E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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.
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E.1.1.1 | Medical condition in easily understood language |
Life-threatening bronchiolitis in babies who require support from a breathing machine. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038718 |
E.1.2 | Term | Respiratory syncytial virus bronchiolitis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065188 |
E.1.2 | Term | Lower respiratory tract infection viral |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.
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E.2.2 | Secondary 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. |
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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 |
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). |
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E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is the duration of mechanical ventilation from randomisation, defined as time to final extubation in hours. |
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 30 |