The Imperial Clinical Trials Unit is providing monitoring and oversight for this study for Imperial College London (sponsor). Please see Fig. 4 for overall reporting structure.
Composition of the coordinating centre and trial steering committee {5d}
The Imperial Clinical Trials Unit is the coordinating centre and is a UK Clinical Research Collaboration (UKCRC) registered clinical trials unit. A trial steering committee (TSC) will be convened including as a minimum an independent chair, independent clinician, the chief investigator, and trial manager. The role of the TSC is to provide overall supervision of trial conduct and progress. Details of membership, responsibilities, and frequency of meetings will be defined in a separate charter.
Composition of the data monitoring committee, its role and reporting structure {21a}
The Data Monitoring and Ethics Committee (DMEC) will be comprised of at least 2 independent clinicians, one with experience in clinical trials and an independent statistician. One of the independent clinicians will have experience in the regulatory aspects of clinical trials involving medical devices. The role of the DMEC will include the following: monitoring the data and making recommendations to the TSC on whether there are any ethical or safety reasons why the trial should not continue, considering the need for any interim analysis, advising the TSC regarding the release of data and/or information, and considering data emerging from other related studies. The DMEC will continually assess both safety and efficacy data on a regular basis with additional meetings convened in the event of any safety concerns. The DMEC should be independent of both the investigators and the funder/sponsor and should be the only body that has access to unblinded data. At least two independent members of the DMEC should convene to make the committee quorate.
Adverse event reporting and harms {22}
It is recognised that the patient population in the ICU will experience a number of common aberrations in physiological values, laboratory values, signs and symptoms due to the severity of their underlying disease and the impact of standard therapies. These will not necessarily constitute an AE unless they require significant intervention, lead to discontinuation of intervention, or are considered to be of concern in the investigator’s clinical judgement.
Clinical outcomes from ARDS are exempt from adverse event reporting, unless the investigator deems the event to be related to the use of the device. The following events will be considered clinical outcomes.
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Death related to ARDS and ensuing multi-organ failure
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Neurological insult, e.g. intracranial bleeding
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Cardiovascular failure, including the need for vasopressors/inotropes
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Hepatic failure
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Renal failure, including the need for renal replacement therapy
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Haematological/coagulation failure, including thrombocytopaenia
Device deficiency
The definition of device deficiency is as follows: inadequacy of a medical device related to its identity, quality, durability, reliability, safety, or performance, such as malfunction, misuse, or use error and inadequate labelling. Device deficiencies include malfunctions, use errors, and inadequate labelling. Any device deficiencies should be reported to the device manufacturer (Mermaid Care A/S) as soon as possible after the event, but not longer than 72 h. Device deficiencies should also be reported in the SMART Trial eCRF, in the form for “Any discontinuation of the Beacon Device.”
Adverse event (AE)/adverse device (ADE) event
Any untoward medical occurrence in a patient or clinical study subject and which does not necessarily have a causal relationship with this treatment (i.e. any unfavourable or unintended change in the structure (signs), function (symptoms), or chemistry (lab data) in a subject to whom a treatment/study procedure has been administered, including occurrences unrelated to that product/procedure/device).
ADE is an untoward and unintended response to a medical device. The phrase “responses to a medical device” means that a causal relationship between the device under investigation and an AE is at least a reasonable possibility, i.e. the relationship cannot be ruled out.
All cases judged by either the reporting medically qualified professional or the sponsor as having a reasonable suspected causal relationship to the device qualifies as a device effect. This also includes any event resulting from insufficiencies or inadequacies in the instruction for use or deployment of the device and includes any event that is a result of a user error.
Serious adverse events (SAE)/serious adverse device effects (SADE)
In the event of a serious adverse event (SAE), serious adverse device effect (SADE), or unanticipated serious adverse device effect (USADE) occurring during the subject’s participation in the study, the SAE/USADE must be reported to the CI, and the sponsor should be informed. Reporting of the SADE/USADE will also be reported to the device manufacturer. For ICTU sponsored studies, this will be reported directly to the Joint Research Compliance Office (JRCO) and relevant regulatory authorities where applicable, e.g. USADE. A SAE form or eUSADE will need to be completed.
Serious adverse events (SAE)
Any untoward and unexpected medical occurrence or effect that:
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Results in death
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Is life-threatening—refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe
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Requires hospitalisation or prolongation of existing inpatients’ hospitalisation
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Results in persistent or significant disability or incapacity
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Is a congenital anomaly or birth defect
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Is otherwise considered medically significant by the investigator
Life-threatening” in the definition of “serious” refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. “Hospitalisation” means any unexpected admission to a hospital department. It does not usually apply to scheduled admissions that were planned before study inclusion or visits to casualty (without admission). Medical judgement will be exercised in deciding whether an AE is serious in other situations. Important AEs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above should also be considered serious.
Serious adverse device effects (SADE)
A serious adverse device effect (SADE) is any untoward medical occurrence seen in a patient that can be attributed wholly or partly to the device which resulted in any of the characteristics or led to characteristics of a serious adverse event. SADE is also any event that may have led to these consequences if suitable action had not been taken or intervention had not been made or if a circumstance has been less opportune. All cases were judged by either the reporting medically qualified professional or the sponsor.
Unanticipated serious adverse device effect (USADE)
Any serious adverse device effect on health or safety or any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that related to the rights, safety, or welfare of the subject.
Adverse event recording
AEs will be recorded from the time of consent in the adverse event section of the relevant case report form. All clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source document using the event terms and grading given in the relevant CRF/eCRF pages. For the purposes of the study, AEs will be followed up according to local practice until the event has stabilised or resolved, or the follow-up visit, whichever is the sooner. SAEs will be recorded throughout the study
Reporting of SAE/SADEs
Reporting of all SAEs (except common ICU-related events) occurring during the study must be performed as detailed in SAE reporting instructions. It is recognised that the patient population in the ICU will experience a number of common aberrations in laboratory values, signs and symptoms due to the severity of their underlying disease and the impact of standard therapies. These will not necessarily constitute an AE unless they require significant intervention or are considered to be of concern in the investigator’s clinical judgement. For Austrian sites: all serious adverse events must be fully registered by the sponsor and reported immediately to the Federal Office for Health Safety (BASG) and the competent authorities of the other affected contracting parties of the EEA in which the clinical trial is being carried out.
All SAEs will be reviewed by the chief investigator or a designated medically qualified representative to confirm expectedness and causality. Reporting of SAEs and review by the CI will be via the trial data collection system (CRF/eCRF).
SAEs that are related and unexpected, SADEs, and USADEs should be notified to the relevant REC and the sponsor within 15 days of the chief investigator becoming aware of the event. In addition, all SAE/SADE/UADEs should be reported to the manufacturer of the device at the same time. Follow-up of patients who have experienced a related and unexpected SAE should continue until recovery is complete or the condition has stabilised. Reports for related and unexpected SAEs should be unblinded prior to submission if required by national requirements.