A SAE is defined as an AE that fulfils one or more of the criteria for severity as defined in Table 1.
Because Hope-ICU is recruiting a population that is already in a life-threatening situation, it is expected that many of the participants will experience SAEs. Events that are expected in this population (i.e. events that are in keeping with the patient’s underlying medical condition) and are collected as outcomes of the trial, including death and organ failure will not be reported as SAEs. Other SAEs will be reported. A serious adverse reaction (SAR) is an SAE which is related to the administration of the study drug. If any of the above are related to the study drug (i.e. they are SARs) they will be reported to the sponsor, DMEC and MHRA according to research governance requirements.
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are considered to be caused by the study drug and are unexpected i.e. their nature or severity is not consistent with the SPC.
If an SAE occurs, reporting will follow the regulatory requirements as appropriate and all SUSARs will be the subject of expedited reporting. SAEs will be evaluated for causality (relationship to the study drug) and expectedness. SAEs will be reported using the SAE form in the CRF and will be reported to the sponsor within 24 hours of becoming aware of the event. Information not available at the time of the initial report will be documented on a follow-up SAE form.
The Chief Investigator or her site co-investigator Dr Stambach is responsible for reporting SAEs to the Sponsor, ethics committee, MHRA and IMB within the required time lines as per the regulatory requirements. The Chief Investigator or Dr Stambach will ensure that all relevant information about a SUSAR that is fatal or life-threatening is reported to the relevant competent authorities and ethics within 7 days after knowledge of such an event and that all relevant information is communicated within an additional 8 days. All other SUSARs will be reported to the relevant competent authorities and research ethics committees within 15 days after knowledge of such an event.
3.13 End of trial
The DMEC will look at the data after 9 months to determine whether there is any reason why recruitment should not continue. The trial will be stopped prematurely if:
Mandated by the Ethics Committee
Mandated by the Medicines and Healthcare products Regulatory Agency (MHRA)
Decided by the Trial Steering Committee after consideration of recommendations from the Data Monitoring and Ethics Committee (DMEC)
Funding for the trial ceases
4.1 Training issues
To ensure accurate, complete and reliable data before recruitment starts the Principal Investigator and research nurse will:
Provide instructional material to all staff
Provide an initiation training session to instruct Consultant Intensive Care colleagues and trial nurses. This session will give instructions on the protocol, the completion of the Case Report Forms and trial procedures.
Be available for consultation by e mail and/or telephone
Review and evaluate the Case Report Form (CRF) data, detect errors in data collection and request data collection.
The Chief Investigator or a delegated nominee will collect all study data for an individual patient and record it in the CRF. The CRFs will be anonymised. Patient identification in the CRF will be through their unique Patient Trial Number allocated at the time of randomisation and initials. Data will be collected from the time the patient is considered for entry into the trial through to their discharge from hospital.
APACHE II scores will be used as part of the description of the trial population. The APACHE II score will be obtained from the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme. All completed CRFs will be forwarded to the database office at Warwick CTU after being checked. Submitted data will be reviewed for completeness and entered onto a secure, backed-up custom database. Due care will be taken to ensure data safety and integrity, and compliance with the Data Protection Act 1998.
The trial number, name, address and other contact details of all patients who survive will be kept separately to allow the patients to be contacted at 6 months for the telephone cognitive status evaluation and the follow-up questionnaires to be posted to them. These details will be kept in a locked filing cabinet in a secure office in the anaesthetic department, Watford General Hospital.
4.3 Follow-up at six months
All survivors will be contacted at six months by phone by an investigator for an assessment of cognitive function using the modified Telephone Interview of Cognitive Status – TICS-M. Any deaths after discharge from hospital will be identified using the NWW Connecting for Health ERS, death status notification reports, to avoid ringing the homes of patients who have died. Trial patients will be asked to let the Chief Investigator know if they move house at any time after hospital discharge; Connecting for Health NWW will enable us to locate any who move without informing the Chief Investigator.
Additionally all survivors will be followed up at six months after randomisation by telephone. The follow-up questionnaire will collect data on disability and health related quality of life, using the telephone version of the EQ-5D questionnaire. Where feasible a surrogate assessment of cognitive function will be obtained using a telephone version of the IQCODE.
4.4 Data storage
All essential documentation and trial records will be stored in conformance with the applicable regulatory requirements and access to stored information will be restricted to authorised personnel.
Trial documentation and data will be archived for at least five years after completion of the trial.