The SToP-BPD study

1. Systemic Hydrocortisone ToPrevent Bronchopulmonary Dysplasia in preterm infants The SToP-BPD study Initiation visit

2. Content • General introduction • Website • Randomization procedure • Medication schedule • What to do at the occurence of hypertension • Prophylactic stress medication • Rescue therapy • SUSAR procedure • Discharge from level III hospital • with study medication? • BPD diagnosis/Oxygen reduction test

3. Purpose of the study • To investigate whether hydrocortisone, initiated 7-14 d after birth reduces the combined outcome death or BPD at 36 wks PMA • To investigate whether a potential beneficial effect on BPD is not at the cause of (inacceptable) adverse effects

4. Inclusion criteria • GA < 30 wks and/or BW < 1250 g • Ventilator dependent between 7-14 days PNA • RI (MAwP x FiO2) ≥ 3.5 • RI during > 12 h/dy and for > 48 uur • Targets SpO2 85-95% / pCO2 of 5.0-7.5 kPa • targets only for calculating RI, after inclusion according to local protocol!

5. Exclusion criteria • Chromosomal defects • Major congenital malformations that: • compromise lung function (SP def., hernia) • result in chronic ventilation (e.g. Pierre Robin sequence) • Congenital cerebral malformations • Use of steroids for improving lung function and respiratory status prior to inclusion

6. No strict exclusion criteria • Sepsis and/or pneumonia • Await the effect of antibiotica 48 uur • Hemodynamic significant ODB • Preferable screening 7 dy and treating according to local protocol • Attempt not to use indo/ibu en HC simultanuous

7. Randomization • Possible between 7-14 days PNA • Hydrocortison or placebo 22 dys • First dose within 24 hours after inclusion • Web-based randomization • Stratification according to center and GA • Twin may be allocated to the same arm • Procedure on the website

8. Website on www.neonatologiestudies.nl (NNRN)

9. eCRF Website E-learning Guideline SToP-BPD

10. eCRF layout Screening & Eligibility Randomization (twins) Visits Daily reports Conditions Range Validation Derivation

11. Print out Daily reports

12. Medication

13. HC course Hydrocortison Pharmachemie (100 mg/ml) Cumul. dose 72,5 mg/kg (=2.5 mg/kg dexa): 5 mg/kg/d in 4xday during 7 dys 3,75 mg/kg/d in 3xday during 5 dys 2,5 mg/kg/d in 2xday during 5 dys -1,25 mg/kg/d in 1xday during 5 dys Total duration 22 days

14. Placebo course ACE pharmaceuticals Zeewolde, NL Mannitol as base (pH en Osmol identical to HC) Same concentration/dose as HC On the shelf stable for 3 years

15. Study medication Transported via AMC, delivered in badges of 10 pieces Issue locally by the pharmacy (per patient or per badge) Stock will be automattically suplemented according to use Medication kit contains of 23 vials

16. Study medication After randomization a medication order can be printed from the website

18. Study medication Preparation protocol Diluent from own stock Preparation of medication per dag Medication recorded on drug accountability form

19. Medication schedule

21. Details medication Occurring of hypertension Prophylactic stress medication Go to website/protocol

22. Rescue therapy

23. Treatment failure of vroege rescue Reason for considering open label rescue: deterioration with RI>10 for >6 uur no improvement (RI<10) and: At least 10 dys study medication Attempt to extubate failed < 24 hrs Rescue with HC according to study schedule and stop study medication

24. Late rescue treatment Patient still ventilator dependent after 22 d Attempt to extubate failed Late rescue possible with HC according to study protocol

25. Safety and reportingAE/SAE/SUSAR • AE: Any undesirable experience occurring to a subject duringthis trial, whether or not considered related to the investigational. • An AE is a SAE if: • Resulted in death • Life-threatening • Required (prolongation of existing) hospitalisation • Persistent or significant disability/incapacity • Another important medical condition

26. Context-specific SAEs • Study population at high risk of serious complications, • inherent to their vulnerable condition • unrelated to the intervention which is under evaluation • Endpoints of the study in the CRF • Immediate reporting of these complications will not enhance the safety of this trial • Reporting of these events to the DMC and METC on a annual basis.

27. Suspected (Unexpected) Serious Adverse Reactions (SUSAR) • SUSAR : adverse reactions, of which the nature, or severity, is not consistent with the applicable product information or the context-specific SAEs as listed above. • Reporting < 24 hrs on AE page of CRF and by telephone to the PI

29. Web-based Alert procedure Alert Procedure (automated email to stop-bpd@amc.nl) should be used with • Death • Simultanuous treatment of indomethacine/ibuprofen and study medication • Occurrence of solitair gastointestinal perforation • Occurence of hypertension, as defined in the protocol • Use of open label hydrocortisone Reporting should be done < 72 hrs of the occurence of the event.

30. Discharge from level III hospital • Letter for general pediatrician on the website

31. Oxygen reduction test • Criteria: only O2 defined • Depending on saturation targets or other diseases • Practical guideline on the website

32. Logistics oxygen reduction test • Local? • Familiair with reduction test • Training of local pediatricians • Regional? • Research nurse? • Recording?

33. Vragen?