The SToP-BPD study Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants Initiation visit

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

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

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 SpO % / pCO2 of kPa –targets only for calculating RI, after inclusion according to local protocol!

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

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

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

Website on (NNRN)

eCRF Website E-learning Guideline SToP-BPD

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

Print out Daily reports

Medication

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

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

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

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

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

Medication schedule

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

Rescue therapy

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

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

Safety and reporting AE/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

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.

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

Web-based Alert procedure Alert Procedure (automated to should be used 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.

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

Oxygen reduction test Criteria: only O 2 defined Depending on saturation targets or other diseases Practical guideline on the website

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

Vragen?