Clinical Trials Register

Summary
EudraCT Number:	2021-002617-33
Sponsor's Protocol Code Number:	VS01-IIa-01
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-08-30
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-002617-33

A.3

Full title of the trial

A Phase 2a, open-label, randomized, controlled, multi-center, proof of concept study, to assess the efficacy, safety and tolerability of VS-01 on top of standard of care, compared to standard of care alone, in adult patients with acute-on-chronic liver failure (ACLF) grades 1 and 2 and ascites

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to evaluate a new medicinal product VS-01 in patients with
an acute episode on top of a chronic liver disease (called acute-on-chronic
liver failure) who experience accumulation of fluid in the abdominal cavity
(called ascites) as well as intellectual, behavioral decay and physical
decay.

A.3.2

Name or abbreviated title of the trial where available

UNVEIL

A.4.1

Sponsor's protocol code number

VS01-IIa-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Versantis AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Versantis AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Versantis AG
B.5.2	Functional name of contact point	Head of Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Technoparkstrasse 1,
B.5.3.2	Town/ city	Zuerich
B.5.3.3	Post code	8005
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41792329073
B.5.5	Fax number	+4144 500 8829
B.5.6	E-mail	clinical@versantis.ch

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1675
D.3 Description of the IMP
D.3.2	Product code	VS-01
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Citric Acid
D.3.9.1	CAS number	77-92-9
D.3.9.3	Other descriptive name	CITRIC ACID, ANHYDROUS PH. EUR.
D.3.9.4	EV Substance Code	SUB171902
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.54
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute-on-chronic liver failure (ACLF) is characterized by hepatic and extrahepatic organ dysfunction and/or failure and highly activated systemic inflammation. It leads to an accumulation of different metabolites, interalias ammonia, which cannot be metabolized. Hyperammonemia leads to Hepatic Encephalopathy (HE). ACLF is a major cause of death in cirrhosis, with an approximately 50% mortality rate. The selected patient population is ACLF grade 1 and 2 patients with ascites.

E.1.1.1

Medical condition in easily understood language

Acute-on-chronic liver failure is an acute complication of a chronic liver disease affecting other organs (e.g., kidney & brain) and leading to
physical, intellectual and behavioral decay or death.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	24.0
E.1.2	Level	PT
E.1.2	Classification code	10077305
E.1.2	Term	Acute on chronic liver failure
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of VS-01 administered intraperitoneally (i.p.)
daily over 4 days on top of standard of care (SOC) vs. SOC alone in
patients with ACLF grades 1 and 2 as measured by Chronic Liver Failure
Consortium Acute on-Chronic Liver Failure (CLIF-C ACLF) score at Day 7

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of VS-01 administered i.p. daily over 4 days on
top of SOC vs. SOC alone in patients with ACLF grades 1 and 2 with
respect to:
a. Time to death through/at Days 28 and 90;
b. ACLF grade change and time to resolution of ACLF;
c. 28-day and 90-day mortality;
d. Transplant-free survival;
- To characterize the safety and tolerability of VS-01 in ACLF patients
following i.p. administration of VS-01

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Cirrhotic patients diagnosed by standard clinical criteria, imaging
findings and/or histology with any underlying etiology;
2. Cirrhotic patients with ACLF Grade 1 or 2 (according to EASL-CLIF
criteria as described in the EASL-Clinical Practice Guideline on decompensated liver cirrhosis (EASL Clinical Practice Guidelines, 2018); organ failures will be calculated based on the CLIF-C OF score) triggered by any acute insult other than those listed in the exclusion criteria:
ACLF grade 1 patients meeting one of the following:
a. Single kidney failure (serum creatinine ≥ 2 mg/dL) without RRT +/-
liver, cerebral, coagulation, circulation or respiratory dysfunction;
b. Liver failure (serum bilirubin ≥ 12.0 mg/dL) with either kidney
dysfunction (serum creatinine ≥ 1.5 – < 2.0 mg/dL) and/or HE grade 1
or 2;
c. Coagulation failure (International Normalized Ratio [INR] ≥ 2.5 - ≤ 3.0) with either kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL) and/or HE grade 1 or 2;
d. Circulatory failure (dopamine ≤15 µg/kg/min, or epinephrine ≤ 0.1
µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min) with either kidney
dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL) and/or HE grade 1
or 2;
e. Brain failure (HE West Haven grade 3 or 4) + kidney dysfunction
(serum creatinine ≥ 1.5 - < 2.0 mg/dL).
a. Single kidney failure (serum creatinine ≥ 2 mg/dL) without RRT +/liver, cerebral, coagulation, circulation or respiratory dysfunction;
b. Liver failure (serum bilirubin ≥ 12.0 mg/dL) with either kidney
dysfunction (serum creatinine ≥ 1.5 – < 2.0 mg/dL) and/or HE grade
1 or 2;
c. Coagulation failure (International Normalized Ratio [INR] ≥ 2.5 - ≤
3.0) with either kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0
mg/dL) and/or HE grade 1 or 2;
d. Circulatory failure (dopamine ≤15 µg/kg/min, or epinephrine ≤
0.1 µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min) with either
kidney dysfunction (serum creatinine ≥ 1.5 - < 2.0 mg/dL) and/or HE grade 1 or 2;
e. Brain failure (HE West Haven grade 3 or 4) + kidney
dysfunction (serum creatinine ≥ 1.5 - < 2.0
mg/dL).
ACLF grade 2 patients meeting one of the following:
f. Kidney failure (serum creatinine ≥ 2 mg/dL) without RRT +
brain failure (HE West Haven grade 3 or 4);
g. Liver failure (serum bilirubin ≥ 12.0 mg/dL) + brain failure (HE
West Haven grade 3 or 4);
h. Kidney failure (serum creatinine ≥ 2 mg/dL) without RRT +
liver failure (serum bilirubin ≥ 12.0 mg/dL);
i. Coagulation failure (INR ≥ 2.5 - ≤3.0) + Brain failure (HE West Haven
grade 3 or 4);
j. Circulatory failure (dopamine ≤15 µg/kg/min, or epinephrine ≤ 0.1
µg/kg/min, or norepinephrine ≤ 0.1 µg/kg/min) with either kidney
failure, liver failure, or brain failure.
3. Onset of ACLF not more than 96 h before SCR;
4. Presence of ascites requiring paracentesis;
5. Patients with body mass index (BMI) < 35 (calculated on dry body
weight);
6. Men and women ≥ 18 and ≤ 64 years of age on the day of signing
Patient Informed Consent Document (PICD);
7. Informed consent:
a. Ability to understand the PICD and comply with the protocol and
sign the PICD or a legal representative can sign PICD. If the patients
are temporarily unable to consent and are considered in an
emergency situation, they will be included according to local law and EC requirements and need to consent as soon as they are able again to do so themselves or by legal representative who can sign the PICD
on behalf of the patient. If legal representative consented on behalf of the patient, consent must also be obtained from the patient for continued participation as soon as it is possible;
b. Signed and dated PICD obtained prior to performing any study procedure, including SCR except for patients who are considered in an emergency situation.

E.4

Principal exclusion criteria

1. Patients with acute or sub-acute liver failure without underlying
cirrhosis;
2. Presence of the following organ(s) failure(s) as per the EASL definitions and CLIF-C OF score:
a. Respiratory failure as defined by Partial pressure of oxygen (PaO2)/
Fraction of inspired oxygen (FiO2) ≤ 200, or oxygen saturation
(SpO2)/FiO2 ≤ 214 or mechanical ventilation;
b. Coagulation failure with an INR > 3.0 or platelet count ≤ 20 x 09/L;
c. Severe cardiovascular failure requiring the use of vasopressors
(dopamine >15 µg/kg/min, or epinephrine > 0.1 µg/kg/min, or
norepinephrine > 0.1 µg/kg/min). It should be clarified that the use of terlipressin or low-dose norepinephrine in case of hepatorenal syndrome (HRS) is not an exclusion criterion;
3. ACLF grade 3: Presence of three or more organ failures as per
EASLCLIF criteria as described in the EASL-Clinical Practice Guideline on decompensated liver cirrhosis; organ failures will be calculated based on CLIF-C OF score);
4. Presence of spontaneous or secondary bacterial peritonitis:
a. presence of neutrophils in a normally sterile body fluid (i.e., neutrophil counts > 250/mm3 in ascitic fluid);
5. Presence of spontaneous bacterial pleural empyema:
a. In case of pleural effusion, positive pleural fluid culture and increased neutrophil count of > 250/mm3 or negative pleural fluid culture and a neutrophil count of 3 > 500/mm in the absence of pneumonia;
6. Patients with medical history of spontaneous bacterial peritonitis
over the past 4 weeks;
7. History of active tuberculosis, or latent tuberculosis requiring
treatment;
8. Presence of uncontrolled and severe infection at SCR or BL (patients may be enrolled provided antibiotics have been administered for at least 24 h before SCR or 48 h before BL with an appropriate response prior to randomization):
a. Infections with hemodynamic instability or septic shock, such as but not limited to UTI, pneumonia, and skin/soft tissue infection;
b. Acute obstructive cholangitis in the presence of cholestasis,
compatible symptoms (right upper quadrant pain and jaundice) and
radiological data of biliary obstruction with hemodynamic instability or septic shock;
c. History of colonization (> 2 sites) or known invasive fungal infection;
d. Patients with sepsis or septic shock of unknown source;
9. Patients with epilepsy;
10. Patients with medical history of gastro-intestinal bleeding over the past 2 weeks, acute bleeding or bleeding upon paracentesis at SCR or BL;
11. Contraindication for paracentesis according to the EASL Clinical
Practice Guidelines 2018, AASLD guideline on the treatment of ascites, spontaneous bacterial peritonitis and HRS-AKI for the management of patients with decompensated cirrhosis;
12. Coagulation disorders such as disseminated intravascular
coagulation (DIC), hemophilia, congenital or acquired Von Willebrand
disease or platelet function defects;
13. TIPS procedure or any major abdominal surgery having occurred in the past 4 weeks prior to SCR;
14. Potential or known hypersensitivity to liposomes;
15. Potential or known risk factors for allergic/anaphylactoid like
reactions (e.g., mastocytosis/elevated basal tryptase) or multiple
hypersensitivities;
16. Patients with known PPHT and hepato-pulmonary syndrome;
17. Patients after organ transplantation receiving immunosuppressive
medication;
18. Any severe disease considered to be potentially detrimental at the discretion of the PI. This includes but is not limited to hepatocellular carcinoma (HCC) outside Milan criteria, cholangiocarcinoma, extrahepatic cancer over the past 2 years, individuals formerly injecting drugs on substitution therapy;
19. Need for RRT or any extracorporeal liver support device (e.g., MARS ® , Prometheus® , Plasmapheresis);
20. Alfapump ® in place to manage ascites;
21. ACLF due to severe alcoholic steatohepatitis in patients with ongoing excessive alcohol intake with a Maddrey Score ≥ 32 requiring steroid treatment (Score formula: Discriminant Function=4.6 * [Patient's Prothrombin time (sec) - Control Prothrombin time (sec)] + total bilirubin (mg/dl)
22. ACLF due to acute viral hepatitis A, B, B+D, C or E requiring antiviral treatment;
23. ACLF due to autoimmune hepatitis (AIH) requiring high-dose steroid treatment;
24. Pregnancy and lactation;
25. Women of child-bearing potential who are not willing to use
adequate contraception;
26. Patients who participate in another clinical trial at the time of SCR or within 4 weeks prior to SCR.

E.5 End points

E.5.1

Primary end point(s)

CLIF-C ACLF score at Day 7

E.5.1.1

Timepoint(s) of evaluation of this end point

CLIF-C ACLF scores on Day 1 pre-dose and Day 7.

E.5.2

Secondary end point(s)

1. Outcome:
a) Time to death through/at Days 28 and 90;
b) Change in ACLF grade through/at Days 7 and 28:
- Time to and rate of ACLF resolution;
-Time to and rate of ≥ one ACLF grade regression;
c) 28-day and 90-day mortality;
d) Transplant-free survival through/at Days 28 and 90;
2. Safety
a) Incidence rate, severity, and relationship to VS-01 of adverse drug
reactions and serious adverse drug reactions.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Outcome:
- Time to death: through/at Days 28 and 90;
- Change in ACLF grade: through/at Days 7 and 28
- 28-day and 90-day mortality;
- Transplant-free survival: through/at Days 28 and 90
2. Safety
- All AEs will be collected by the Investigator throughout the study
period starting from the date of consent until the EOS visit on Day 90

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Controlled study on top of standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

France

Spain

Germany

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Cirrhotic patients with ACLF grades 1 and 2 are enrolled. Patients with HE Grades 2-3 and require legal rep to give consent. Considering the rapid life-threatening evolution of ACLF they may be in emergency situation.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients participating in VS01-IIa-01 will remain on standard of care during and after the study ends.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-12-02

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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