Adverse Events

An adverse event (AE) is generally defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding) syndrome or disease which either occurs during the study, having been absent at baseline, or if present at baseline, appears to worsen. Adverse events are to be recorded regardless of their relationship to the study intervention. With respect to intensity, adverse events are classified as follows:

• Mild some awareness of symptoms, but easily tolerated;
• Moderate symptoms causing enough discomfort to interfere with usual activity;
• Severe incapacitating event causing inability to work or to perform usual activity.

A Serious Adverse Event (SAE) is defined as any experience that suggests a significant hazard or side effect with respect to participants participating in a clinical study. This includes any experience which:

• is fatal or life threatening,
• is permanently disabling, i.e. incapacitating or interfering with the ability to resume normal life patterns,
• requires hospitalisation or prolongation of hospitalisation,
• is a congenital anomaly or defect,
• other medically important circumstance (requires medical treatment to avoid one of the above mentioned conditions).

All adverse events have to be documented in the participant’s CRF. In case the AE results in a persistent disease, the AE has to be classified as a SAE.

Any AE that occurs between the time of randomisation and ICU discharge and any SAE that occurs between randomisation and 6-month follow up will be captured and recorded.

AEs and SAEs are reported mothly to the SAE manager. All related or possibly related events and all unexpected events will be reported within 24 hours to the SAE manager. The SAE manager collects and judges the reports. All related or possibly related events and all unexpected events are forwarded to the DSMB for further review. The DSMB members assess forwarded events and review all SAE and AE from all centers every 6 months or sooner if requested by them. If the DSMB rates an event to be related to the study therapy, the DSMB should inform the principle investigator.

AEs will be reported after begin of the study therapy. The participant will be followed until remission of the symptoms. When reporting a SAE, a clinical narrative on each SAE should be added, which gives the clinical context of the event and allows the DSMB to carefully review the SAE’s.