WP04 - Clinical trial

 

Workpackage lead and partners:

WP leader:
Dr Eugene Dempsey, UCC

WP partners:
K.U.Leuven
CUNI
CHU
UCD
CWIUH
UALBERTA
RCSI

Workpackage objectives: 

  • Perform the clinical trial according to GCP guidelines and to the highest ethical standards
  • To enrol 830 ELBW newborns with hypotension within 3 years
  • To assess the diagnostic criteria used to define hypotension
  • To assess the efficacy of inotropic medications using clinical, echocardiographic, near infrared and EEG monitoring
  • To assess the efficacy of either approach on longterm neurodevelopmental outcome
  • To assess the safety of inotropic drugs in the ELGAN
  • Provide information on safety and efficacy of dopamine as required for a PUMA 

 Workpackage description:

The aim of this work package is to perform a phase III, multinational randomized clinical trial to assess current diagnostic criteria to define hypotension in the ELGAN and to evaluate the efficacy and safety of dopamine for treatment of neonatal hypotension. The results will provide detailed information relating to the safety and efficacy of each of these agents in the ELGAN, which is required for a PUMA application (WP 10).

This trial will need to take account of information required for regulatory processes and the particular issues relating to trials involving newborns. The trial will be supplemented by a prospective survey on the use of current agents in babies across Europe and Canada (WP 03).

This study will be the largest multicenter European study involving the ELGAN and will enrol 830 ELGAN over a 3 year period. The trial will be conducted according to the highest ethical standards and following Good Clinical Practice (GCP) in European accredited centres. We will ensure that the rights, safety and well-being of enrolled babies are the most important consideration of everybody involved in the study.

This novel trial will utilise commonly used non-invasive techniques to objectively assess the efficacy of dopamine . This will include EEG, NIRS and echocardiography and will be the largest study to evaluate the efficacy of these agents using objective measurements. The primary outcome is survival to 36 weeks gestational age, free of moderate-severe IVH or cystic pal (i.e. major event-free survival at 36 weeks gestational age). It is important to combine these two outcomes components because an early death may preclude the formal diagnosis of IVH (but also because survival with moderate IVH predicts long-term adverse neurodevelopment. The other co-primary outcome of neurodevelopmental assessment at 24 months will be performed by WP 09.

Task 1: Responsibilities during the trial

Task 1a: Annual safety reports. These will be provided to the sponsor by WP 12

Task 1b: Recruitment numbers. Total numbers of enrolled patients will have to be analysed on a monthly basis by WP 12 and communicated to the study coordinator (ED).

Task 1c: End of trial. When the last enrolled baby is discharged from hospital, the sponsors or the SC on behalf of the sponsors will complete the End of Trial Form and send it to the appropriate authorities and committees. This will mark the end of the interventional phase (treatment phase). This is followed by the non-interventional phase (neurodevelopmental follow-up) which will end with the follow-up assessment of the last child.

Task 1d: End of trial documents. At the end of the trial, the following documents will be produced by the SC: audit certificate, final trial close-out monitoring report, treatment allocation and decoding in collaboration with WP 12.

Task 2: Responsibilities and duties of local investigators

Several investigator sites at highly specialised neonatal units from four different European

Countries and Canada will manage the clinical studies locally. All these centres are level three neonatal intensive care units caring for anywhere from 40 -100 ELGAN annually. These centres have been involved in many previous interventional studies of preterm infants, including the recent INIS trial and the current NIPPV trial. The staff in each of these units is experienced in the challenges involved in interventional trials in newborns, in particular the ELGAN. Whilst the day-to-day management of the babies will be done by the clinical team, all data collection, monitoring and trial interventions will be done or facilitated by the research fellows, research nurses or physicians involved in the HIP Trial. Supervision will be by members of the consortium and scientific team leaders.

Task 2a: Site file. It is the responsibility of each local investigator to keep a site file (see WP 01) which will include the following documents: signed protocol, signed informed consent forms, source documents, subject screening log, subject identification log, subject enrolment log. These have to be updated on a regular basis and be available for inspection.

Task 2b: Recruitment and randomisation. The aim is to enrol 800 babies with hypotension over a 3 year period. Eight  centres will recruit babies meeting all inclusion criteria after written informed consent from parents has been obtained. Accurate randomisation of patients will be done via a web-based system. Patient data will be entered into the secure web-based system on a daily basis.

Task 2c: Efficacy assessments. Assessment and documentation of primary outcome as defined by survival free of severe cranial ultrasound abnormality. This assessment will be performed blind to treatment allocation. Data on efficacy as assessed by NIRS, ECHO and EEG will also be performed blinded by treatment allocation (WP06, 07, 08).

Task 2d: PK assessments. Blood samples will be taken and will be either sent or stored according to guidelines from the lead investigator in WP 10.

Task 2e: Drug accountability. This is the responsibility of each local PI; the overall responsibility lies with the sponsor

Task 2f: Data collection and transfer. Data collection and transfer of forms to the electronic database has to be performed in a timely manner, ideally on a daily basis. This will be done in WP 12 and monitored by WP 05. It is the duty of local centres to respond to requests for data clarification from the study monitor and in an orderly and timely manner with input from WP 04. The overall responsibility lies with the sponsor.

Task 2g: Safety assessments. It is the duty and responsibility of the local investigators to:

  • Assess and document patient safety according to defined standards. Any adverse events or adverse drug reactions have to be documented and reported to the sponsor if serious or unexpected.
  • Report all Serious Adverse Events and Reactions immediately to the Sponsor and WP 04.

They will then decide to perform an evaluation with respect to seriousness, causality and expectedness and inform the European Medicines Agency (EMEA), national ethics committees, national authorities, and investigators. The data and safety monitoring board (DSMB) will be informed within 48hrs.

Task 2h: Discharge. Families will be given a patient diary providing information about follow-up arrangements (WP 09) and contact details of study investigators. Major assessment points will be at two years and each centre will determine the frequency of contacts at other ages. Families will be asked to provide their contact details, including telephone numbers and email addresses, and the contact details for one grandparent. Contact will be reinforced by the distribution of a 6 monthly newsletter (from WP 02 and WP 04).

Task 3: Responsibilities and duties of WP 04 after the end of the clinical trial

Task 3a: WP 04 will support WP 09 with data collection of neurodevelopmental outcome measures.

Task 3b: WP 04 will be involved in cleaning and analysing the data (in conjunction with WP 12).

Task 3c: WP 04 will be involved in preparing reports about pivotal trial for PUMA application and publication.