DEPTAbnormal Doppler Enteral Prescription Trial

ISRCTN 87351483, MREC ref. 05/Q1606/121, Version 2, September 2007

Handbook

September 2007

ISRCTN87351483

We would like to thank our funders:

Action Medical Research

and the

Garfield Weston Foundation

ADEPT is sponsored by:

Oxford UniversityResearch ServicesLevel 3The John Radcliffe HospitalHeadingtonOxfordOX3 9DU

Contents1. INTRODUCTION 1

1.1 Overview of the study design 1Eligibility 1Randomisation 2Interventions 2Outcomes 2

2. CO-ORDINATION OF THE STUDY 3

2.1 Central co-ordination 3

2.2 Local co-ordination 3

2.3 Study documentation 4

3. RECRUITING BABIES TO THE STUDY 5

3.1 Which babies can be recruited to ADEPT? 5

3.2 Until what age are babies eligible? 6

3.3 Talking to parents in the antenatal period 6

3.4 On admission of the baby to the neonatal unit 6

4. CONSENT 7

4.1 Randomisation 7

4.2 Randomisation in error 8

4.3 Events occurring between randomisation and intervention 8

5. ADEPT FEEDING SCHEDULES 9

5.1 Feed Groups: Early and Late 9

5.2 Advancing feeds 9

5.3 Parenteral nutrition 9

5.4 Mode of feeding 9

5.5 Type of milk 9

5.6 Feed intolerance 10

5.7 Reintroduction of feeds 10

5.8 Abdominal pathology 10

6. DATA COLLECTION 11

7. TRANSFERS 13

7.1 Transfer of a baby recruited to ADEPT from your unit 13

7.2 Instructions for transfer of the baby 13

7.3 Transfer and type of milk feed 14

7.4 Transfer of a baby into your unit 14

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8. SERIOUS ADVERSE EVENT (SAE) AND SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) REPORTING 15

9. WITHDRAWAL OF A BABY FROM THE STUDY 16

10. CONTACT WITH PARENTS 17

10.1 Going Home Pack 17

10.2 Newsletters 17

11. FREQUENTLY ASKED QUESTIONS 18

12. DEFINITIONS OF TERMS USED IN THE ADEPT STUDY 21

12.1 Entry Form 21

12.2 Discharge Form 23

12.3 Episode of NEC or other Abdominal Pathology Form 25

12.4 Serious Adverse Event (SAE) & Suspected Unexpected Serious Adverse Reaction (SUSAR) Form 26

13. APPENDIX 27

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1. INTRODUCTIONThe Abnormal Doppler Enteral Prescription Trial (ADEPT) is a national multi-centre randomised controlled trial which will evaluate whether a policy of starting milk feeds early is beneficial for babies born before 35 weeks gestation who are small for gestational age at birth and who had abnormal umbilical artery blood flow or cerebral redistribution in the antenatal period.

A meta-analysis of observational studies has suggested an increased incidence of necrotising enterocolitis (NEC) in babies who had absent or reversed end diastolic flow velocity (AREDFV) in the umbilical artery before birth1.

The best time to start milk feeds and the optimum rate at which to increase milk feeds are areas of clinical uncertainty in this at-risk group. The purpose of this study is to improve knowledge of how to feed these high-risk babies.

The study is designed to be as simple as possible so that staff in participating units will be able to recruit babies to the study without difficulty and without a large investment of time.

1.1 Overview of the study design

Eligibility Babies are eligible to be recruited to ADEPT if they meet the following four criteria:

Gestational age less than or equal to 34 weeks + 6 days AND Antenatal ultrasound showing either: absent or reversed end diastolic flow velocities on at least 50% of the Doppler waveforms from the umbilical artery on at least one occasion during pregnancy OR cerebral redistribution, defined as occurring when both the umbilical artery pulsatility index is greater than the 95th centile and the middle cerebral artery pulsatility index is less that the 5th centile for gestational age ANDSmall for gestational age (birth weight < 10th centile for gestational age based on Child Growth Foundation Charts – see page 5) AND Postnatal age 20-48 hours

Babies transferred in to a participating centre are eligible for the study if they meet the above criteria.

Infants are not eligible if any of the following are present:

major congenital abnormality including known chromosomal abnormalitytwin-twin transfusion intra-uterine transfusion or exchange transfusionRhesus iso-immunisationsignificant multi-organ failure prior to trial entryinotropic drug support prior to trial entryalready receiving or have received enteral feeding

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Dorling JS, Kempley ST, Leaf A. Feeding growth-restricted preterm infants with abnormal antenatal Dopplers. Arch Dis Child. 2005; 90: F359-F363.

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Randomisation This is through the central randomisation service based at the National Perinatal Epidemiology Unit (NPEU) in Oxford. The randomisation service is a website with telephone back up. This will provide a random allocation to one of the study groups, either “early” or “late” commencement of enteral feeds.

InterventionsEarly group: enteral milk feeds started on day 2 after birth (between 24 and 48 hours of age).

Late group: enteral milk feeds started on day 6 after birth (between 120 and 143 hours of age).

Feeds are started and increased in line with the study feeding schedule (see section 5, page 9)

Outcomes The primary outcomes of the study are age at which full enteral feeding is established (defined as 150ml/kg/day sustained for 72 hours) and the occurrence of NEC. Secondary outcomes include mortality, length of hospital stay, duration of parenteral nutrition, growth and cholestasis.

For more details of the background to the study, the choice of feeding schedule and the study design, please refer to the protocol in the ADEPT Documentation Box.

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2. CO-ORDINATION OF THE STUDY

2.1 Central co-ordination The study is co-ordinated by the ADEPT Co-ordinating Centre, National Perinatal Epidemiology Unit, Oxford, where the full-time Study Co-ordinator is based.

ADEPT Co-ordinating Centre National Perinatal Epidemiology UnitUniversity of Oxford, Old Road CampusOxfordOX3 7LFTel: 01865 289745 Fax: 01865 289740 Email: adept@npeu.ox.ac.ukWebsite: www.npeu.ox.ac.uk/adept

2.2 Local co-ordinationIn each participating neonatal unit there is a local co-ordinating team consisting of a neonatologist or paediatrician and a neonatal nurse.

Names of local co-ordinators

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2.3 Study documentationAll the documentation for ADEPT is stored in a black ADEPT Documentation Box kept in the neonatal unit. The local co-ordinators also have copies of all documents.

The contents of the ADEPT Documentation Box are:

Contact details of the Study TeamProtocol Summary protocolHandbook Information leaflets:

Antenatal Information Leaflet: Information for parents whose unborn baby has been found to have altered blood flow Parent Information Leaflet: Information for parents whose baby is receiving special or intensive care

Pre-consent discussion labelsBaby packs:

Consent FormBLISS booklet ‘How to feed your preterm baby’ The North Bristol NHS Trust Leaflet ‘Breast milk for sick and preterm babies’.Cot Card MagnetEntry FormDaily Feed LogDischarge FormGoing Home pack

Other data collection forms:Serious Adverse Event (SAE) and Suspected Unexpected Serious Adverse Reaction (SUSAR) Reporting FormsEpisodes of NEC or other Abdominal Pathology Forms

Transfer packsExtra Data Collection Forms Extra Going Home packs Eligibility cardsFeeding Regimen posterFREEPOST envelopes Documentation re-order forms

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3. RECRUITING BABIES TO THE STUDY

3.1 Which babies can be recruited to ADEPT?Babies are eligible to be recruited to ADEPT if they meet the following four criteria:

Gestational age less than or equal to 34 weeks + 6 days ANDAntenatal ultrasound showing either: absent or reversed end diastolic flow velocities on at least 50% of the Doppler waveforms from the umbilical artery on at least one occasion during pregnancy OR cerebral redistribution, defined as occurring when both the umbilical artery pulsatility index is greater than the 95th centile and the middle cerebral artery pulsatility index is less that the 5th centile for gestational age ANDSmall for gestational age (birth weight < 10th centile for gestational age based on Child Growth Foundation Charts – as defined in the Table of Eligible Birth Weights). AND Postnatal age 20-48 hours

Table of eligible birth weights

Gestational age range Birthweight(g)Weeks/days Weeks/days

lower upper Male Female34+4 34+6 <1978 <1908

33+4 34+3 <1802 <1723

32+4 33+3 <1622 <1548

31+4 32+3 < 1454 <1382

30+4 31+3 < 1299 < 1231

29+4 30+3 < 1159 < 1093

28+4 29+3 < 1033 < 970

27+4 28+3 < 919 < 861

26+4 27+3 < 814 < 760

25+4 26+3 < 718 < 666

24+4 25+3 < 626 < 577

23+4 24+3 < 537 < 491

22+4 23+3 < 450 < 406

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ReferencesFreeman JV, Cole T J, Chinn S, Jones PRM, White EM & Preece MA. Cross-sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995; 73:17-24.Subsequently, the weight reference was extended down to 23 weeksCole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med 1998; 17(4):407-29.

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3.2 Until what age are babies eligible?Babies admitted to the neonatal unit should be recruited before they are 48 hours old as those randomised to the early feeding group should start feeds between 24 and 48 hours of age.

The randomisation program will not accept a baby before 20 hours of age and after 48 hours of age.

3.3 Talking to parents in the antenatal periodIt is anticipated that many eligible babies will be identified in the antenatal period as being small for gestational age and having abnormal umbilical blood flow. Where possible parents will be approached prior to delivery and provided with information about the ADEPT study. An Antenatal Information Leaflet is available.

3.4 On admission of the baby to the neonatal unitWhen an eligible baby is admitted to the neonatal unit, the parents should be given a copy of the Parent Information Leaflet and ADEPT should be discussed with them. Informing parents about ADEPT at this stage allows them time to consider entering the study.

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4. CONSENTAgreement to participate in the study should ideally be sought from both parents of an eligible baby. Legally, the father may only sign the consent form if the parents are married or the father is named on the birth certificate.Consent forms are provided in the baby packs which are kept in the ADEPT Documentation Box. They consist of four sheets (writing on the top sheet is copied automatically onto the other sheets).When the Consent Form has been completed, the white copy should be given to the parents, the green copy should be returned to the ADEPT Co-ordinating Centre using one of the FREEPOST envelopes provided in the ADEPT Documentation Box, the yellow copy should be put in the Principal Investigator’s folder and the pink copy should be stored in the baby’s notes.

4.1 RandomisationWhen a baby is eligible to join ADEPT and parental consent has been obtained the baby can be randomised into the study. Consent may be taken at any time after birth but:

the baby must be at least 20 hours old before he or she can be randomised on the ADEPT website.the baby should be recruited before he or she is 48 hours old as those randomised to the early feeding group should start feeds between 24 and 48 hours of age.

The randomisation program will not accept a baby before 20 hours of age and after 48 hours of age.

Fill in questions 1 to 9 of the Entry Form.Check that the baby is eligible (i.e. answers to questions 1 to 8 are as required). Access the randomisation website when the baby is at least 20 hours old and follow the on screen instructions (https://rct.npeu.ox.ac.uk/adept).Write the study number under Question 9 of the Entry Form.The program will calculate when feeds should be started.Under Question 9 of the Entry Form tick which feed regimen has been allocated and the dates and times between which the feeds should be started.

The baby has now been enrolled and randomised into the ADEPT Study.

Fill in the rest of the Entry Form (questions 10 to 21) and put the top sheet into the Principal Investigator’s folder. Please send the copy to the ADEPT Co-ordinating Centre in one of the FREEPOST envelopes provided in the ADEPT Documentation Box. Complete the front sheet of the Daily Feed Log.

If the website is unavailable or if you experience any difficulties with the website, you may randomise by:

A. Telephone:Telephone 07623 947508, hold to speak to an operator and then leave the following message: “Please phone <YOUR NAME>, at <YOUR HOSPITAL>, on <YOUR FULL TELEPHONE NUMBER> about ADEPT”

Please DO NOT give the number of the busiest telephone on the unit, another call might block the line when Sarah is trying to call you back!

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B. Via the internet: (this is faster than option 3 - email)Log on to the Paging Website at www.npeu.ox.ac.uk/pager.Enter your email address (be accurate!) in the box as requested.Enter the following message in the <Message> box: “Please phone <YOUR NAME>, at <YOUR HOSPITAL>, on <YOUR FULL TELEPHONE NUMBER> about ADEPT”Click on “Send pager message”.

Please DO NOT give the number of the busiest telephone on the unit, another call might block the line when Sarah is trying to call you back!

C. By sending an Email:

Send an email to 947508.corep@p1c.net

You will receive an email acknowledgement that the message has been accepted. Do remember that this method does depend on the speed with which your Internet Service Provider delivers your message. The total message size is limited to 175 characters.

Whichever method of contact you use you should receive a reply within 15 minutes of the message acknowledgement. If you do not get a response then we suggest that you try again and wait for another 15 minutes. If there is still no reply then telephone the following number: 07885 720537 (you might occasionally be diverted to voice mail but we will respond as soon as we get your message).

4.2 Randomisation in errorIf it is felt that a baby has been randomised to ADEPT inappropriately, the clinical team caring for the baby must decide whether or not to continue with the feeding regimen allocated. Regardless of what decision is made, the central Co-ordinating Centre should be contacted on 01865 289745 and the baby’s information should continue to be recorded on the ADEPT data collection forms until hospital discharge.

4.3 Events occurring between randomisation and interventionA baby may become unwell between the time of randomisation and starting feeds. Management of the baby should be at the discretion of the attending clinician. Once randomisation has occurred babies are considered to be in the study even if feeds are not then started at the advised time. These babies should have their study data entered in the Daily Feed Log regardless of whether feeding has commenced at the anticipated time and should have a Discharge Form completed at the time of discharge, transfer or death.

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5. ADEPT FEEDING SCHEDULES

5.1 Feed Groups: Early and LateBabies will be randomised to either early or late feed groups. This is defined as:

Early feed groupBabies start milk feeds between 24 and 48 hours of age, i.e. on day 2.Late feed groupBabies start milk feeds between 120 and 143 hours of age, i.e. on day 6.

5.2 Advancing feedsThe rate of feed advancement in ADEPT is the same for babies in both the early and late groups; only the time of starting feeds differs. The rate of increase should be adhered to unless the clinical state of the baby requires this approach to be modified.

Feeding schedules for the study can be found in the appendix to this handbook (pages 26 and 27).

Items 5.1 and 5.2 are requirements of the study and should be adhered to. The following points are recommendations only.

5.3 Parenteral nutritionMaintenance intravenous fluids will be started at birth in line with local policy with introduction of protein, fat and electrolytes by the second or third day after birth.

5.4 Mode of feedingIt is anticipated that these babies will be fed through a gastric tube. Whether this is nasal or oral is at the discretion of the local centre. Feeds should be given hourly or continuously. However, if the local centre wishes to have longer intervals between feeds then the volume of milk given at each feed should be increased so that the daily total volume remains in line with the schedule.

5.5 Type of milkFor the purposes of the ADEPT Study the choice of milk recommended, in descending order of preference, is: mother’s own breast milk, donated breast milk, infant formula. Whether preterm or term formula is given initially will be at the discretion of the local clinician but the recommendation would be for formula fed infants with gestation less than 34 weeks to be fed preterm formula within one week of milk commencement. Babies may have mixed feeding.

The final choice of which milk is used will rest with the infant’s mother and the local clinician. Breast milk fortification may be considered if additional nutritional support is required once the baby is tolerating full milk feeds of breast milk of > 150ml/kg/day.

Some mothers may have difficulty in expressing adequate volumes of breast milk. This may be overcome by using donated breast milk in those units that have a breast milk bank. Each unit should make full use of the breast feeding support staff who are available to nursing mothers. Information leaflets to encourage early milk expression and breast feeding are provided in the Baby Packs (the BLISS booklet and North Bristol NHS Trust leaflet).

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5.6 Feed intoleranceThe feeding schedule should be followed regardless of the type of milk fed, ventilation status or the presence of umbilical catheters unless deviation is specifically requested by the local clinician. A decision to withhold feeds or deviate from the schedule because of clinical deterioration will remain at the discretion of the local clinician. Any deviation from the feeding schedule should be recorded on the Daily Feed Log along with the reasons for the deviation.

Gastric residuals are common in preterm infants. If the infant is well with no abnormal abdominal signs it is usually safe to continue with enteral feeds when the residuals are less than 2-3ml.

5.7 Reintroduction of feedsIf feeds are withheld, the clinician is free to start from day 1 of the schedule or re-start at the volume tolerated previously then increase as scheduled, or hold for one or more days at a set volume before increasing as scheduled.

5.8 Abdominal pathologyThe management of abdominal pathology including NEC will be according to the policy of the local centre and the discretion of the local clinicians. An Episode of NEC or other Abdominal Pathology Form should be filled out (including NEC staging) for each completed episode of abdominal pathology. The definitions of the modified Bell’s Staging of Necrotising Enterocolitis are on the reverse of the form and on page 24 in the Definitions section of this handbook. Reintroduction of feeds is as section 5.7 above.

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6. DATA COLLECTIONThe following forms should be completed for babies enrolled in the ADEPT Study. All forms should be sent to the ADEPT Co-ordinating Centre in Oxford when the baby is discharged home or transferred from your hospital or dies, using the ADEPT Study FREEPOST envelopes supplied in the documentation box.

Entry FormQuestions 1-9 must be completed in order to randomise the baby. Neonatal details (Q10 – Q16) can then be completed. Antenatal details (Q17 - Q21) should be completed by reference to the mother’s notes. Q21 should be completed for the five most recent antenatal Doppler studies.

The top sheet should be put into the Principal Investigator’s folder and the copy should be sent to the ADEPT Co-ordinating Centre using the FREEPOST envelope provided in the documentation box as soon as the Entry Form has been completed.

Daily Feed LogComplete the front sheet with the baby’s study details and first feed details. Fill out the Daily Feed Log at the end of every 24 hour period. One column should be completed for each 24 hour period, it would be best to coincide with completion of your daily intensive care chart. If feeding is interrupted ensure that the reason for the interruption is entered using the key at the foot of the log. An example of a completed log can be seen on the back page of the Daily Feed Log. If the baby hasn’t reached 150ml/kg/day for 3 days by day 28 OR is less than 28 days old please continue the Daily Feed Log on an additional form until 150/kg/day for 3 days is reached. Extra copies of the Daily Feed Log are provided in your documentation box.

Put the completed top sheet of the Daily Feed Log into the Principal Investigator’s folder and forward the copy to the ADEPT Co-ordinating Centre using the FREEPOST envelope provided in the documentation box when the baby is transferred from your hospital, discharged home or dies.

36 Week Form Please complete this form when the baby is 36 weeks old. An email reminder will be sent one week before the baby is 36 weeks old and again one day before the baby is 36 weeks old.

Discharge FormThis is to be completed at discharge, transfer or death. If transferred, please record only the events that occurred in your hospital up until the time the baby was transferred. Once completed the top sheet should be put into the Principal Investigator’s folder and the copy should be returned to the ADEPT Co-ordinating Centre using the FREEPOST envelope provided in the documentation box.

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Episodes of NEC or other Abdominal Pathology FormComplete this form for every completed episode of abdominal pathology that the baby has by ticking the appropriate boxes. The definitions for NEC staging are given on the reverse of the Episodes of NEC or other Abdominal Pathology Form.

Please send the copy of this form to the ADEPT Co-ordinating Centre using the FREEPOST envelope provided in the documentation box when the baby is discharged home, transferred from your hospital or dies. The top sheet should be put in the Principal Investigator’s folder.

Serious Adverse Event (SAE) / Suspected Unexpected Serious Adverse Reaction (SUSAR) FormPlease complete a form for each serious (unexpected) adverse event (SAE) or suspected unexpected serious adverse reaction (SUSAR). The SAE/SUSAR Form can be found in the documentation box, instructions for its completion are on the reverse of the form. Once completed this form should be faxed to the ADEPT Co-ordinating Centre on 01865 289740.

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7. TRANSFERS

7.1 Transfer of a baby recruited to ADEPT from your unitMany babies are transferred between hospitals and it is important that data collection is continued for the whole of the baby’s stay in hospital. Each hospital with a baby taking part in ADEPT should complete a Discharge Form when the baby leaves that hospital, whether it is discharged home, transferred or dies. Each Discharge Form will include details of the baby’s stay in that hospital only. Babies that are transferred will therefore have two or more Discharge Forms, each one recording the details of the baby’s stay in each hospital.

To help the receiving hospitals (which may not be recruiting to ADEPT) those centres taking part in ADEPT have been provided with Transfer Packs, which contain all of the necessary instructions and documentation for completing the data collection for a baby who is transferred to a different hospital.

The transfer pack contains:

Full instructions for the receiving hospitalsA Study HandbookA Feeding ScheduleA Daily Feed Log A Discharge FormA Serious Adverse Event Form, in case of serious adverse events in the receiving hospitalAn Episodes of NEC or other Abdominal Pathology Form, in case of episodes of abdominal pathology in the receiving hospitalA Going Home PackA FREEPOST envelope, for return of the completed data collection forms

Please telephone the ADEPT Co-ordinating Centre on 01865 289745 or fax 01865 289740 and let us know which hospital the baby has been transferred to. If telephoning out of hours please leave a message on the answering machine including:

Your name and the hospital you are calling fromBaby’s nameBaby’s ADEPT study numberBaby’s hospital numberName of hospital to which the baby is being transferredThe name of the receiving paediatrician

7.2 Instructions for transfer of the babySite specific assessment (LREC) approval is not necessary for centres to continue treatment which has already been allocated, it is only needed for the hospitals where babies are recruited to ADEPT.

If a baby who has been recruited to ADEPT is to be transferred to another hospital then please follow the instructions below and liaise closely with the hospital the baby is being transferred to (these instructions are also provided with the Transfer Packs).

On the day the baby is transferred complete a Discharge Form for the time that the baby has been in your unit. Return the copy of the form to the ADEPT Co-ordinating Centre in a FREEPOST envelope provided in the documentation box. Keep the top sheet in the Principal Investigator’s folder.

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Take a Transfer Pack from the ADEPT Documentation Box and complete the following in the Discharge Form (taken from the Transfer Pack):

Baby’s ADEPT study numberBaby’s nameBaby’s date of birth

This will allow the receiving hospital to identify the ADEPT baby.

If the baby has established full enteral feeding (defined as 150ml/kg/day for 3 days) and is older than 28 days, return the copy of the completed Daily Feed Log with the Discharge Form to the ADEPT Co-ordinating Centre in a FREEPOST envelope provided in the documentation box.

If the baby has not established full enteral feeding (defined as 150ml/kg/day for 3 days) OR is less than 28 days old, then:

Please make 2 photocopies of the Daily Feed Log. Retain one photocopy in the Principal Investigator’s folder and send one copy, along with a completed Discharge Form and any other relevant forms (i.e. NEC Form), to the ADEPT Co-ordinating Centre using a FREEPOST envelope provided in the documentation box. Please send the original Daily Feed Log and the Transfer Pack with the baby to the receiving hospital.

7.3 Transfer and type of milk feedOccasionally a baby may be transferred to a unit where a particular type of milk is not available. This may occur for example in units that have a breast milk bank or have a preferred milk formula. When possible, feeding should continue with milk which most closely resembles that fed in the referring centre for the first 48 hours after transfer. The type of milk feed remains at the discretion of the local clinician and the mother.

7.4 Transfer of a baby into your unitA baby that has been recruited to ADEPT may be transferred into your hospital. If this happens, the baby should arrive with a Transfer Pack and may also arrive with a partly completed Daily Feed Log. If a Transfer Pack does not arrive with the baby, please contact the ADEPT Co-ordinating Centre on 01865 289745.

The following instructions are provided with the Transfer Pack:

Please continue the completion of the Daily Feed Log, if necessary. Please complete an Episodes of NEC or other Abdominal Pathology Form, and/or a Serious Adverse Event (SAE) / Suspected Unexpected Serious Adverse Reaction (SUSAR) Form should either or both of these events occur. A completed SAE/SUSAR Form should be faxed to the ADEPT Co-ordinating Centre on 01865 289740.Please complete the enclosed Discharge Form on the baby’s discharge, subsequent transfer or death. The completed Discharge Form and any completed Episodes of NEC or other Abdominal Pathology Forms can be sent back to the ADEPT Co-ordinating Centre in the Freepost envelope provided.If the baby is transferred to you before 36 weeks of age a 36 Week Form will be sent to you in due time.

Information to be recorded on the forms is for the baby’s time in your unit only.

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When the baby is being discharged home please give the Going Home Pack, which was enclosed in the Transfer Pack, to the parents. The Going Home Pack contains a letter about the study and a Change of Address card.

8. SERIOUS ADVERSE EVENT (SAE) AND SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) REPORTINGPlease complete a SAE/SUSAR Form for each serious (unexpected) adverse event (SAE) or suspected unexpected serious adverse reaction (SUSAR).

SAE: A serious (unexpected) adverse event is one which is not anticipated, not known to be related to the condition being studied or the intervention being used.

In the context of this study, SAEs will include:

Death Severe central line complication: cardiac tamponade, major vessel thrombosisOther serious adverse events

SUSAR: an adverse reaction, the nature or severity of which is not consistent with the expected outcomes of the treatment being offered.

If an SAE or SUSAR occurs:

Complete both pages of the SAE/SUSAR Form, which can be found in the documentation box, within 48 hours of the eventFax it immediately, to the ADEPT Co-ordinating Centre in Oxford (Fax: 01865 289740)

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9. WITHDRAWAL OF A BABY FROM THE STUDYDuring the study a parent or clinician may wish to withdraw the baby from the intervention.

Please clarify with the parents or clinician whether they would agree to data collection being continued until discharge. Even if the intervention is no longer being followed please document this in the baby’s notes and contact the ADEPT Co-ordinating Centre (01865 289745) to inform them of the withdrawal and whether data will continue to be collected.

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10. CONTACT WITH PARENTSNewsletters will be sent at regular intervals to parents whose babies have participated in ADEPT. Extreme care will be taken prior to the newsletter being sent to ensure that families who have been bereaved are contacted by letter asking if they would like to receive a newsletter. All babies taking part in the study will be ‘flagged’ through the NHS Central Register so we will be notified of any deaths after discharge from hospital.

10.1 Going Home PackWhen the baby is being discharged home please give the enclosed Going Home Pack to the parents. This pack contains a letter about the study and a Change of Address card.

10.2 NewslettersCopies of newsletters will be sent to Co-ordinators of all participating centres.

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11. FREQUENTLY ASKED QUESTIONSCan I bolus feed or do feeds need to be given continuously? The mode of feeding is at the discretion of the clinician looking after the baby. The feeding charts in the Appendix (pages 26 and 27) show the hourly and daily volumes of feed the baby should be receiving.

Do feeds need to be given hourly or can I feed less frequently e.g. 2 hourly? The frequency of feeding is at the discretion of the clinician looking after the baby. The feeding charts in the Appendix (pages 26 and 27) show the hourly and daily volumes of feed the baby should be receiving. If a baby is being fed 2 hourly rather than hourly simply double the hourly rate shown in the chart e.g. an 800g baby on day 4 of feeding would be on an hourly rate of 1.5 ml/kg/hr. If you choose to feed the baby 2 hourly then the volume would be 3.0ml/kg/2 hourly.

Can I enrol a baby into the study if the mother says she will only accept breast milk feeding for her baby? Yes this is acceptable. Obviously if that baby is randomised to the early feeding group we would aim to have some breast milk available by 48 hours for the baby to start. You could refer to the leaflets on breast milk expression which are included in the ADEPT Documentation Box to give Mum advice.

What do I do if a mother will only accept breast milk and I don’t have any? As with the previous question you can only give the baby the milk which the mother agrees to. We would ask that the mother is given help to enhance her own breast milk production so that the shortfall of maternal milk is minimised. The Daily Feed Log still needs to be completed stating how much milk the baby actually received as our analysis will be by ‘intention to treat’ i.e. it will compare the two groups at randomisation regardless of what feeds were actually received.

What milk should I give if a mother is expressing breast milk but there is not enough to keep up with the feeding schedule? We would encourage lactation as early as possible in all study mothers and ensure that the NICU and postnatal midwifery staff are aware that the woman is taking part in the ADEPT Study. We would ask to maintain the recommended study milk volumes by supplementing the maternal milk with donor breast milk or formula according to the discretion of the clinician looking after the baby and maternal acceptance.

Does it matter which formula milk I use? No. The choice of formula used is at the discretion of the clinician looking after the baby. Our only recommendation is that babies fed with formula ought to be receiving a preterm formula within one week of milk commencement.

Can I fortify the feeds? Yes – but only once the baby has reached 150ml/kg/day of feed.

Should middle cerebral artery Dopplers be performed in all cases of suspected IUGR where umbilical artery Dopplers are abnormal? If the antenatal ultrasound shows absent OR reversed end diastolic flow velocities on at least 50% of the Doppler waveforms on at least one occasion during pregnancy – the baby can be enrolled into the study. If the antenatal ultrasound shows reduced end diastolic flows but they are not absent or reversed, then the baby can only be recruited if there is evidence of cerebral

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redistribution on the antenatal scans. If your fetal scanning department do not routinely do scans of the middle cerebral artery then you might consider asking for this to be done to determine if the baby could be enrolled into the study. If they are not available and there is no absent or reversed end diastolic flow in the umbilical artery then the baby does not meet the entry criteria and cannot be enrolled.

Can I enrol term babies with absent or reversed end diastolic flows who are below the 10th centile for weight at birth? No. The study is only for babies up to 34 weeks and 6 days.

Can a baby on my unit be enrolled into more than one study? Yes. Essentially there is no problem with a baby being enrolled into more than one study providing the parents have given consent. If you feel that there might be a specific reason why a baby might not be eligible please discuss this with the Study Co-ordinator on 01865 289745.

What do I do if a baby in the study has suspected NEC? The baby should be treated in accordance with the view of the clinician looking after the baby. We would ask that you complete and return an Episodes of NEC or other Abdominal Pathology Form to the ADEPT Study Co-ordinator in a FREEPOST envelopes provided in the documentation box.

What do I do if a baby in the study has repeated abdominal symptoms? Treatment would be in accordance with the view of the attending clinician. We would ask that an Episodes of NEC or other Abdominal Pathology Form is completed for EACH episode and returned to the ADEPT Study Co-ordinator in a FREEPOST envelope provided in the documentation box.

I see the Daily Feed Log should have a complete column for each 24-hour period - when should I start entering data? Data should be collected from birth onwards, so as soon as the baby starts IV fluids. The first day of data collection will usually not be a complete 24-hour period. For the first column, collect the data from the time when fluids start to the time when you start your new daily ITU chart. From then on it will be easy to fill in the data on the Daily Feed Log for every 24 hours at the time when you normally add up totals for the day.

How long do I have to fill in the Daily Feed Log for? We want data for the first 28 days of feeding in these babies. However, if by 28 days of feeding the baby has not reached 150ml/kg/day of enteral feeds for 3 consecutive days we want to continue to collect data on a Daily Feed Log until the baby has been on 150ml/kg/day of enteral feed for 3 consecutive days.

What happens if a baby receives inotropes or develops multi-organ failure after randomisation? Once a baby is recruited to the ADEPT Study they remain part of the study and full data should be collected for them. Feeds should be withheld until the clinician considers that the baby is fit to receive enteral feeds. On the Daily Feed Log record the reason why feeds were omitted as ‘Other’ and specify the reason in the space provided (e.g. ‘on inotropes’). Once feeds are restarted the rate of progress of feeds should follow the recommended regimen.

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What happens if a baby is found to have a congenital abnormality or chromosomal abnormality after randomisation? The baby’s data should continue to be collected up to discharge. Contact the ADEPT Co-ordinator and give the diagnosis in the ‘Additional Information’ section on page 4 of the Discharge Form. Full data on the patient is vital when detailing excluded patients in the study results.

What happens if an exclusion criterion becomes apparent after randomisation? Collect all data but flag it up on the Discharge Form in ‘Additional Information’.

What should I do if a larger baby (>33wks) is demanding a larger volume than the protocol suggests? If a baby >33 weeks gestation is hungry and demanding larger volumes of feed than the protocol suggests then your clinical discretion should be used and the volumes given to the baby should be recorded in the Daily Feed Log.

If any questions arise please contact:

ADEPT Co-ordinating CentreNPEUUniversity of OxfordOld Road CampusOxfordOX3 7LFTel: 01865 289745Email: adept@npeu.ox.ac.uk

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ReferencesFreeman JV, Cole T J, Chinn S, Jones PRM, White EM & Preece MA. Cross-sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995; 73:17-24.Subsequently, the weight reference was extended down to 23 weeksCole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med 1998;17(4):407-29.

12. DEFINITIONS OF TERMS USED IN THE ADEPT STUDY

12.1 Entry Form

Table of eligible birth weightsAn infant is eligible for recruitment if their birthweight is LESS than the 10th centile for NEAREST week of gestational age at birth.

Gestational age range Birthweight(g)Weeks/days Weeks/dayslower upper Male Female34+4 34+6 <1978 <1908

33+4 34+3 <1802 <1723

32+4 33+3 <1622 <1548

31+4 32+3 < 1454 <1382

30+4 31+3 < 1299 < 1231

29+4 30+3 < 1159 < 1093

28+4 29+3 < 1033 < 970

27+4 28+3 < 919 < 861

26+4 27+3 < 814 < 760

25+4 26+3 < 718 < 666

24+4 25+3 < 626 < 577

23+4 24+3 < 537 < 491

22+4 23+3 < 450 < 406

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Absent or reversed end diastolic flow velocities (AREDFV) Absent or reversed end diastolic flow velocities on at least 50% of the Doppler waveforms from the umbilical artery on at least one occasion during pregnancy.

Absent Flow in Diastole:

Reversed End Diastolic Flow:

Estimated date of deliveryThis is the best estimate based on ultrasound scan or date of last menstrual period (whichever method is usually used in your hospital) based on a 40 week gestation.

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12.2 Discharge FormVentricular dilatation (distance from midline to lateral border of the lateral ventricle at the level of the foramen of Munro) is defined as a ventricular index 4mm above the 97th centile for corrected gestational age.

CholestasisConjugated bilirubin level > 25 micromol/litre

GI PathologyPlease complete an Episodes of NEC or other Abdominal Pathology Form

for each episode of GI pathology. If a baby develops abnormal signs which develop into NEC resulting in GI perforation requiring surgery, count this as one episode. If, however, a baby has an episode of suspected NEC which resolves, enteral feeding is re-commenced, and then two weeks later develops a further episode of suspected NEC, count these as two episodes. If you are uncertain whether the baby has had one or two episodes please complete two Episodes of NEC or other Abdominal Pathology Forms.

Definition of levels of neonatal intensive care (British Association of Perinatal Medicine (BAPM) Standards for Hospitals Providing Neonatal Intensive Care, 2nd edition 2001)

Intensive Care includes babies:Receiving any respiratory support via a tracheal tube and in the first 24 hours after its withdrawalReceiving Nasal CPAP for any part of the day and less than five days oldBelow 1000g current weight and receiving Nasal CPAP for any part of the day and for 24 hours after withdrawalLess than 29 weeks gestational age and less than 48 hours oldRequiring major emergency surgery, for the pre-operative period and post-operatively for 24 hoursRequiring complex clinical procedures:

Full exchange transfusionPeritoneal dialysisInfusion of an inotrope, pulmonary vasodilator or prostaglandin and for 24 hours afterwards

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Any other very unstable baby considered by the nurse-in-charge to need 1:1 nursingA baby on the day of death

High dependency care includes babies:Receiving Nasal CPAP for any part of the day and not fulfilling any of the criteria for intensive careBelow 1000g current weight and not fulfilling any of the criteria for intensive care Requiring parenteral nutritionHaving convulsionsReceiving oxygen therapy and below 1500g current weightRequiring treatment for neonatal abstinence syndromeRequiring specified procedures that do not fulfil any criteria for intensive care:

Care of an intra-arterial catheter or chest drainPartial exchange transfusionTracheostomy care until supervised by the parent

Requiring frequent stimulation for severe apnoea

Definition of infectionAny baby with clinical signs compatible with sepsis with positive culture of blood, CSF, or other normally sterile site, and with haematological markers of infection including one or more of the following: raised CRP, high or low white blood cell count, thrombocytopenia.

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12.3 Episode of NEC or other Abdominal Pathology Form

Disseminated intravascular coagulopathy (DIC)For the purposes of the study, DIC is defined as thrombocytopenia (platelet count <100 x 1012/L) with abnormal coagulation studies or raised D-dimers or elevated fibrin degradation products as indicated by specific laboratories normal ranges.

Modified Bells Staging of Necrotising Enterocolitis (Walsh et al. 1986)Stage IA - Suspected NEC:

Systemic signs: temperature instability, apnoea, bradycardia, lethargyIntestinal signs: Elevated pre-gavage residuals, mild abdominal distension, emesis, haem-positive stoolsRadiologic signs: Normal or intestinal dilatation, mild ileus

Stage IB - Suspected NEC:

Systemic signs: Same as stage IAIntestinal signs: bright red blood from rectumRadiologic signs: same as stage IA

Stage IIA - Definite NEC (mildly ill):

Systemic signs: Same as stage IAIntestinal signs: Same as stage IA, plus absent bowel sounds, +/- abdominal tendernessRadiologic signs: intestinal dilatation, ileus, pneumatosis intestinalis

Stage IIB - Definite NEC (moderately ill):

Systemic signs: Same as stage IIA, plus mild metabolic acidosis, mild thrombocytopeniaIntestinal signs: Same as stage IIA, plus absent bowel sounds, definite abdominal tenderness, +/- abdominal cellulitis or right lower quadrant massRadiologic signs: Same as stage IIA plus portal vein gas, +/- ascites

Stage IIIA - Advanced NEC (severely ill, bowel intact):

Systemic signs: Same as stage IIB, plus hypotension, bradycardia, severe apnoea, combined respiratory and metabolic acidosis, DIC, neutropeniaIntestinal signs: Same as stage IIB, plus signs of generalized peritonitis, marked tenderness, and distension of abdomenRadiographic signs: Same as stage IIB, plus definite ascites

Stage IIIB - Advanced NEC (severely ill, bowel perforated):

Systemic signs: Same as stage IIIAIntestinal signs: Same as IIIARadiologic signs: Same as stage IIB, plus pneumoperitoneum

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12.4 Serious Adverse Event (SAE) & Suspected Unexpected Serious Adverse Reaction (SUSAR) FormSAE: A serious (unexpected) adverse event is one which is not anticipated, not known to be related to the condition being studied or the intervention being used.

In the context of this study serious (unexpected) adverse events will include:

DeathSevere central venous line complication: cardiac tamponade, major vessel thrombosisOther serious adverse events

SUSAR: An adverse reaction, the nature or severity of which is not consistent with the expected outcomes of the treatment being offered.

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13. APPENDIX

Table 1: Feeding schedule – ml/kg/HOUR(NB feed advancement schedule is the same for babies in EARLY or LATE groups: only the timing of initiation of feeds differs)

Day of feeding

Volume of milk according to birth weight (ml/kg/HOUR)

<600g 600-749g 750-999g 1000-1249g ≥1250g1 0.5 0.5 0.5 0.5 1.02 0.5 0.5 0.5 1.0 1.53 0.5 1.0 1.0 1.5 2.04 1.0 1.5 1.5 2.0 2.55 1.5 2.0 2.0 2.5 3.06 2.0 2.5 2.5 3.0 3.57 2.5 3.0 3.0 3.5 4.0 - 4.58 3.0 3.5 3.5 4.0 - 4.5 5.0 - 5.59 3.5 4.0 4.0 - 4.5 5.0 - 5.5 6.0 - 6.25

10 4.0 4.5 - 5.0 5.0 - 5.5 6.0 - 6.2511 4.5 - 5.0 5.5 - 6.0 6.0 - 6.2512 5.5 - 6.0 6.2513 6.2514 Increase as required

Where 2 numbers are in a cell separated by a hyphen the first number indicates hourly volume/kg to feed for the first 12 hours of each 24 hour period. The second number in each cell indicates hourly volume/kg to feed for the second 12 hours of each 24 hour period.

Feeds should be given hourly or continuously. However, if there are longer intervals between feeds, e.g. 2 hourly feeds, then the milk volume should be increased accordingly.

Red border = feeds increase by 0.5ml/kg every 12 hours.

Blue border = feed volume reached 150ml/kg/day (6.25ml/kg/hour). Feeds can be increased as required.

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Table 2: Feeding schedule – ml/kg/DAY(NB feed advancement schedule is the same for babies in EARLY or LATE groups: only the timing of initiation of feeds differs)

Day of feeding

Volume of milk according to birth weight (ml/kg/DAY)

<600g 600-749g 750-999g 1000-1249g ≥1250g1 12 12 12 12 242 12 12 12 24 363 12 24 24 36 484 24 36 36 48 605 36 48 48 60 726 48 60 60 72 847 60 72 72 84 96 - 1088 72 84 84 96 - 108 120-1329 84 96 96-108 120-132 144-150

10 96 108-120 120-132 144-150 11 108-120 132-144 144-150 12 132-144 150 13 15014 Increase as required

Where 2 numbers are in a cell separated by a hyphen the first number indicates equivalent daily volume/kg to feed for the first 12 hours of each 24 hour period. The second number in each cell indicates equivalent daily volume/kg to feed for the second 12 hours of each 24 hour period.

Feeds should be given hourly or continuously. However, if there are longer intervals between feeds, e.g. 2 hourly feeds, then the milk volume should be increased accordingly.

Red border = feeds increase by 12ml/kg every 12 hours.

Blue border = Feed volume reached 150ml/kg/day (6.25ml/kg/hour). feeds can be increased as required.