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    Summary
    EudraCT Number:2018-001125-15
    Sponsor's Protocol Code Number:ATB-202
    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:2018-05-14
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2018-001125-15
    A.3Full title of the trial
    Phase III, randomized, double-blind, placebo controlled, parallel-group, study of AB103 as compared to placebo in patients with necrotizing soft tissue infections (NSTI)
    Etude de phase III, randomisée, en double-aveugle, contrôlée contre placebo, en groupe parallèle, étudiant l’efficacité d’AB103 comparé au placebo chez des patients ayant des infections nécrosantes des tissus mous (NSTI)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a Phase III, randomized, double-blind, placebo controlled, parallel-group multicenter study to determine the efficacy and safety of AB103 as compared to placebo, in patients diagnosed with necrotizing soft tissue infections (NSTI).
    A.3.2Name or abbreviated title of the trial where available
    ACCUTE
    A.4.1Sponsor's protocol code numberATB-202
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02469857
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAtox Bio
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAtox Bio
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCentre Hospitalier Universitaire de Limoges
    B.5.2Functional name of contact pointClinical Trial Operations Manager
    B.5.3 Address:
    B.5.3.1Street Address2 avenue Martin Luther King
    B.5.3.2Town/ cityLIMOGES
    B.5.3.3Post code87042
    B.5.3.4CountryFrance
    B.5.4Telephone number330555058849
    B.5.5Fax number330555058057
    B.5.6E-mailmarie.leveque@chu-limoges.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code AB103
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Necrosis of soft tissue infections (NSTI)
    Infections nécrosantes des tissus mous
    E.1.1.1Medical condition in easily understood language
    Rare but severe type of bacterial infection that spreads quickly and kills the muscles, skin and underlying tissue. (Necrotizing means “causing the death of tissues.”)
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10065769
    E.1.2Term Soft tissue necrosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10017068
    E.1.2Term Fournier's gangrene
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028885
    E.1.2Term Necrotising fasciitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with NSTI, using a clinical composite success endpoint (NICCE score)
    E.2.2Secondary objectives of the trial
    - To demonstrate the safety of AB103 when administered as a single dose of 0.50 mg/kg to patients diagnosed with NSTI
    - To demonstrate efficacy of AB103 in relation to the critical care and hospital stay parameters:
    a. intensive care unit (ICU) days
    b. ICU-free days
    c. Days on ventilator
    d. Ventilator free days
    e. Vasopressor days
    f. Vasopressor free days
    g. Hospital length of stay
    -To determine the incidence of Stage 2 and 3 acute kidney injury (AKI) (using the KDIGO criteria) and compare the rates of complete recovery by Day 28 between the AB103 treated patients and the placebo treated patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age: ≥18 years
    2. Surgical confirmation of NSTI by attending surgeon (e.g. presence of necrotic tissue, thrombosed vessels in the subcutaneous tissue, lack of bleeding and “dishwater” (cloudy, thin, gray) fluid) due to presumed bacterial infection (necrotizing cellulitis (most commonly group A strep), necrotizing fasciitis, necrotizing myositis and myonecrosis, NSTI of the perineum, bacterial synergistic gangrene, Clostridial gas gangrene) that may be supported by specific signs and symptoms (e.g. tense edema outside area of compromised skin, pain disproportionate to appearance, skin discoloration, ecchymosis, blisters/bullae, necrosis, tense edema, crepitus and/or subcutaneous gas).
    • Patients with NSTI following intra-abdominal operation are eligible if adequate source control of intra-abdominal process has been established
    3. mSOFA score ≥3 (in any one or combination of the 5 major components of SOFA score with any one organ component having a score of at least 2: cardiovascular, respiratory, renal, coagulation, CNS), measured as close as possible to the first debridement, (but before first debridement is performed).
    4. IV drug administration within 6 hours from the clinical diagnosis and the decision at the study site, to have an urgent surgical exploration and debridement (drug should not be administered until surgical confirmation is established).
    5. If a woman is of childbearing potential, she must consistently use an acceptable method of contraception from baseline through Day 28. Acceptable birth control methods include oral contraceptive medication, an intrauterine device (IUD), an injectable contraceptive (such as Depo-Provera®), a birth control patch, a barrier method (such as condom or diaphragm with spermicide) or abstinence.
    o Non-childbearing potential is defined as current tubal ligation, hysterectomy, or ovariectomy or post-menopause (1 year without menses with an appropriate clinical profile at the appropriate age e.g. >45 years).
    6. 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.
    7. Signed and dated ICF as defined by the IRB and, if applicable, California Bill of Rights. By signing the ICF, the patient agrees to release any medical records pursuant to current Health Insurance Portability and Accountability Act (HIPAA) Guidelines. If patient is unable to comprehend or sign the ICF, patient’s legally acceptable representative may sign the ICF
    E.4Principal exclusion criteria
    1. BMI > 51;
    2. Patient who has been operated at least once for the current NSTI infection and had a curative deep tissue debridement (patients who underwent prior diagnostic minor surgery are allowed to enter into the study);
    3. Patients with overt peripheral vascular disease in the involved area - associated with ischemic wounds/ulcers or gangrene, and /or other significant symptoms of inadequate vascular supply or where limb amputation is considered likely within 7 days due to the peripheral vascular disease;
    4. Diabetic patients with peripheral vascular disease who present with below the ankle infection;
    5. Removed
    6. Patient with burn wounds;
    7. 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 screening 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,
    8. Chronic neurological impairment that leads to a neuro mSOFA component ≥2
    9. Recent cerebrovascular accident in the last 3 months.
    10. Patients with cardiac arrest requiring cardiopulmonary resuscitation within the past 30 days;
    11. 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);
    12. Patient or patient’s family are not committed to aggressive management of the patient’s condition, or the combination of necrotizing skin infection and underlying illness makes it unlikely that life support will be maintained;
    13. 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:
    o CHF {NYHA class III-IV}
    o Severe 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)}
    o Liver dysfunction {Childs-Pugh class C}
    o Immunosuppression (see Appendix F, Section 15.6 for list of excluded immunosuppressive medications)
    o Neutropenia < 1,000 cells/mm3not due to the underlying infection
    o Idiopathic Thrombocytopenic Purpura (ITP)
    o Receiving or about to receive chemotherapy or biologic anti-cancer treatment although hormonal manipulation therapies for breast and prostate malignancies are permitted
    o Hematological and lymphatic malignancies in the last 5 years
    14. Known HIV infection with CD4 count < 200 cells/mm3 or < 14% of all lymphocytes;
    15. Patients with known chronic kidney disease (documented pre-illness creatinine value(s) ≥2.0) or patients receiving renal replacement therapy for chronic kidney disease: either hemodialysis, peritoneal dialysis, hemofiltration such as Continuous Veno-Venous Hemofiltration (CVVH) or hemodiafiltration
    16. Patients that are treated with continuous hemofiltration (e.g. Continuous Veno-Venous Hemofiltration) for acute kidney dysfunction, not due to NSTI, starting prior to study drug administration.
    Exception: Patients with acute kidney dysfunction due to NSTI may be enrolled in the event that the patient is off the treatment from time of study drug administration and up to at least one hour post study drug administration.
    17. Pregnant or lactating women; Women of childbearing potential must have a negative subunit hCG pregnancy test immediately prior to study entry
    18. 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.
    19. Previous enrollment in this protocol, ATB-202 or the Phase 2 trial of AB103, ATB-201.
    E.5 End points
    E.5.1Primary end point(s)
    To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with NSTI, using a clinical composite success end point (NICCE)
    : Success is defined as meeting all 5 components of the composite score: Alive until Day 28, (ii) Day 14 debridements ≤3 (iii) No amputation done after the first debridement (iv) Day 14 mSOFA score ≤1 (v) Reduction of ≥3 score points between Baseline and Day 14 mSOFA score.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Days 14 and 28 after the inclusion of the patient
    E.5.2Secondary end point(s)
    Secondary endpoints have been specified from several domains including a similar composite endpoint but defined on the basis of Day 21 mSOFA, individual components of the primary composite endpoint, time to resolution of organ dysfunction, critical care and hospital stay parameters, clinical local parameters, and clinical systemic parameters. Analyses for these endpoints will generally be descriptive, with emphasis on characterizing clinical effect sizes. l. AKI endpoints will be assessed in several ways include incidence of Stage 2/3 AKI and among incident cases, resolution of AKI.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Various time points including Days 1-14 for time to resolution of organ dysfunction, Days 14 and 28 to evaluate individual components of composite endpoint, Day 28 to evaluate resolution of AKI and variable time period to evaluate hospital length of stay, ventilator days, ICU days.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 245
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Critically ill adults necrotizing fasciitis and dysfunction of one or more organ systems who may be incapable of providing consent due to requiring mechanical ventilation, sedated or 'unconscious' due to critical illness.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 290
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-18
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