletion and anemia. Added reference 
to §3.2 with known risks associated with extracorporeal circulations. 
§15. Added paragraph on vulnerable unconscious patients: local and national 
regulations must be complied with prior allowing inclusion of an unconscious 
patient. 
§18. Adjusted version and date of signature page. 
§19. Adjusted bibliography to reflect current references. 

Clinical Investigation Plan 
CIP YAQ-002 
Version: 7.0  10 October 2019  
 
 
 (Yaqrit Ltd Confidential, Not For Release) 
p. 88 of 88 
Appendix 1: Adjusted table with ACLF definitions, provided more complete 
reference information. 
Appendix 2: Incerted definitions of AKI criteria and Lille score. 
Appendix 3-4: provided more complete references for MELD score and West 
Haven criteria. 
Appendix 6: added specific AE-reporting requirements for the countries AU, 
RO, BE, DK. 
Appendix 7: Added summary of DSMB outcome review meeting after 1st  and 
2nd cohort of patients. 
Appendix 8: added illustrations of clinical procedures to apply treatlment and 
perform blood/uring/biomarker sampling correctly. 
Appendix 9: updated table with current changes. 
 
 
 
8.Substantial 
amendment 
(all countries) 
Version 7.0 
10 Oct 2019 
§2.2. Definition of first dialysis session on DAY 0 is further clarified. 
§2.2. Timing of effluent sampling is specified to be between 8-10 hrs instead of 
8-12 hrs. 
§5.4. Added weight/height measurements on Day 2 and Day 3 of study 
schedule of the DIALIVe-arm 
§5.4. Removed the note under graph of study schedule as redundant. 
§ 7. 1.1. Added paragraph on how to avoide confusion when ‘day 1 of 
treatment’ falls on DAY 0 of the study schedule. 
§12. Made lay-out changes to have correct numbering of paragraphs. 
§15. Added section on the assignment of legal representative.