Clinical Trials Register

Summary
EudraCT Number:	2018-002547-29
Sponsor's Protocol Code Number:	ATB-203
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-10-11
Trial results	View 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

2018-002547-29

A.3

Full title of the trial

Phase 2 randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of Reltecimod as compared to placebo in addition to standard of care in patients with sepsis-associated acute kidney injury (SA-AKI)

A.3.1

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

This is a Phase 2 randomized, double-blind study to determine the safety and efficacy of Reltecimod as compared to placebo in patients who have acute kidney injury due to an intra-abddominal infection causing sepsis in which all patients receive usual standard of care treatment for their infection.

A.3.2

Name or abbreviated title of the trial where available

REAKT

A.4.1

Sponsor's protocol code number

ATB-203

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03403751

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	Atox Bio
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	Atox Bio, 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	Centre Hospitalier Universitaire de Limoges
B.5.2	Functional name of contact point	Clinical Trial Operations Manager
B.5.3	Address:
B.5.3.1	Street Address	2 avenue Martin Luther King
B.5.3.2	Town/ city	LIMOGES
B.5.3.3	Post code	87042
B.5.3.4	Country	France
B.5.4	Telephone number	330555058849
B.5.5	Fax number	330555058057
B.5.6	E-mail	marie.leveque@chu-limoges.fr

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	Reltecimod
D.3.2	Product code	AB103
D.3.4	Pharmaceutical form	Powder for solution 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	RELTECIMOD
D.3.9.2	Current sponsor code	AB103
D.3.9.4	EV Substance Code	SUB188659
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	1
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
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 injection/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

Acute kidney injury due to intra-abdominal infection/sepsis

Lésion rénale aiguë due à une infection intra-abdominale / un sepsis

E.1.1.1

Medical condition in easily understood language

Patients who develop severe kidney dysfunction due to infection in the abdomen (for example, perforation of the intestines, complicated appendicitis, diverticulitis, perforated stomach ulcer)

Patients qui développent un dysfonctionnement rénal sévère dû à une infection de l'abdomen (par exemple, perforation de l'intestin, appendicite compliquée, diverticulite, ulcère gastrique perforé)

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

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	10080269
E.1.2	Term	Stage 2 acute kidney injury
E.1.2	System Organ Class	100000004857

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	10080271
E.1.2	Term	Stage 3 acute kidney injury
E.1.2	System Organ Class	100000004857

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	10079983
E.1.2	Term	Complicated intra-abdominal infection
E.1.2	System Organ Class	100000004862

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	10040050
E.1.2	Term	Sepsis NOS
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary Objective:
• To compare the rates of complete recovery (alive, free of dialysis and return of serum creatinine to <150% of reference baseline; equivalent to acute kidney disease (AKD) category 0) at Day 14 between the Reltecimod-treated patients and the placebo-treated patients
• To demonstrate the safety and tolerance of Reltecimod when administered as a single dose of 0.50 mg/kg to patients diagnosed with SA-AKI

E.2.2

Secondary objectives of the trial

• To compare the rates of complete recovery at Day 28 between Reltecimod and placebo-treated patients
• To compare the rates of overall recovery defined as complete recovery or partial recovery at Days 14 and 28, respectively between Reltecimod and placebo-treated patients
• To compare time to complete recovery from AKI between the Reltecimod and placebo-treated patients
• To compare time to overall recovery from AKI between the Reltecimod and placebo-treated patients
• To compare the distributions of acute kidney disease stages at Days 14 and 28, respectively between Reltecimod and placebo-treated patients
• To compare AKI-free days over 14 and 28 days between Reltecimod and placebo-treated patients
• To compare the resolution of organ dysfunction between the Reltecimod and placebo-treated patients over time and at Day 14
(all secondary objectives are detailled in the study protocol)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

2 optional substudies:
- AKI biomarkers substudy
- systemic inflamatory biomarker substudy

E.3

Principal inclusion criteria

1. Age: 18-80 years
2. Has either suspected or confirmed diagnosis of abdominal sepsis requiring treatment with parenteral antibiotics and planned or completed surgical (laparotomy or laparoscopy) or interventional radiologic procedures within 24 hours of evaluation by medical personnel. Recommended surgical or interventional radiologic procedures be performed within 12 hours of evaluation by medical personnel.
• Suspected clinical diagnosis of abdominal infection as evaluated by the attending surgeon including any of the following clinical criteria:
- Abdominal pain and/or tenderness
- Localized or diffuse abdominal wall rigidity
- Mass
- Ileus
AND
- Any of the following radiologic findings
• Free air
• Intraabdominal abscess
• Free peritoneal fluid
• Confirmed diagnosis of abdominal infection by any of the of the following criteria:
- Perforation and/or necrotic bowel with surgical confirmation of peritonitis
- Presence of intraabdominal abscess by surgical confirmation or drainage of purulent fluid from interventional radiologic procedure
3. Planned or current admission to a hospital ward.
4. Initial diagnosis of AKI established either upon presentation to medical care at the study site in those patients with suspected abdominal sepsis or in those patients in whom the initial diagnosis of AKI is established during the 48-hour period from the suspected diagnosis of abdominal sepsis.
AKI Stage 2 or 3 according to the following KDIGO AKI criteria:
• Stage 2 AKI
o Increase in serum creatinine to > 200% (≥ 2.0–fold) from a reference creatinine value (see below) in the absence of primary underlying renal disease
OR
o Urine output < 0.5ml/kg/hr x 12 hours following adequate fluid resuscitation
• Urine output should be calculated using IBW (using the Miller formula)
• Stage 3 AKI
o Increase in serum creatinine to > 300% (≥ 3.0–fold) from a reference creatinine value in the absence of primary underlying renal disease
OR
o Serum creatinine ≥4 mg/dL
OR
o Urine output < 0.3ml/kg/hr x 24 hours or anuria x 12 hours following adequate fluid resuscitation
• Urine output should be calculated using IBW (using the Miller formula)
The reference creatinine value is the serum creatinine value according to the following order:
o Value within 3 months of the hospital admission.
• If single value available, then use the single value for reference
• If two values available, then use average of two values for reference
• If three or more values available, then use the median of the three most recent values for reference
o Value between 3 and 12 months prior to hospital admission
• If single value available, then use the single value for reference
• If two values available, then use average of two values for reference
• If three or more values available, then use the median of the three most recent values for reference
o At hospital admission
• Patients without a reference creatinine value would also be considered to have Stage 2 or 3 AKI if they have a serum creatinine ≥200% (>2.0-fold) the normal creatinine value for age, race, and gender and a renal ultrasound or computed tomography showing normal kidney size within the past 90 days. Normal kidney size is defined as:
o Renal Ultrasound
• <60 years if either kidney >10 cm length
• >60 years if either kidney >9.5 cm length
o Computed Tomographic Scan
• If either kidney is >9 cm length
5. Study medication must be administered within 6 hours of confirmation of onset of Stage 2 or 3 AKI as established at the study site, under the following criteria:
• After the decision is made by the attending surgeon at the study site for a surgical or interventional radiology procedure for the abdominal infection
OR
• After confirmed diagnosis of abdominal infection has been established by a surgical or interventional radiology procedure
6. Females of childbearing potential, she must consistently use an acceptable method of contraception from baseline through Day 28. Females of childbearing potential must have a negative β-subunit hCG pregnancy blood test immediately prior to study entry.
• Non-childbearing potential is defined as current tubal ligation, hysterectomy, or ovariectomy or post-menopause.
• Acceptable methods of contraception for this study is defined as abstinence, hormonal therapy, intra-uterine device, diaphragm with spermicide, condom with spermicide.
7. If a male patient’s sexual partner is of childbearing potential, the male patient must acknowledge that they will consistently use an acceptable method of contraception (defined above) from baseline through Day 28.
8. Signed and dated informed consent form as defined by the institutional review board. By signing the ICF, the patient agrees to release any medical records pursuant to French local privacy regulations. If patient is unable to comprehend or sign the ICF, patient’s legally acceptable representative or an independent physician may sign the ICF.

E.4

Principal exclusion criteria

1. Has known prior history of CKD with a documented estimated GFR (eGFR) < 30 mL/min by a commonly used formula such as Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or known GFR < 30 mL/min.
• Exception: Patients with history of CKD but no available prior estimated GFR who have documented normal kidney size on ultrasound or computed tomographic (normal size defined above) evaluation (performed within 90 days of screening) will be eligible
2. Patients receiving RRT for chronic kidney disease: either hemodialysis, peritoneal dialysis, hemofiltration such as Continuous Veno-Venous Hemofiltration (CVVH) or hemodiafiltration.
3. Patients that are treated with RRT for acute kidney dysfunction, starting prior to study drug administration or in whom there is an immediate plan to initiate RRT upon diagnosis of AKI.
4. Previously diagnosed with documented AKI in the last 30 days.
5. Documented primary glomerular disease or toxic tubulo-interstitial nephritis or other underlying renal diseases significantly effecting renal function (e.g., renal amyloidosis, polycystic kidney disease, renal cancer, renal abscess) at the time of AKI diagnosis.
6. Current condition of: (a) Inability to maintain a mean arterial pressure > 50 mmHg and/or systolic blood pressure > 70 mmHg for at least 1 hour prior to dosing despite the presence of vasopressors and IV fluids or (b) a patient with respiratory failure such that an SaO2 of 80% cannot be achieved or (c) a patient with refractory coagulopathy (INR >5) or thrombocytopenia (platelet count <20,000) that does not partially correct with administration of appropriate factors or blood products.
7. Severe neurological impairment due to cerebrovascular accident or cardiac arrest.
8. Recent cerebrovascular accident in the last 3 months.
9. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days.
10. Patient is not expected to survive throughout 28 days of study due to underlying medical condition, such as poorly controlled neoplasm (e.g. Stage III or IV cancer).
11. Classified as “Do Not Resuscitate”, or “Do Not Treat”, or the patient’s family is not committed to aggressive management of the patient’s condition. A “no cardiopulmonary resuscitation (CPR)” order is acceptable if the patient and/or the family are still committed to aggressive care short of CPR.
12. Any concurrent medical condition, which in the opinion of the Investigator, may compromise the safety of the patient or the objectives of the study or the patient will not benefit from treatment such as:
• Congestive heart failure (CHF) {New York Heart Association (NYHA) class III-IV}
• Severe chronic obstructive pulmonary disease (COPD) {GOLD stage III-IV. or chronic hypoxemia (PaO2 <55 mmHg) on room air, or chronic use of home ventilation, or unable to climb stairs or perform household duties due to chronic obstructive disease resulting in severe exercise restriction, or use of continuous home oxygen prior to hospital admission (sleep apnoea treated with continuous positive airway pressure or biphasic positive airway pressure oxygen during sleep is acceptable)}
• Liver dysfunction {Childs-Pugh class C}
• Primary or acquired immunodeficiency or immunosuppression due to treatment with immunosuppressive medications (see Appendix G for list of excluded immunosuppressive medications)
• Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all lymphocytes
• Neutropenia < 1,000 cells/mm3 not due to the underlying infection
• Receiving or about to receive chemotherapy or biologic anti-cancer treatment, although hormonal manipulation therapies for breast and prostate malignancies are permitted
• Hematological and lymphatic malignancies in the last 5 years
13. Patient with >20% body surface area burn wounds.
14. Has acute pancreatitis with no established source of infection, uncomplicated appendicitis, or cholangitis or cholecystitis without peritonitis.
15. Pregnant or lactating women.
16. Concurrent or previous enrollment in a clinical trial involving investigational drug or a medical device within 30 days before provision of written informed consent for the study or within five half lives of the investigational drug, whichever is longer.
17. Previous enrollment in any Reltecimod protocol (ATB-203, ATB-202 or ATB-201) or concurrent enrollment in ATB-202.
18. Patients under guardianship or trusteeship.
19. Absence of social insurance.

E.5 End points

E.5.1

Primary end point(s)

• To compare the rates of complete recovery (alive, free of dialysis and return of serum creatinine to <150% of reference baseline; equivalent to acute kidney disease (AKD) category 0) at Day 14 between the Reltecimod-treated patients and the placebo-treated patients

E.5.1.1

Timepoint(s) of evaluation of this end point

14 Days

E.5.2

Secondary end point(s)

Secondary endpoints have been specified from several domains including an endpoint similar to the primary endpoint but defined at Day 28.
Additional secondary endpoints include evaluation of SOFA score over time;, time to complete renal recovery, time to at least partial renal recovery, critical care and hospital stay parameters (ICU and ICU-free days, ventilator days and –free days, vasopressor days and –free days,renal replacement days and-free days, hospital length of stay (LOS)). Analyses for these endpoints will generally be descriptive, with emphasis on characterizing clinical effect sizes. Nominal p-values will be presented. Categorical outcomes will be described using counts and percentages with nominal p-values determined through chi-square or exact methods. Critical care and hospital stay endpoints will be described using non-parametric approaches including using concordance statistics to characterize clinical effect sizes and Wilcoxon rank sum tests to determine nominal statistical significance. Methods appropriate for time-to-event endpoints including survival and life-table methods will be used for time-to-recovery endpoints.

E.5.2.1

Timepoint(s) of evaluation of this end point

Variable

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

Belgium

France

United States

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

Last Visit Last Subject (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)

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

Critically ill adults acute kidney injury due to complicated intra-abdominal infection who may be incapable of providing consent due to requiring mechanical ventilation, sedated or 'unconscious' due to critical illness

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

120

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)

None

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

2019-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-10-21

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IMP with orphan designation in the indication
Orphan Designation Number:
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