Clinical Trials Register

Summary
EudraCT Number:	2021-003273-66
Sponsor's Protocol Code Number:	ENX-CL-02-002
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-06-07
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2021-003273-66

A.3

Full title of the trial

A Phase 2, Multi-Center, Randomized, Placebo-Controlled, Dose-Finding Study Evaluating Efficacy, Safety and Tolerability of Different Doses and Regimens of Allocetra-OTS for the Treatment of Organ Failure in Adult Sepsis Patients

Étude de phase 2, multicentrique, randomisée, contrôlée par placebo, de détermination de la dose évaluant l'efficacité, la sécurité d'emploi et la tolérance de différentes doses et schémas posologiques d'Allocetra-OTS
pour le traitement de l'insuffisance organique chez des patients adultes atteints de sepsis

Een fase 2, gerandomiseerd, placebogecontroleerd, dosisbepalingsstudie in meerdere centra ter beoordeling van de werkzaamheid, veiligheid en verdraagbaarheid van verschillende doses en regimes van allocetra-OTS voor de behandeling van orgaanfalen bij volwassen sepsispatiënten

A.3.1

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

Phase 2 study, conducted in few medical centers, patients will be allocated randomly to receive active drug or placebo. The study will evaluate the efficacy and safety of different doses of the drug in patients with organ failure due to sepsis condition.

Étude de phase 2, menée dans certains centres médicaux, les patients seront répartis au hasard pour recevoir le médicament actif ou un placebo. L'étude évaluera l'efficacité et l'innocuité de différentes doses du médicament chez des patients souffrant de défaillance d'organe dû à un sepsis.

A.4.1

Sponsor's protocol code number

ENX-CL-02-002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04612413

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	Enlivex Therapeutics R&D Ltd.
B.1.3.4	Country	Israel
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	Enlivex Therapeutics R&D Ltd.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Accelsiors CRO and Consultancy Services Ltd.
B.5.2	Functional name of contact point	Regulatory unit
B.5.3	Address:
B.5.3.1	Street Address	103 Háros Str
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1222
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+3612990091
B.5.5	Fax number	+3812165 03 380
B.5.6	E-mail	regulatory@accelsiors.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	Allocetra-OTS cells
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Allogeneic peripheral blood mononuclear cells induced to apoptotic state
D.3.9.2	Current sponsor code	Allocetra-OTS
D.3.9.3	Other descriptive name	Allogeneic peripheral blood mononuclear cells induced to apoptotic state
D.3.9.4	EV Substance Code	SUB199514
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2500000000
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	Yes
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
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

Sepsis

E.1.1.1

Medical condition in easily understood language

Sepsis is a life-threatening, medical emergency caused by an infection in the blood stream that can affect different organs.

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10040047
E.1.2	Term	Sepsis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

to compare the safety and efficacy of different doses and regimens of Allocetra-OTS to that of Placebo in the treatment of organ failure in adult sepsis patients

E.2.2

Secondary objectives of the trial

To compare other clinical manifestations of different doses and regimens of Allocetra-OTS associated with organ failure in sepsis patients and assess long term safety follow up

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female ≥18 years and ≤90 years of age.
2. Diagnosis of Sepsis meeting Sepsis 3 criteria, defined by the presence of organ dysfunction as identified by a total SOFA score ≥5 points above pre-admission (pre-illness) SOFA. Patients in septic shock with SOFA score up to 13 may be included.
3. Initiation of antibiotics treatment for the suspected infection causing sepsis.
4. Sepsis due to infection in at least one of the below organs:
4.1. Suspected, presumed or documented Community-Acquired Pneumonia (CAP).
4.2 Urinary tract infection/urosepsis
4.3. Acute cholecystitis
4.4. Acute cholangitis
4.5. Other Intra-Abdominal Infections (IAI)
4.6. Skin or soft tissue infection
5. Adequate infectious source control if necessary as determined by the investigator, or source control is scheduled to be completed prior to IP administration. In case source control will not be completed prior to IP administration, Sponsor pre-approval is
required for IP administration.
6. Signed written informed consent by the patient, or consent obtained according to local regulations if the patient is unable to provide informed consent.
7. Women of childbearing potential and all men must agree to use 2 methods of an adequate contraception: One barrier method (e.g. diaphragm, or condom or sponge, each of which are to be combined with a spermicide) and one hormonal method (e.g. oral, transdermal patch, implanted contraceptives or intrauterine device) prior to study entry and for the duration of study participation through 4 weeks following IP administration. Subjects that are highly unlikely to conceive (e.g. surgically sterile, postmenopausal, or not heterosexually active) are exempt.
Non-childbearing potential is defined as (by other than medical reasons):
≥45 years of age and has not had menses for over 2 years.
<45 years of age and amenorrhoeic for > 2 years without a hysterectomy and oophorectomy and a Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon pre-trial (screening) evaluation.
For women, post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation and vasectomy for men at least 6 weeks prior to screening. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.

E.4

Principal exclusion criteria

1. Sepsis due to infection other than lung infection, UTI, IAI, skin/soft tissue infection or sepsis patients where site of infection is unclear or unknown.
2. Patients on chronic dialysis.
3. Patients with acute pancreatitis (serum amylase > 3 ULN with clinical abdominal pain).
4. Moribund patients at a high risk of death within 48 hours of treatment.
5. Weight <50 kg or >120 kg or Body Mass Index (BMI) >40 kg/m2.
6. SOFA score ≥ 14 at screening.
7. Patients with risk of nosocomial infection due to hospitalization or surgery within 30 days prior to diagnosis of sepsis.
8. A known malignancy that is progressing or has required active treatment within the past 3 months.
9. Patient with end-stage disease (unrelated to sepsis) defined as patients who prior to the current hospitalization are expected to live < 6 months (as assessed by the study physician).
10. Known active symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or chronic viral infections, such as, hepatitis B virus (HBV) or hepatitis C virus (HCV), human immunodeficiency virus (HIV) or other chronic infections.
11. Chronic respiratory disease requiring home oxygen therapy on a regular basis for > 6 h/day.
12. Known active upper gastrointestinal (GI) tract ulceration or hepatic dysfunction including but not limited to biopsy-proven cirrhosis; End-stage cirrhosis (Child Pugh Class C); portal hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or prior episodes of hepatic failure, encephalopathy, or coma.
13. Known New York Heart Association (NYHA) class IV heart failure or unstable angina, ventricular arrhythmias, acute coronary disease, or myocardial infarction within six months prior to diagnosis of sepsis.
14. Known immunocompromised state or medications known to be immunosuppressive as follows:
• Hydrocortisone (for the treatment of septic shock) > 300 mg /d;
• Cyclophosphamide in the last 60 days;
• Chemotherapy in the last 3 months;
• Anti-tumor necrosis factor (TNF) agents, interleukin (IL)-1 receptor antagonists (IL-1-RA), CTLA-4 fusion proteins, anti-CD20, anti-CD52, anti-IL-2, anti-IL-6R, anti-IL-12/23 or integrin inhibitor agents within the last 8 weeks.
15. Organ allograft or previous history of stem cell transplantation.
16. Women who are pregnant or breastfeeding. Child-bearing potential females must have a negative serum ß-hCG or hCG blood test at screening. Pregnancy testing is not required for postmenopausal or surgically sterilized women.
17. Known hypersensitivity to any component of study treatment or excipients.
18. Participation in an interventional investigational study within 30 days prior to diagnosis of sepsis.
19. Likely to be non-compliant or uncooperative during the study (e.g. substance abuse such as drug or alcohol abuse, uncontrolled psychiatric disorder or any chronic condition that may interfere with study conduct).

E.5 End points

E.5.1

Primary end point(s)

Efficacy: Change from baseline in SOFA score throughout 28 days.
Safety: Number and severity of AEs and Serious Adverse Events (SAEs) throughout 28 days follow up period.

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days

E.5.2

Secondary end point(s)

Ventilator-free days over 28 days
Vasopressor-free days over 28 days
All-cause mortality at Day 28 following first dose
Days without renal replacement therapy (dialysis) (evaluation up to 12 months)
Time in ICU and time in hospital (evaluation up to 12 months)
Number of days with creatinine ≤ Baseline levels +20% (evaluation up to 12 months)
Changes from baseline in C-reactive protein (CRP) levels (evaluation up to 12 months)
Detection of autoimmune and human leukocyte antigen (HLA) antibodies (evaluation up to 12 months)
Number and severity of AEs and SAEs throughout 12 months follow-up period (evaluation up to 12 months)

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days and throughout 12 months follow-up period

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

Yes

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

Yes

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

Israel

Belgium

France

Greece

Spain

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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)

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

Some subjects may be in a medical condition where they cannot give consent. Legal rep. may provide consent on their behalf, or a delayed consenting will be performed, in a matter that fully complies with local competent authority requirements.

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

115

F.4.2.2

In the whole clinical trial

160

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)

No additional treatment or follow up is planned following study end.

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

2022-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-10-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-12-16

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