Clinical Trials Register

Summary
EudraCT Number:	2019-003051-11
Sponsor's Protocol Code Number:	HEP102
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-12-16
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

Latvia - SAM

A.2

EudraCT number

2019-003051-11

A.3

Full title of the trial

Randomized, placebo-controlled, double blind, multi-centre Phase IIb study to evaluate the efficacy and safety of HepaStem in patients with Acute on Chronic Liver Failure (ACLF) - DHELIVER

Randomizēts, ar placebo kontrolēts, dubultmaskēts, daudzcentru 2.b fāzes pētījums HepaStem efektivitātes un drošuma vērtēšanai pacientiem ar hroniskas aknu slimības akūtas dekompensācijas izraisītu orgānu mazspēju (ACLF).

A.3.1

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

This trial will evaluate the safety and efficacy of HepaStem compared to placebo in patients with a cirrhotic liver condition called Acute on Chronic Liver Failure (ACLF). The study will be performed in multiple centers and in a double-blinded manner, meaning neither the patients nor the treating physicians know who is on placebo or the study drug.

Šajā pētījumā vērtēs HepaStem drošumu un efektivitāti salīdzinājumā ar placebo pacientiem ar cirotisku aknu slimību, ko sauc par hroniskas aknu slimības akūtas dekompensācijas izraisītu orgānu mazspēju (Acute on Chronic Liver Failure; ACLF). Pētījums tiks veikts vairākos centros un dubultmaskētā veidā, kas nozīmē, ka ne pacienti, ne ārstējošie ārsti nezinās, kurš saņem placebo, bet kurš pētāmās zāles.

A.3.2

Name or abbreviated title of the trial where available

HEP102 - DHELIVER

A.4.1

Sponsor's protocol code number

HEP102

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	Promethera Therapeutics
B.1.3.4	Country	Belgium
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	Promethera Therapeutics
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Promethera Therapeutics
B.5.2	Functional name of contact point	Welcome desk
B.5.3	Address:
B.5.3.1	Street Address	Rue Granbonpré, 11
B.5.3.2	Town/ city	Mont-Saint-Guibert
B.5.3.3	Post code	B-1435
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3210394300
B.5.5	Fax number	+3210394301
B.5.6	E-mail	Regulatory@promethera.com

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	HepaStem
D.3.2	Product code	HALPC
D.3.4	Pharmaceutical form	Dispersion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	HALPC
D.3.9.3	Other descriptive name	Human allogenic liver-derived progenitor cells
D.3.9.4	EV Substance Code	SUB199771
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
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	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Tissue engineered product (EMA/CAT/391889/2016) in the treatment of fibroinflammatory liver diseases.
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cirrhotic patients who are hospitalized for Acute on chronic liver failure (ACLF), ACLF combines an acute deterioration of liver function in an individual with pre-existing chronic liver disease and extrahepatic organ failures characterized by high short-term mortality (30-40% at 28days). The development of ACLF is associated with exacerbated systemic inflammation that may indeed cause organ failures.

E.1.1.1

Medical condition in easily understood language

ACLF is an acute deterioration of liver function in an individual with cirrhosis and organ failures with systemic inflammation and high short term mortality.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10008954
E.1.2	Term	Chronic liver disease and cirrhosis
E.1.2	System Organ Class	100000004871

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10049844
E.1.2	Term	Acute liver failure
E.1.2	System Organ Class	100000004871

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

The primary objective is to demonstrate the efficacy of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg (7-day interval) on the overall survival proportion 90 days post-first infusion.

E.2.2

Secondary objectives of the trial

1. Safety of 2 infusions (i.v.) of HepaStem at 1.0 million of cells/kg (7-day interval).
2. Efficacy on the transplant-free survival proportion 90 days post-first infusion.
3. Efficacy on the overall survival, transplant-free survival, and post-transplant survival proportion up to 1-year post-infusion.
4. Efficacy on the liver function parameters, such as the MELD score and bilirubin levels, up to 1-year post-infusion.
5. Efficacy on the inflammatory parameters, up to 1-year post-infusion.
6. Efficacy on the transplant proportion, the duration of hospitalization in ICU, the duration of the overall hospitalization, the number of
rehospitalization for ACLF, liver function, Quality of Live (QoL), and Investigator's and patient's opinion on the IMP.
Exploratory: Efficacy on the survival proportion 90 days post-first infusion based on ACLF grading defined by IHDST NACSELD ACLF criteria.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must fulfil all of the following criteria in order to be eligible for trial enrolment:
1. Adult aged 18 years and above.
2. Initial diagnostic of ACLF, at the investigational site, maximum 3 days before signature of the ICF.
3. Patient with Acute on Chronic Liver Failure Grade 1 or 2 according to the CLIF definition*.
4. Bilirubin value ≥5 mg/dL.
5. Signed Informed Consent.
N.B: In case of hepatic encephalopathy, if the patient is not able to fully understand the study based on the investigator's judgment, the Informed Consent must be signed by a patient's legal or authorized representative according to local regulation, and by the patient, if possible, after encephalopathy improvement.
* ACLF grading is based on the number of organ failure as defined per the CLIF-OF score (Arroyo et al. 2015); http://www.efclif.com/scientific-activity/score-calculators/clif-c-aclf

E.4

Principal exclusion criteria

Patients presenting with any of the following will not be included in the study:
1. ACLF grade 3.
2. Active uncontrolled bleeding or patient with high risk of short term bleeding up to investigator's judgment.
3. Model for End-Stage Liver Disease (MELD) score >35.
4. Cerebrovascular, myocardial, limb arterial thrombotic event, or history for both thrombotic and hemorrhagic cerebrovascular events within 12 months prior to the screening and not considered stabilized by the investigator.
5. Mechanical ventilation due to respiratory failure, except for hepatic encephalopathy.
6. Inability to maintain mean BP >60 despite use of vasopressors.
7. Patients receiving immunosuppressive drugs, except glucocorticoids.
8. Thrombosis of portal vein.
9. Underlying cirrhosis due to biliary disease (primary sclerosing
cholangitis, primary biliary cholangitis…).
10. Underlying cirrhosis due to autoimmune hepatitis.
11. Coagulation disturbances defined as (Drolz et al. 2016; Nadim et al. 2016):
a. fibrinogen < 80 mg/dL
b. platelets < 50 x 10³/mm³
12. Uncontrolled bacterial infection upon judgment of the investigator.
13. Proven or probable invasive aspergillosis (Gustot et al. 2014).
14. Major invasive procedure within 2 weeks before the infusion. These are open surgeries (the proper healing of the scar should be verified by the investigator). N.B.: Liver biopsy (trans jugular or percutaneous), paracentesis, TIPS are not considered as a major invasive procedure.
15. Previous organ transplantation and/or treatment with cells.
16. Previous hepatectomy.
17. Severe pulmonary arterial hypertension defined as mean pulmonary arterial pressure (MPAP) ≥45 mmHg.
18. Hepatopulmonary syndrome.
19. Known or suspected hypersensitivity or allergy to any of the components of the HepaStem Diluent (human albumin, heparin sodium and sodium bicarbonate, DMSO), bovine serum, or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions.
20. Patients with active cancer or history of cancer unless adequately treated and/or in complete remission for five or more years.
21. Hepatocellular carcinoma.
22. On haemodialysis due to chronic kidney disease.
23. Known infection with human immunodeficiency virus (HIV).
24. Pregnancy (negative β-HCG test required) and nursing women, or women with childbearing potential who decline to use highly effective contraception methods during the study. Authorized methods of contraception are listed in Section 10.14.2.
25. Participation in any other interventional study within the last 4 weeks, or participation and/or under follow-up in another clinical trial.
26. Any significant medical or social condition or disability that, in the Investigator's opinion, may warrant a specific treatment, or may interfere with the patient's optimal participation or compliance with the study procedures.
27. Patients who are employees of the Sponsor or investigator, or otherwise dependent on them; Patients committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
28. Accepted as High Urgency status patient by the organ allocation system (ex: Eurotransplant or equivalent)
Depending on the reason of screening failures, a patient could be retested again (Visit 1 re-test) after consultation with the sponsor.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival proportion at 90 days post first infusion.

E.5.1.1

Timepoint(s) of evaluation of this end point

90 days post first infusion.

E.5.2

Secondary end point(s)

• Overall Survival proportion up to 1-year post first infusion.
• Liver Transplant-free survival proportion at 90 days post first infusion.
• Liver Transplant-free survival proportion up to 1-year post first infusion.
• Liver transplantation-free proportion at 90 days post first infusion.
• Liver transplantation-free proportion up to 1-year post infusion.
• Post-liver transplant survival proportion up to 1-year post infusion.
• Overall survival time.
• Liver transplant-free time.
• Liver transplant-free survival time.
• West Haven, CLIF-OF, ACLF grade, CLIF-C ACLF score, CLIF-C AD, MELD score, Child Pugh score up to 1-year post first infusion.
• Quantitative measurement of liver function parameters (bilirubin, AST, ALT, GGT, INR, albumin, ALP) up to 1 Year.
• Quantitative measurement of kidney function parameters (creatinine, urea/BUN).
• Quantitative measurement of inflammatory parameters (CRP, IL6, IL1β, IL8).
• Quantitative measurement of leukocytes and neutrophils.
• Change in QoL questionnaires (EQ-5D-5L and SF-36 QoL) up to 1 year.
• The duration of hospitalization in ICU, the duration of the overall hospitalization, the number of rehospitalization for ACLF, and Investigator’s and patient’s opinion on the IMP.

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 1 year post first infusion.

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

E.6.7

Pharmacodynamic

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

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

Belarus

Georgia

North Macedonia

Serbia

Turkey

Austria

Belgium

Bulgaria

Croatia

Denmark

Estonia

France

Germany

Italy

Latvia

Lithuania

Netherlands

Poland

Portugal

Romania

Slovakia

Slovenia

Spain

United Kingdom

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

LVLP

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 months

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:

290

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

In case of hepatic encephalopathy, if the patient is not able to fully understand the study, the ICF must be signed by a patient's legal or authorized representative according to local regulation, and by the patient after improvement if possible.

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

297

F.4.2.2

In the whole clinical trial

363

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)

At Month 12 study visit, patients who received at least 1 infusion of HepaStem will be invited to be included in the Patient Long term follow up registry study PROLONGSTEM.

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

2019-12-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-30

P. End of Trial
P.	End of Trial Status	Ongoing

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