Guidance Sheet 3: IMP (a) Trial medication stock control · EudraCT No: 2013-005336-23, REC Ref: 14/EM/0172 Guidance Sheet 3_Version 5 dated 27/02p/18 Page 8 of 14 Ibuprofen or placebo

EudraCT No: 2013-005336-23, REC Ref: 14/EM/0172 Guidance Sheet 1_Version 2.0 dated 29/07/15 Page 1 of 14 EudraCT No: 2013-005336-23, REC Ref: 14/EM/0172 Guidance Sheet 3_Version 5 dated 27/02/2018 Page 1 of 14

Guidance Sheet 3: IMP

(a) Trial medication stock control

Stock arrives in pharmacy.

Check for damage/inconsistency.

Pharmacy: Completes ‘Stock Balance

Log’ Logs in packs at Pharmacy

https://rct.npeu.ox.ac.uk/babyoscar/menu_main.php

Infants consented and randomised to the trial will be allocated a Baby-OSCAR pack

from the NICU stock using the Baby-

OSCAR website randomisation program https://rct.npeu.ox.ac.uk/babyoscar

Baby-OSCAR randomisation program tracks the movement

and allocation of packs and flags sites which need to resupply NICU and pharmacy stocks. Effective control of stock is only possible

if pack delivery and movement is logged onto the Baby-OSCAR website accurately and promptly.

When NICU stock falls below a specified number of packs the randomisation

program assigns a further set of packs to the NICU.

When the pharmacy stock falls below a specified number of packs, the Trial Office notifies Stockport Pharmaceuticals, who resupply the pharmacy.

Allocate a new pack using the Baby-OSCAR

website randomisation program https://rct.npeu.ox.ac.

uk/babyoscar

At the end of the medication, any unused Baby-OSCAR ampoules will be collected

by the LRN or Pharmacy (depending on

your local arrangement) and recorded on the IMP Accountability Log, which is returned to NPEU CTU for authorisation of destruction.

Pharmacy to log on to the randomisation

program and assign a set of packs to the NICU.

Pharmacy to physically supply NICU with the assigned trial pack.

Pharmacy / NICU to log in packs at NICU.

Log in packs at NICU

https://rct.npeu.ox.ac.

uk/babyoscar/menu_main.php

EudraCT No: 2013-005336-23, REC Ref: 14/EM/0172 Guidance Sheet 3_Version 5 dated 27/02p/18 Page 2 of 14

Guidance Sheet 3: IMP (a)(i) Trial medication stock control; IMP allocation and management of packs It is essential that the movement and allocation of Baby-OSCAR packs are carried out and recorded in an accurate and timely fashion by site staff to allow effective control of stock by the randomisation program. The following scenario illustrates the movement of packs.

From NPEU Co-ordinating Centre

The Baby-OSCAR Co-ordinating Centre will allocate packs to a centre – the manufacturer will send packs to the centre’s pharmacy. Packs will show as “in transit”, to pharmacy once “Send” is clicked and an email is generated to the pharmacy similar to the message below.

From Centre Pharmacy

1. Pharmacy Admin should log in to the website using their username and password. https://rct.npeu.ox.ac.uk/babyoscar


2. Click “Login packs at pharmacy”, in this example there are 20 packs for logging in (shown in brackets).

3. Click on “Login packs at pharmacy” to view pack IDs and to log in the stock. This is an opportunity for checking the integrity of the packs before you log them in, so that damaged packs for destruction or missing packs can be indicated on the website by clicking on individual pack numbers. You can click on the packs, which become highlighted in blue, and mark them as either ‘Available for use’, or ‘Damaged’, or ‘Missing’. If not highlighted, then ALL packs will be logged in.


4. Confirm “Available for use” and then confirm by clicking “Yes”.

“Pack status summary” will show pharmacy stock pack availability increased AND if stock on NICU has fallen below normal levels or is zero, then pharmacy is prompted to assign and log in those pack IDs to NICU.

5. Pharmacy (or NICU) can click on “Login packs at NICU” and the assigned packs will be listed, and can then be taken directly to NICU OR Packs can be logged in by delegated neonatal ward staff, on the ward, by clicking on “Pack status summary” and logging the packs in.

In addition, an email to the clinical trials pharmacist’s email address is automatically generated showing which packs have been sent and which are to be assigned to NICU. If pharmacists have agreed with NICU to log packs in on their behalf, and ward stock levels have fallen below a certain number of packs, then these assigned packs must be logged in as shown above (Login at NICU) and despatched to NICU immediately. The pack management system maintains ward stock levels by prompting pharmacy in this way to assign specific further packs to the ward.


From NICU Login of packs

1. If NICU research staff are logging in assigned packs delivered from pharmacy, the following page will display on their NICU page “Pack status summary” Login packs on NICU by clicking here

If pharmacist has logged them in already, then packs can be stored in the allocated locked trials drug cupboard/storage area by designated research staff.

2. Click on “Pack status summary” to log packs in to ward area. Pack IDs will be listed.

3. Click on “Login at NICU”. Click on “Yes” Packs in stock in Pharmacy, and on NICU or allocated to babies can be viewed on “Pack list (detailed)”


During Randomisation

During each Baby-OSCAR infant randomisation the screen will show which number pack is to be taken from the NICU stock to use for that particular study number infant.

If an ampoule breaks, or there is a spillage

The guidance is to use another ampoule as there are 4 in each IMP pack. If all 4 ampoules are used and more IMP is required to make up the dose, you can allocate next pack for continuing administration by clicking on “Allocate next pack” from the main menu. You will be prompted to enter the baby’s study number and previous pack ID.

Click “Continue” and the pack ID to take from NICU stock for this particular baby will be indicated. Equally you may phone the NPEU CTU on: 01865 617 965 (normal office hours Mon – Fri (apart from bank holidays)), or Message Direct on: 0800 138 5451.

It is very important that Baby-OSCAR study babies only receive IMP from the assigned pack numbers


Guidance Sheet 3: IMP (b) Prescribing, preparation and

administration of trial medication

The decision for eligibility and trial enrolment must be made by a medically qualified doctor and there should be clear documentation of this in the baby’s notes. Prescribing by a nurse or pharmacist will depend on local practice – as long as they meet certain 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. Prescribing

Once it has been confirmed that a baby meets the eligibility criteria, written informed consent has been obtained, and the baby has been randomised, the Baby-OSCAR trial medication can be prescribed.

The allocated medication will be either: o Ibuprofen, an initial dose of 10 mg/kg followed by two doses of 5 mg/kg at 24

and 48 hours apart. 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 will be required.

o A matched placebo, which will be given as a 2 ml/kg infusion followed by two infusions of 1 ml/kg at 24 and 48 hours.

The required volume to be given to the baby should be determined according to body weight, and should be injected intravenously as a short infusion over 15 minutes and the first dose administered soon after randomisation, after 6 hours of age and within 72 hours of birth.

If the local practice requires dilution of the drug, it can be diluted using normal saline or 5% glucose. Add 6 ml of NS/5%G to 2 ml of IMP then the active drug concentration will be 1.25 mg of ibuprofen per ml. This diluted solution can be administered as 8 ml/kg for loading dose and 4 ml/kg for further 2 doses 24 hours apart. The dilution volume can be altered as per local practice if required but the volume of administration should be calculated as per the dose.

Babies will be allocated a Trial Medication Pack ID number during randomisation. This number will correspond to a pack containing 4 ampoules of either ibuprofen or placebo. You will not know whether the baby has been allocated ibuprofen or placebo. In the event of an emergency, unmasking is possible (see Protocol, Section 8.6).


Ibuprofen or placebo is an Investigational Medicinal Product and must be prescribed electronically or on the baby’s drug chart, to be given by intravenous injection using the wording ‘Baby-OSCAR clinical trial medication, loading dose 2 ml/kg, maintenance doses two and three, 1 ml/kg, [enter 5-character alphanumeric value e.g. P1234]’. The Pack ID ‘P1234’ of the allocated pack is an essential component of the prescription.

Following randomisation, the medication should commence after 6 hours of age and within 72 hours of birth.

The total volume of solution should take into account the total daily fluid volume administered.

Packs of trial medication must only be administered to the baby to whom it was allocated. If there is any doubt about which pack an ampoule has come from, discard the ampoule (recording it on the IMP Accountability Log), log onto the website and re-allocate a pack.

The Reference Safety Information for Sodium Chloride of ibuprofen is contained within the SmPC, which is in the Pharmacy File and Investigator Site File, Section 6.1.


Preparation The box below lists the items needed:

Baby’s drug chart with the prescription for Baby-OSCAR trial medication

The pack of Baby-OSCAR Trial Medication allocated to the baby

A syringe

An IV line

Obtain an ampoule from the baby’s allocated treatment pack.

Verify that the Pack ID on the ampoule matches the Pack ID allocated to the baby (it

will be stated on the randomisation confirmation print out) and should be recorded on Form 2: Trial Medication.

Record the baby’s name, Study Number and Pack ID, along with the date and time of all

doses on the Trial Medication Form (2), located in the Documentation Box.

Consulting the dosing chart over the page, draw the required loading dose and then

maintenance dose.


Loading dose:

Infant

body

weight kg

Dose in mg to

give at

10mg/kg

Dose volume

using solution

10mg/2ml

0.4 4 mg 0.8 ml

0.5 5 mg 1.0 ml

0.6 6 mg 1.2 ml

0.7 7 mg 1.4 ml

0.8 8 mg 1.6 ml

0.9 9 mg 1.8 ml

1.0 10 mg 2.0 ml

1.1 11 mg 2.2 ml

1.2 12 mg 2.4 ml

1.3 13 mg 2.6 ml

1.4 14 mg 2.8 ml

1.5 15 mg 3.0 ml

1.6 16 mg 3.2 ml

1.7 17 mg 3.4 ml

1.8 18 mg 3.6 ml

1.9 19 mg 3.8 ml

2.0 20 mg 4.0 ml

Maintenance dose – dosing chart Infant body weight kg

Dose in mg to give at 5mg/kg

Dose volume using solution 10mg/2ml

0.4 2.0 mg 0.4 ml

0.5 2.5 mg 0.5 ml

0.6 3.0 mg 0.6 ml

0.7 3.5 mg 0.7 ml

0.8 4.0 mg 0.8 ml

0.9 4.5 mg 0.9 ml

1.0 5.0 mg 1.0 ml

1.1 5.5 mg 1.1 ml

1.2 6.0 mg 1.2 ml

1.3 6.5 mg 1.3 ml

1.4 7.0 mg 1.4 ml

1.5 7.5 mg 1.5 ml

1.6 8.0 mg 1.6 ml

1.7 8.5 mg 1.7 ml

1.8 9.0 mg 1.8 ml

1.9 9.5 mg 1.9 ml

2.0 10.0 mg 2.0 ml

Administration

The IMP should be administered in line with your local practice and be based on the pragmatic decision of the clinical team locally both in terms of when they give subsequent (2nd and 3rd) doses and if they give the subsequent doses.

The 2nd and 3rd dose can be delayed based on clinical practice. The Protocol is not prescriptive about duration to withhold further doses, however as guidance:

o 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.

o If the IMP cannot be given in the time as stipulated above, the trial medication should be stopped.

If anuria, marked oliguria (<0.6 ml/kg/hr), or clinically significant bleeding is evident at the scheduled time of the second or third dose, no additional dosage should be given until laboratory results indicate that renal function has returned to normal, or bleeding has stopped. In the event of GI perforation discontinue trial medication.

Once the IMP is given, record the administration on the baby’s drug chart and Form 2: Trial Medication.

Omitted doses must also be recorded on Form 2: Trial Medication.


Guidance Sheet 3: IMP (c) Reconciliation of trial medication

The investigators need to be able to account for each ampoule of the Baby-OSCAR trial

medication. There are three documents involved in tracking allocated medication use: the baby’s drug chart, Form 2: Trial Medication and the accountability log.

To enable reconciliation of the medication it is essential that the following events are recorded in these documents:

o on the baby’s drug chart the prescription, the daily administration and when applicable any omitted or additional doses of the allocated medication.

o in Form 2: Trial Medication date and time of doses and for any omitted doses.

o any wasted ampoules (due to damage, spillage, expiration or contamination) should be recorded on the IMP Accountability Log.

In the event of a missed dose, record on the baby’s drug chart noting why and complete an Incident Report Form (9) (kept in the Site File), administer the medication again as soon as is possible.

If a dose or doses are omitted for clinical reasons record on the baby’s drug chart noting why. An Incident Form is not required, but please ensure this is documented in Form 2. Administer the medication again as soon as it is deemed safe to do so. This will not significantly affect the treatment and no further action is required.

At the end of the baby’s medication course (after 3 doses, permanent discontinuation of treatment, or death) please do the following:

o Cancel the prescription and retain all unused ampoules in the allocated pack o Depending on local practice, ampoules which have been used as and when

dosing, can be placed in a sharps bin for destruction. o Place any unused packs in a clear plastic holding container labelled ‘Baby-

OSCAR Trial; used packs for reconciliation’. o All ampoules should be returned to Pharmacy or the LRN (dependent on your

local arrangement) and an IMP Accountability Log completed. The log is then sent to NPEU CTU, who authorise the Site to destroy the IMP; Hospital then destroys at site and returns the slip as proof of destruction.


Guidance Sheet 3: IMP (c) Reconciliation of trial medication

(flow diagram)

The flow diagram below illustrates the events that need to be recorded to ensure

complete reconciliation of the allocated trial medication.

The baby is allocated medication at randomisation

Record the allocated

pack ID number (1 letter + 4 digits) in Form 1:

Trial Entry

Start medication – loading dose of 2 ml/kg, followed by

1 ml/kg 24 and 48 hours

after the initial loading dose. ampoules can be disposed of

in the sharps bin, as and when doses are administered

Record administration in: - the baby’s drug

chart

- Form 2 if possible and when applicable note any omitted or additional doses

Accountability log is completed and sent to the

NPEU CTU to confirm accountability is

demonstrated, and for

authorisation of destruction of any remaining ampoules

Record ampoule wastage in the IMP Accountability Log

Unused ampoules are recorded and collected by the LRN/Pharmacy

Destruction of left over medication is recorded by the Pharmacy after NPEU CTU approval

Cancel the medication prescription in the baby’s

drug chart; record the date of the last dose and number of omitted doses in Form 2

Prescribe the allocated

medication in the baby’s drug chart noting the

Pack ID Number Word as follows: ‘Baby-OSCAR clinical trial medication, loading dose 2 ml/kg, maintenance doses two and three, 1 ml/kg, [enter 5-character alphanumeric value e.g. P1234]’

At the end of the baby’s course of medication, retain

unused ampoules for collection by the LRN/Pharmacy


Guidance Sheet 3: IMP (d) End of trial medication procedure

The daily administration of the trial medication should continue until all 3 doses have been administered. The medication may be discontinued sooner than this if the baby dies or at clinician or parental request. Data collection should continue until discharge, or death, except if the baby is completely withdrawn from the trial at parental request. This sheet details what should happen in each circumstance. Baby death

If a baby dies before being discharged from hospital, complete a Form 6: Baby Outcomes (Transfer, Discharge or Death) covering the period that the baby was an inpatient in your hospital

In addition, please send a copy of the discharge summary and, if and when available, a copy of the post-mortem examination report.

Clinician decision to stop the medication permanently

There will be very few instances where the clinician will need to permanently discontinue the medication. It will be far more common for the medication to be temporarily discontinued for clinical reasons, and restarted when it is deemed safe to do so

If permanently discontinued, cancel the prescription, but the baby should remain in the trial and complete data collection procedures as normal.

Parent request to withdraw from the trial

A parent has the right to withdraw their baby from the trial at any time and for any reason, without prejudice to the baby’s care; they do not have to provide a reason for their decision

o It is important that you clarify with the parent(s) whether, despite stopping the medication, they would agree to:

retention and use of the data already collected, and for data collection to continue to completion, i.e. any outstanding ECHO

(due around 3 weeks of age) (if applicable), and an Oxygen Reduction Test (due at 36 weeks of postmenstrual age) (if applicable)

After consulting the parents complete Form 7: Baby withdrawal recording their wishes regarding the withdrawal

o Cancel the baby’s prescription, and, o Place a copy of the completed Form 7 in the baby’s clinical notes and send the

original to the Trial Co-ordinating Centre. In all instances retain the unused ampoules in the allocated pack. The LRN will collect all used packs and reconcile, or send to the Pharmacy for reconciliation.


Guidance Sheet 3: IMP (e) Storage monitoring

In the Baby-OSCAR Trial there is a provision for IMP being held on the neonatal unit and/or pharmacy. On the neonatal unit the IMP should be stored in a locked cupboard or room. In the hospital pharmacy, the IMP should be stored in a designated area for trial IMPs and records will be maintained in accordance with pharmacy’s standard operating procedure.

There is no specific requirement for temperature monitoring for the Baby-OSCAR IMP as stated in the SmPC for Pedea. The IMP should be stored as per Trust procedures.

If there are any concerns regarding the Baby-OSCAR IMP, contact the Baby-OSCAR Trial team immediately (by calling extension 01865 617965 within office hours or emailing [email protected] outside office hours).

The site team will report any IMP issues using the Baby-OSCAR Incident and Deviation Reporting Form and document any further action in response to the reported issue.

mailto:[email protected]

Documents

Guidance Sheet 3: IMP (a) Trial medication stock control · EudraCT No: 2013-005336-23, REC Ref: 14/EM/0172 Guidance Sheet 3_Version 5 dated 27/02p/18 Page 8 of 14 Ibuprofen or placebo