Amendment 01 (Protocol version 2.0) -Previous text instructed a sedation re-assessment after 30 min for both dose increases and dose reductions. However, according to clinical experience and PK properties of the sedative drugs (IMP) a longer observation period after dose decrease was considered to be more appropriate to evaluate the desired effects. For the sedation assessment, different intervals of re assessment after increase (30 min) compared to decrease (3 hours) of the IMP dose were introduced. The change in protocol allowed sufficient time (a 6 hour observation period) after a dose decrease of IMP for it to take effect prior to re-assessing level of pain and sedation. Some flexibility was included to allow investigators to judge, in certain cases, that a further dose decrease was required and could be given without deviating from the dose adjustment regimen of the protocol. - Patients within the hospital of the study site, (e.g. patients who come to the PICU department from another ward), and who would already have been intubated and initially treated with sedative/analgesic therapy, were considered eligible for inclusion in the study. - The use of propofol as a short term bridging therapy for any relevant patient was allowed and not restricted to only subjects acutely admitted to PICU. - An instruction was introduced to more precisely define how and at what point investigators should return subjects to the dose escalation regimen after a dose decrease. - Clarification that urine samples for PK analysis purposes were optional was added.

Amendment 02 (Protocol version 3.0) - In order to enhance recruitment, the exclusion criterion excluding patients who had received clonidine in the 7 days prior to admission to PICU was removed and a PK sample immediately prior to IMP administration was made mandatory in all patients that had received either clonidine or midazolam at least once within 5 days prior to IMP administration. -The exclusion criterion regarding patients on CPAP was removed as it was considered that there was no medical reason for this requirement because from the experience of the investigators, patients could be on CPAP at screening and undergo surgery later followed by >24h mechanical ventilation and sedation. - The definition of circulatory failure, was redefined using criteria adapted from Goldstein et al 2005. - From the experience of the investigators, there was no medical reason why subjects with acute asthma and paralytic ileus should have been excluded from the study and therefore the relevant exclusion criteria were removed. Please note that following review of the amendment by the Czech CA (SUKL), this specific amendment point did not apply in that territory. -A new section regarding interaction and incompatibilities with concomitant drugs was added at the request of the Swedish Competent Authority (MPA). -The text regarding emergency unblinding was revised to achieve conformity with ICH-GCP in accordance with the requirements of the MPA. -Text regarding the definition, recording and reporting of suspected unexpected serious adverse reactions (SUSARs) was added in response to a comment from the MPA.

Amendment 03 (Protocol Version 3.1) This amendment provided only clarifications and corrections to the protocol and was submitted to the Competent Authorities and ECs only and approved in Germany only. No site received this protocol amendment.

Amendment 04 (Protocol version 4.0) - A section was added to take into account local standard practice for tapering patients off sedatives to clarify how the IMP may have been stopped by dose tapering. - The renal insufficiency exclusion criterion was removed and others were simplified to be more inclusive of the PICU-patient population and enlarge the eligible study population, without compromising subject safety. It was left to the investigators’ discretion if the condition would impact the sedation evaluations. - As the infusion pumps were mostly only accurate to 1 decimal place, information regarding infusion rates to be used in the study was amended to allow for dose changes as required in the protocol. Additionally, sites were no longer permitted to calculate the dose by hand but to use the study-specific tables provided. - The reduction of the morphine background infusion doses was amended to be at the discretion of the investigator and not mandated. - The use of propofol was amended to be more in alignment with standard of care. - As additional sedatives and analgesia during a procedure could have increased the subject’s level of sedation temporarily, advice regarding over sedation was added into the section on dose adjustment of IMP and morphine according to level of sedation and pain. - To simplify the dosing regimen, the additional pain and sedation score required 2 hours after the 2nd or 3rd loading dose and at the end of the lock-out period was removed. - It was sufficient to collect only the medication and dosing information for 1 week prior to Visit 1 instead of 3 weeks. -Time windows were added for vital signs and a paragraph regarding the recording of vital signs in patients without arterial lines was introduced in order to reduce inappropriate stress on the subjects. - The exact periodicity of PK sample shipments was removed based on the availability of new sample stability data.

Amendment 5 (Protocol version 4.1) This amendment was an amendment to protocol version 3.1. It included all changes detailed in amendment 4 and information regarding the risk-benefit of changes made in amendment 4 were added as requested by the German CA (BfArM). No subjects were recruited under this amendment.