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    Summary
    EudraCT Number:2018-001169-18
    Sponsor's Protocol Code Number:UoL001360
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-08-21
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-001169-18
    A.3Full title of the trial
    The efficacy and mechanism of surfactant therapy for critically ill infants with bronchiolitis: The Bronchiolitis Endotracheal Surfactant Study.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The efficacy and mechanism of surfactant therapy for critically ill infants with bronchiolitis: the Bronchiolitis Endotracheal Surfactant Study (BESS)
    A.3.2Name or abbreviated title of the trial where available
    The Bronchiolitis Endotracheal Surfactant Study (BESS)
    A.4.1Sponsor's protocol code numberUoL001360
    A.5.4Other Identifiers
    Name:Funder ReferenceNumber:15/21/01
    Name:REC ReferenceNumber:18/SC/0427
    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 SponsorUniversity Of Liverpool
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNIHR Efficacy and Mechanism Evaluation Programme
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinical Trials Research Centre (CTRC)
    B.5.2Functional name of contact pointBESS Trial
    B.5.3 Address:
    B.5.3.1Street AddressInstitute of Child Health, Alder Hey Children's Hospital, Eaton Road
    B.5.3.2Town/ cityLiverpool
    B.5.3.3Post codeL12 2AP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0151 795 8757
    B.5.5Fax number01517958770
    B.5.6E-mailbess@liverpool.ac.uk
    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 Yes
    D.2.1.1.1Trade name Curosurf
    D.2.1.1.2Name of the Marketing Authorisation holderChiesi Farmaceutici S.p.A
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.1Product nameCurosurf
    D.3.4Pharmaceutical form Endotracheopulmonary instillation, suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPEndotracheopulmonary use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPoractant alfa
    D.3.9.1CAS number 129069-19-8
    D.3.9.3Other descriptive namePulmonary surfactant
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 placeboEndotracheopulmonary instillation
    D.8.4Route of administration of the placeboEndotracheopulmonary use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Critical Illness due to Bronchiolitis of infancy requiring conventional invasive Mechanical Ventilation (MV)
    Diagnosis of bronchiolitis per clinical criteria defined in national guidance NICE-NG9.
    E.1.1.1Medical condition in easily understood language
    Life-threatening bronchiolitis in babies who require support from a breathing machine.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10038718
    E.1.2Term Respiratory syncytial virus bronchiolitis
    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 10065188
    E.1.2Term Lower respiratory tract infection viral
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    BESS is a study that comprises three work packages. The Trial is Work Package A (WP-A), the parent and staff experience substudy is work package B (WP-B) and the mechanistic substudy is work package C (WP-C).

    The hypothesis we are testing in The Trial (WP-A) is: Endotracheal surfactant reduces duration of mechanical ventilation by 18 hours.

    This trial will test whether giving surfactant into the lungs of babies suffering from severe bronchiolitis reduces the time they spend on a mechanical ventilator to help them breathe.

    We will do this by measuring the total time babies spend on a mechanical ventilator in hours and comparing the time required by babies given a surfactant (called poractant alfa) to babies given air (a dummy or placebo treatment). "18 hours" is included in the hypothesis as this is considered to be the smallest period of time that would be of benefit to a baby's wellbeing. The study will run over 3 winter seasons and involve about 284 babies.
    E.2.2Secondary objectives of the trial
    Secondary objectives of the BESS Trial (Work Package A of the BESS study) are:
    1. To describe the impact of the intervention on infants’ long-term respiratory symptoms
    2. To describe secondary outcomes of efficacy including physiological indices and duration of other modes of respiratory support.
    3. To assess the safety of the intervention for infants with life-threatening bronchiolitis


    We are also conducting sub-studies that leverage the opportunity the study provides for exploratory and translational work.
    Work Package B is the study of parent and staff experiences, the objective of which is to explore staff and parent experiences of trial recruitment, consent and conduct.

    Work Package C is the mechanistic sub-studies, the objective of which is to explore the mechanisms for treatment efficacy and failures at a patient level by describing associations between trial outcome with markers of infection, inflammation, and surfactant composition in patient Bronchoalveolar Lavage Fluid.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    First sub-study: Parent and staff perspectives on recruitment and consent. Described in the protocol as Work Package B.
    Objective: To explore staff and parent experiences of trial recruitment, consent and conduct in season 1 to inform season 2 and 3.

    Second sub-study: Understanding the mechanism of efficacy for exogenous surfactant. Described in the protocol as Work Package C.
    Objective: To explore the mechanisms for treatment efficacy and failure at a patient level by describing associations between trial outcome with markers of infection, inflammation, and surfactant composition in participants' Bronchoalveolar Lavage fluid.

    N.B. None of the outputs from Work Package B and C will contribute to outcomes of the BESS trial (described in protocol as Work Package A).
    E.3Principal inclusion criteria
    1. Term-born infants < 26 weeks old and preterm-born infants < 26 weeks corrected age†
    2. Diagnosis of bronchiolitis (see below)
    3. Requires conventional invasive MV via tracheal intubation
    4. Parent or person with parental responsibility has given written informed consent for trial participation
    †Premature born infants have their age corrected to account for weeks of lost gestation
    E.4Principal exclusion criteria
    1. Major congenital anomalies, including complex or haemodynamically compromising cardiac anomalies.
    2. Congenital neuromuscular disease
    3. Already intubated for MV for >48 hours or likely to have been intubated for MV for >48 hours by randomisation
    4. Have received or are receiving extracorporeal membrane oxygenation (ECMO) or oscillation during this episode of bronchiolitis
    5. Have received or are receiving intratracheal administration of any surfactant during this episode of bronchiolitis
    6. Receiving MV for primary apnoea rather than respiratory failure
    7. A decision to wean to extubation has already been made
    8. Clinical judgement of futility
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the duration of mechanical ventilation from randomisation, defined as time to final extubation in hours.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This is an event which may occur at any time following intubation; there is no specific timepoint when this will be evaluated.
    E.5.2Secondary end point(s)
    BESS consists of three separate work packages:
    In work package A (WP-A) the secondary endpoints are:
    1. Time from randomisation to meeting study criteria for readiness for Spontaneous Breathing Test
    2. Number of trial interventions given
    3. Change over time from baseline of Ventilation Index (VI) and Oxygenation Index (OI) Oxygen Saturation Index (OSI) while mechanically ventilated, or other respiratory support & SpO2/FiO2 (SF) ratio while mechanically ventilated and receiving supplemental oxygen
    4. Duration of oxygen supplementation
    5. Use of steroids to assist extubation
    6. Duration of post-extubation non-invasive respiratory support
    7. Duration of stay on PICU and in hospital
    8. The score (value) of patient reported outcome measure of respiratory systems in the “Liverpool Respiratory Symptom Questionnaire” (LRSQ)

    In work package B (WP-B) the aim is to explore parents' experience of participation in a trial where recruitment occurs during the early (acute - emergency) phase of admission at the time of particularly heightened parental anxiety due to critical illness of their baby. The end point is:
    9. Staff and parent experiences of trial recruitment, consent and conduct (assessed on data from season 1)

    In work package C (WP-C) the aim is to explore the mechanisms for treatment efficacy and failure by describing associations between trial outcome with markers of infection, inflammation and surfactant composition in patient BAL fluid. Secondary end points are:
    10. At all sites indicators of inflammation and infection in BAL fluid from all infants
    11. At all sites composition and concentration of surfactant phospholipids in BAL fluid from all infants
    12. At all sites concentration of surfactant proteins A and D in BAL fluid from all infants
    13. Optional and with specific written informed consent at two sites (Liverpool and Southampton), incorporation of D-choline into BAL fluid phosphatidylcholine as a measure of endogenous surfactant phospholipid synthesis.
    E.5.2.1Timepoint(s) of evaluation of this end point
    WP-A Timepoints:
    For end point 3:
    Capillary blood gas sampling immediately prior to intervention and then at 6, 12, 24, 36 and 48hrs while still on MV; to continue daily after 48hrs if still on MV.

    For end point 8:
    LRSQ at 6 months and 12 months post randomisation in seasons 1 and 2, and at 6 months only in season 3.

    N.B. Due to the nature of other secondary end points there are no specific associated timepoints for evaluation.

    WP-B Timepoint:
    Questionnaire and/or telephone interview <2 months after randomisation, if consent provided

    WP-C Timepoints:
    For end points 10-13:
    BAL fluid samples taken immediately prior to each intervention and at 36 hours post first intervention
    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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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 concerned14
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    The end of the trial is defined as the date on which data for all participants are frozen and data entry privileges are withdrawn from all trial databases.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days30
    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: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 50
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 175
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 59
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    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 No
    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
    Patients will be <26 weeks old and thus unable to give informed consent. Parents or those with parental responsibility will give consent for their child to participate.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state284
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 284
    F.4.2.2In the whole clinical trial 284
    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)
    If effective, the intervention is only indicated for the early treatment of critical illness requiring mechanical ventilation. After extubation (removal of tube facilitating mechanical ventilation), there is no indication for continued provision of the intervention. Care of the patient after the trial intervention period will follow standard treatment and depending on the needs of each patient.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-15
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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