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    Summary
    EudraCT Number:2016-002427-28
    Sponsor's Protocol Code Number:CIT-003-01
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-16
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2016-002427-28
    A.3Full title of the trial
    A Phase III Double-Blind, Randomized, Placebo Controlled, Multi-Center Clinical Study to Evaluate the Efficacy and Safety of Intravenous L-citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury induced by Cardiopulmonary Bypass in Pediatric Subjects Undergoing Surgery for Congenital Heart Defects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study, with treatment unknown to the patients and doctors, to test the effectiveness and safety of the L-citrulline given directly into a vein for the prevention of harmful consequences of acute lung injury from heart-bypass after surgery for congenital heart defects in children
    A.4.1Sponsor's protocol code numberCIT-003-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02891837
    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 SponsorAsklepion Pharmaceuticals, LLC
    B.1.3.4CountryUnited States
    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 supportAsklepion Pharmaceuticals, LLC
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAsklepion Pharmaceuticals, LLC
    B.5.2Functional name of contact pointDirector of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street Address729 E. Pratt Street; Suite 360
    B.5.3.2Town/ cityBaltimore
    B.5.3.3Post codeMD 21202
    B.5.3.4CountryUnited States
    B.5.4Telephone number+0410 545 0494104
    B.5.6E-mailcindy.zychowicz@asklepionpharm.com
    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 L-citrulline
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNno INN and no proposed INN available
    D.3.9.1CAS number 372-75-8
    D.3.9.2Current sponsor codeL-citrulline
    D.3.9.3Other descriptive nameL-CITRULLINE
    D.3.9.4EV Substance CodeSUB182097
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    D.8 Placebo: 2
    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
    Post-operative pulmonary dysfunction induced by cardiopulmonary bypass in pediatric subjects undergoing surgery for congenital heart defects.
    E.1.1.1Medical condition in easily understood language
    Breathing difficulties following heart surgery that is caused by heart bypass in patients at or below the age of 18 undergoing surgery for inborn heart defects.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to determine if L-citrulline delivery given perioperatively reduces clinical sequelae of acute CPB-induced lung injury in pediatric subjects undergoing repair of congenital heart defects, as evidenced by the reduction of post-operative need for mechanical ventilation and inotrope therapy.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to evaluate the effect of L-citrulline compared with placebo regarding
    • safety and tolerability
    • hemodynamic improvement post-operatively
    • the usage and length of time on vasodilators
    • length of hospitalization
    • the duration of chest tube placement
    • the plasma concentrations of citrulline
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects, parents, or legal guardian of the subject who are willing and able to sign informed consent
    • Male and female subjects aged ≤18 years of age
    • Infants, children and adolescents undergoing CPB for repair of a large unrestrictive VSD, an ostium primum ASD, or a partial or complete AVSD
    • Pre-operative echocardiogram that confirms the cardiovascular anatomy and defect to be surgically repaired
    • Patient weight must be 4.0 kg or greater at the time of screening
    E.4Principal exclusion criteria
    • Evidence of pulmonary artery or vein abnormalities on the pre-operative echocardiogram that will not be addressed surgically. Specific abnormalities excluded include the following:
    - Significant pulmonary artery narrowing not amenable to surgical correction
    - Previous pulmonary artery stent placement
    - Significant left sided AV valve regurgitation not amenable to surgical correction
    - Pulmonary venous return abnormalities not amenable to surgical correction
    - Pulmonary vein stenosis not amenable to surgical correction
    • Preoperative requirement for mechanical ventilation or i.v. inotrope support
    • Presence of fixed or idiopathic pulmonary hypertension (i.e. Eisenmenger’s Syndrome) prior to surgical repair
    • Pre-operative use of medications to treat pulmonary hypertension
    • Pregnancy; Sexually active females of child-bearing potential must be willing to practice an acceptable method of birth control for the duration of study participation (e.g. oral contraceptive, hormonal implant, intra-uterine device)
    • Participation in another clinical trial within 30 days of Screening or while participating in the current study, including the 28 days of follow-up post study drug administration.
    • Patient is < 28 days of age
    • Any condition which, in the opinion of the investigator, might interfere with the study objectives
    E.5 End points
    E.5.1Primary end point(s)
    A composite variable consisting of the longer of either (1) length of time on mechanical ventilation or (2) length of inotrope use.
    The definition of mechanical ventilation shall include invasive mechanical ventilation or noninvasive mechanical ventilation including bilevel (biphasic) positive airway pressure (BPAP) or continuous positive airway pressure (CPAP).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 0 - 28
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints
    • Length of time on mechanical ventilation
    • Length of time on positive pressure ventilation
    • Length of time of inotrope use
    • Inotrope score calculated each hour post-operatively from the time of separation from bypass until the completion of study drug; additionally, the total inotrope score over time until Day 28 or hospital discharge will be derived
    • Hemodynamic improvement (heart rate, systemic arterial blood pressure, oxygen saturation, and central venous pressure)
    • Thoracotomy output; duration and volume of chest tube drainage
    • Length of time of intubation
    • Length of PICU stay
    • Length of time on vasodilators
    • Length of hospitalization
    • Plasma concentrations of citrulline

    Secondary Safety Endpoints
    • Occurrence of adverse and serious adverse events
    • Incidence of refractory hypotension
    • Change from baseline in laboratory values (serum electrolytes, blood urea nitrogen [BUN], creatinine, complete blood count [CBC] with differential, activated clotting time [ACT] & liver enzymes)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 0 - 28
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Austria
    Germany
    Israel
    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 months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 190
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 5
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 136
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 43
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    F.1.3Elderly (>=65 years) No
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The clinical trial enrolls minors.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 190
    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)
    After the last study-specific visit the patients will be treated according to normal clinical practice.
    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 Decision2018-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-23
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