Do we have a minimum target for recruits per year set by the Sponsor?
We are anticipating 1-2 babies will be recruited from each site, per month, to achieve the sample size of 730 babies from participating centres, in the trial duration agreed with the HTA. We will be liaising with the PI/Local research team regarding recruitment, as this will formulate part of trial monitoring.
What are the guidelines for who has to complete GCP?
According the MHRA Grey Guide, each person involved in a Clinical Trial must receive some training in GCP commensurate with their roles and responsibilities e.g. recording/causality of adverse events, documentation of activities in source notes, or CRF’s, escalating any issues they may identify as appropriate. This will also need to meet the local R&D requirements. The GCP training of personnel involved in the trial should commensurate with the local R&D regulations.
As long as the person taking consent is:
GCP trained, and
on the delegation log, and
is familiar with the study e.g. eligibility, procedures, potential risks and benefits
Then they can consent the parent(s).
As Baby-OSCAR is a CTIMP, eligibility must be confirmed by a doctor if consent is taken by a nurse. This must also be documented in the notes. In addition question 16 on Form 1: Trial Entry, asks for confirmation of this.
Prescribing by a nurse or pharmacist will depend on local practice – as long as they meet local conditions i.e. supplementary prescribers to prescribe and administer prescription-only medicines.
The responsibility should be documented in the delegation log and the approval for supplemental prescribing should be maintained in the training files.
Administering imp/management of the participant
Since this is similar to standard care in terms of treating a PDA with ibuprofen, then the administering of the IMP will be dependent on:
whether the person is familiar with the study e.g. eligibility, procedures etc.
A study physician (investigator) is responsible for reviewing a serious adverse event and considering whether the event was related to the study drug(s). The local responsibility remains with the local Principal Investigator.
A physician, who is not a member of the study team, may offer an opinion as to whether the event was related to the study drug(s) and this opinion should be documented in the participant’s medical records.
Who can sign consent?
The consent form can be signed by the mother, or by the partner having parental responsibility for the baby e.g. married to, or in civil partnership with the mother at the time of birth.
Where the father signs, the birth mother must always countersign the consent form as soon as possible and before the baby is discharged. This is because we ask for some maternal data, which will help us ‘flag / trace’ the baby through the Health and Social Care Information Centre (HSCIC), (or named derivative), and other central UK NHS bodies.
Can participants be enrolled into Baby-OSCAR and another study?
Possibly. Please contact the Baby-OSCAR Coordinating Centre to discuss involving infants in Baby-OSCAR and any other study.
Co-recruitment has been agreed for the following trials:
ELFIN (A multi-centre randomised placebo-controlled trial of prophylactic enteral lactoferrin supplementation to prevent late-onset invasive infection in very preterm infants) ISCTRN: 88261002 led by the NPEU CTU
PREVAIL (PREVenting infection using Antimicrobial Impregnated Long lines) ISCTRN: 81931394 led by Medicines for Children Clinical Trials Unit, University of Liverpool
Infants cannot be co-recruited into:
Minidex (The efficacy and safety of very low dose dexamethasone used to facilitate the extubation of ventilator dependent preterm babies who are at high risk of bronchopulmonary dysplasia) ISCTRN: 81191607 led by the NPEU CTU
Tinn2 (Treat Infection in NeoNates 2) led by the French National Institute for Health and Medical Research
After randomising, how will I know which treatment pack the baby should receive?
Allocation information will appear on the randomisation website, as well as on the print out of your answers to Form 1 via the web randomisation website.
In addition the information will be emailed to the named research nurse(s) as soon as randomisation occurs. Allocation information can be accessed at any time on the randomisation website under ‘Recruitment list’.
What is the intervention?
Ibuprofen will be provided as a clear sterile solution for intravenous injection. An initial dose of 10 mg/kg will be followed by two doses of 5 mg/kg at 24 and 48 hours after the initial dose. The solution of ibuprofen is provided at a concentration of 5 mg/ml in a single-use 2 ml ampoule, thus 2 ml/kg, followed by two administrations of 1 ml/kg of undiluted IMP will be required.
What is the placebo?
Placebo will be supplied as a clear sterile solution of 0.9% Sodium Chloride for injection. The solution will be indistinguishable from that of ibuprofen. It will be given as a 2 ml/kg infusion followed by two infusions of 1 ml/kg undiluted at 24 and 48 hours.
How do I calculate doses & administer?
Doses to be calculated on birth weight and administered as a short infusion over 15 minutes, preferably undiluted. If required the IMP can be diluted to appropriate volume with 5% glucose or 0.9% Sodium Chloride and first dose administered soon after randomisation, after 6 hours of age and within 72 hours of birth.
Safety reporting as described in this section for the baby will be monitored from first dose until 7 days after completing trial medication. If listed as ‘Foreseeable’ in safety section of protocol, record only on the data collection forms accordingly. If ‘Unforeseeable’, report with 24 hours of first knowledge of the event using Form 8 for SAE reports.
SARs are to be reported up until 7 days after last dose of trial medication.
What happens when the IMP is delivered to hospital pharmacy?
All packs will be delivered to the hospital pharmacy, where the pharmacist will need to check the packs for any damage etc. and then record the fact that the packs have arrived safely. Trial drug packs will be allocated by the central randomisation system and will be recorded by the NPEU CTU and the dispensing pharmacy.
A certain number of packs will be allocated and stored on the NICU, so that the designated staff are able to enrol a baby into the trial 24-hours a day. The web-randomisation programme will select packs allocated from the NICU stock, rather than pharmacy’s supplies.
Site staff will be required to write the baby’s trial number and initials on the trial pack allocated. Part used packs are to be kept separate from unused packs.
The Baby-OSCAR drug containing ibuprofen, or the placebo, is an investigational medicinal product and must be prescribed electronically, or on the baby’s drug chart to be given by intravenous injection - the ward staff will do this at the point of administering the Baby-OSCAR IMP.
Why were different brands of ibuprofen used in the pilot study and main trial?
NeoProfen® was used only for the pilot phase and will not be used in the main trial.
Version 4 of the protocol, relates to NeoProfen®, the active drug used for the pilot - a formulation of ibuprofen lysine (approved by the US FDA in 2006) for the treatment of PDA was unlicensed for use within the EU.
The licensed alternative, Pedea® was unavailable during the pilot phase.
NeoProfen® was used under the notification of intention to import ‘the medicines for human use (manufacturing, wholesale dealing and miscellaneous amendments) regulations (SI 2005/2789).’ the formulations are non-equivalent; however, the recommended posology is identical.
Version 6 of the protocol references Pedea®, including the updated safety profile and reference safety information.
What temperature should the packs be stored at?
The Baby-OSCAR IMP does not require any special storage conditions. The requirement for IMP temperature monitoring ceased on 4th September 2017.
What are the dimensions of the Baby-OSCAR IMP for the main trial?
The dimensions of the packs are: L, 108.5 mm X W, 30.5 mm X H, 82 mm.
We have received stock of Baby-OSCAR IMP, what do I do?
Effective control of stock is only possible if pack delivery and movement is logged onto the Baby-OSCAR website accurately and promptly.
You may not be able to randomise a baby because the packs are not recorded as being received in either the Pharmacy, or NICU.
Please refer to Guidance Sheet 3(a): Trial intervention stock control.
A member of the pharmacy team
A member of the pharmacy team will need to log onto the web-based pack management system and receipt the packs.
The username and passwords are available on request, but should be contained within your ‘Pharmacy Site File’.
You will need to select ‘login packs at pharmacy’ and follow the on-screen prompts.
A member of the team will need to log onto the web-based pack management system and receipt the packs at NICU. The username and passwords are available on request, but should be contained within the ‘Investigator’s Site File’, or ‘Pharmacy Site File’.
You will need to select ‘login packs at NICU’ and follow the on-screen prompts.
What do I do about documentation if I drop an ampoule of the IMP, or I don’t use it after making it up?
Note the loss of the ampoule on the ‘IMP Accountability Log, Recruiting Centre’ in the ampoule spoilt/wasted column. If the dose has not been given at all, document ‘not used’ on the ‘IMP Accountability Log, Recruiting Centre’.
Please refer to Guidance Sheet 3(C): Reconciliation of trial intervention.
What is the procedure for delayed doses?
The 2nd and 3rd dose can be delayed based on clinical practice. Administer the next dose as soon as possible when deemed suitable to do so. The Protocol is not prescriptive about duration to withhold further doses, however as guidance:
If the 2nd dose is delayed beyond 24 hours, give as per local practice, preferably within 72 hours. The 3rd dose should then be given 24 hours after the 2nd dose, also within 72 hours of administering the 2nd dose.
If the IMP cannot be given in the time as stipulated above, the trial medication should be stopped.
For the purposes of the trial, please assume the IMP to be Ibuprofen, and take the clinical action locally practiced, with the use of Ibuprofen.
If you look at section 7.9 of protocol (version 5), we have mentioned when to delay/stop trial medication and given an example of oliguria (urine output <0.6ml/kg/hr) and significant bleeding which are definitive indications for delaying or stopping IMP.
For serum creatinine levels, please refer to [the paper] - Thayyil et al. J Perinatol 2008;28:226-229.
When looking at the platelet count, use the cut-off given in the exclusion criteria of <50,000, as this cut off could also apply when considering subsequent doses.
What is the procedure for doses not given?
Document the dose not given on Form 2 – Trial Intervention section B and state the reason, and on the infant’s drug chart in the Trusts agreed method of documenting non administration of medicines.
If a baby transfers:
Phone the NPEU Co-ordinating Centre to inform them of the transfer (they will check for approvals)
If appropriate; Carry out a 3 week ECHO scan and complete Form 3. Form 3 to be completed around 3 weeks of age, or last ECHO after completing trial medication prior to transfer, or death, or discharge if sooner
Carry out a 36 week ‘Oxygen Reduction Test’. Complete Form 4, OR record on the transfer envelope the date the test is due
Complete Form 6: Baby Outcomes - in Section C, make sure you complete tab ‘B’ only
If appropriate: Give the last dose possible of IMP – no doses will be administered at the continuing care site.
What happens if an infant is transferred to another unit, within the same Trust/Board, for a specific investigation or procedure?
Any transfer of 24 hours or less, e.g. for surgery, is classed as a drive through procedure and the recruiting sites maintain responsibility for the completion of the paperwork. The recruiting site should inform the surgical centre of the transfer in order that things like blood culture results can be collected easily. This is likely to be where the recruiting site would have infant back post-surgery.
Any transfer lasting over 24 hours is to be classed as a transfer and the responsibility for paperwork then lies with the centre as a continuing care site. A local Consultant needs to accept the infant under the trial protocol. It remains the responsibility of the local research nurse to ensure that the infant receives the dose at the recruiting site and that all data collection forms are completed at the recruiting/continuing care site and returned to the co-ordinating centre.
What happens if an infant is transferred to the Paediatric ward for long-term care?
The infant will need to be followed up until discharge home or death as per protocol. If they are still an inpatient at the time of locking the trial database, they will be flagged as an inpatient. The NPEU CTU will then liaise with the research team in these rare circumstances.
Continuing Care Sites
Is a CCS responsible for administering the IMP?
No, babies are mostly dosed within the first week of birth. We anticipate that ongoing pharmacy involvement will no longer be the case, and there is no expectation to transfer the IMP with the baby.
Is a CCS responsible for entering a baby into the study or seeking parental consent?
No, these activities, along with administering all of the doses, take part at a recruiting site.
Is there any clinical support for a continuing care site?
The Baby-OSCAR nurse will be responsible for liaising with the continuing care site, ensuring the PI identified fully understands the trial and, for establishing and maintaining an audit trail for the movement of each transferring baby.
The Baby-OSCAR nurse at the recruiting site will be responsible for following up the outcomes of babies transferred to continuing care sites to ensure that:
On-going training is provided if required
Staff are familiar with the trial protocol
SAEs are reported in a timely manner
Assistance with the oxygen reduction test at 36 weeks, if required / appropriate
Trial specific training material, to a level appropriate to the work, will be provided to all continuing care sites including training in reporting SAEs by the Baby-OSCAR nurse from the recruiting site.
What does a continuing care site need to do?
As a continuing care site the paperwork is limited, approx. 20 questions on the discharge/transfer form (Form 6) regarding the care the baby received at your hospital. Other than that, an Oxygen Reduction Test at 36 weeks, for babies whose oxygen requirements are <30% and not receiving respiratory support, is when the baby is around 36 weeks of post-menstrual age.
The forms which could apply to a continuing care site are:
Form 4: 36 Weeks; for completion by any site at this time point.
Form 5: Open-label treatment; for completion by any site should this event occur
Form 6: Baby Outcomes; for completion by any site
Form 6a: NEC; for completion by any site should this event occur
Form 7: Baby withdrawal; for completion by any site should this be the parent(s) request
Form 8: Serious Adverse Events (SAE); for completion by any site should this event occur
General – all sites
Where is the Baby-OSCAR trial taking place?
Baby-OSCAR started with a small pilot of 5 sites in 2015 and launched the main phase in Spring 2017 recruiting at 32 sites across the UK.
Where is our nearest recruiting site?
Details of recruiting sites with NHS permission and continuing care sites already with permission, can be on the Baby-OSCAR Sites page.
Is open-label treatment permitted?
Responsibility for the care of the baby will remain fully with the neonatal clinical team irrespective of the trial.
Open-label treatment (both medical and surgical) is permitted within the protocol if the following minimum criteria are met and other medical management strategies have been tried.
Surgical treatment however should only be considered if the PDA remains persistently large after one course of treatment with a COX inhibitor or in circumstances where medical treatment may be contraindicated or time does not permit medical open-label treatment first.
Open-label Treatment Criteria
Inability to wean on ventilator (ventilated for at least 7 days continuously) and any of: inability to wean oxygen; persistent hypotension; pulmonary haemorrhage; signs of cardiac failure
Echocardiographic findings of a large PDA (PDA ? 2.0 mm with pulsatile flow)
Echocardiographic findings of hyperdynamic circulation or ductal steal (refer to Baby-OSCAR ECHO workbook).
Refer to Baby-OSCAR ECHO workbook (see Baby-OSCAR website)
A persistent open PDA requiring open-label treatment (medical or surgical) should be reported to the trial co-ordinating centre using Form 5: Open-label Treatment of PDA.
Where can I view a copy of the Case Report Forms (CRFs)?
Do we have a CRF/ guideline for the Oxygen Reduction Test so it is easier for the clinical staff to complete?
The Oxygen Reduction Test at 36 weeks, for babies whose oxygen requirements are <30% and not receiving respiratory support, is when the baby is around 36 weeks’ of gestation.
Weaning a baby on oxygen is something that you may do automatically on the ward, but not necessarily document it.
The test is not difficult or time consuming, and can be easily followed using the flow diagram displayed in the protocol and on the front page of Form 4.
The local research team at the (original) recruiting site will be able to advise on carrying out the test, or contact the NPEU CTU to arrange for a medically qualified colleague to talk you through the test if required.
How can you measure FiO2 if the babies are not in high flow oxygen/CPAP/ventilation?