ver 2.0: The amended protocol introduced the following changes: If the anesthesia had reached an adequate level with 5 or 10 mL of the investigational anaesthetic and the administration of the additional 10-15 mL could give rise to safety concerns, no additional volume would be administered, and the patient was to be excluded from the study The FAS and PP set definitions were slightly modified to exclude from the analyses patients who were withdrawn from the study because not administered the entire volume (20 mL) of study anaesthetic. The reasons for discontinuation were completed to include patients discontinued because did not receive the entire planned dose of study anaesthetic (20 mL). It was clarified that atropine 0.5 mg would be administered as an i.v. bolus A few typos were corrected.

ver 3.0.The amendment introduced the following changes: Both test and reference investigational anaesthetic agents were to be administered as 5 mL plus 15 mL over 3 minutes instead of 5 mL plus 5 mL plus 10 mL over 5 minutes. Total volume was 20 mL as in the previous protocol version. This change was introduced to achieve surgical anaesthesia rapidly, taking into consideration the common clinical practice and the medical literature. With the new dose regimen, safety of the study subjects increased considering a more rapid and adequate anaesthesia for urgent Caesarean sections. The use of only one test dose as opposed to two test doses as present in the original protocol was balanced against the possible delay in establishing the blockade, which in the setting of foetal compromise may not be acceptable. No published works described the use of two test doses. The one-5 mL initial dose before the injection of the remaining dose was deemed sufficient also considering that in the study population the epidural catheter had already been tested and used to provide analgesia. In the study, before undergoing unplanned Caesarean section patients had a continuous infusion of analgesic through a previously placed epidural catheter for CSE analgesia. For a rapid onset of anaesthesia, it was fundamental that the epidural catheter was in place and used to maintain labour analgesia until anaesthetic injection. Details on the maximal allowed time between end of analgesic infusion and anaesthetic injection were added. Note to file N. 8 was issued on 08AUG2017 to clarify how to grade the correlation between VAS values for pain assessment and AE severity. Note to file Nr. 4 was issued on 07DEC2016 to clarify that, according to the clinical practice, Hetastarch/plasmalyte could be used not only at the end but also during surgery. Drug and alcohol abuse were defined according to the Investigator's opinion on the basis of the Dietary Guidelines for Americans 2015-2020

ver 4.0. The amended protocol introduced the following changes: Three clinical centres were added in the study. The reason was the very low study enrolment rate due to the study inclusion/exclusion criteria, which were particularly restrictive considering the study population, i.e. women in labour undergoing unplanned Caesarean section. Because of the addition of the three new clinical centres the study design was changed from single- to multi-centre This amendment impacted the statistical methodology for the primary and secondary efficacy analyses and the study sample size. The previously planned Wilcoxon-rank sum test was in fact not applicable to the analysis of stratified data and needed to be replaced by the Van Elteren test, a widely used extension of the Wilcoxon rank-sum test for non-parametric 2-way analysis. Thus, the sample size was recalculated and the statistical methods for the primary and secondary efficacy outcome analysis modified accordingly. The CRO Clinical Project Leader and responsible Biostatistician changed. Finally, a few typos found during protocol revision were corrected and a few, minor-impact, text modifications were made.

ver 6.0. The amended protocol introduced the following changes: In the previous protocol versions 4.0 and 5.0, the sample size was calculated considering a non-competitive design, i.e. each study site was to recruit an equal number of patients. The amended protocol introduced a competitive enrolment, i.e. the sites were able to enrol an unlimited number of patients until the total number of patients planned for the study had been reached. As a consequence, a new version of the randomisation list (version 5.0), containing the randomisation scheme for patients still to be enrolled at centre 001 and for all patients at centres 002, 003 and 004, was released. This amendment impacted the statistical methodology for the study sample size calculation and for the primary and secondary efficacy analyses. Thus, the sample size was recalculated and the statistical methods for the primary and secondary efficacy outcome analysis were modified accordingly (please refer to the corresponding sections in the amended protocol). Dr. Eva Roofthooft, site N. 002 Principal Investigator (PI), moved from the Department of Anesthesiology, ZNA Middelheim, Antwerpen (Belgium), to Service Anaesthesiology GZA Ziekenhuizen campus Sint-Augustinus, Wilrijk (Belgium). As a consequence site N. 2 name and address were changed in the protocol. Site N. 002 PI was Dr. Patrick Van Houwe, whereas Dr. Eva Roofthooft became the study sub-Investigator. Site N. 003 PI was Prof. Daniela Marhofer (and not Prof. Oliver Kimberger, as presented in the previous protocol version) The unique subject identifier was clarified (par. 12.2). Minor changes were introduced in the paragraph's wording. Monica Boveri replaced Angelo Vaccani for the study coordination. CTS Clinical Trial Service replaced AML Clinical Services in the blind monitoring of clinical centres N. 001 and 002 starting from AUG2020.