Modifications were recommended by the DMC after evaluation of the first planned interim analysis and the trial was newly set up after protocol amendment 03. The dose of the test arm was reduced from 3 x 14 g/m² Treosulfan to 3 x 10 g/m². In addition, the treatment regimen of the test arm was changed so that administration of both test and reference drug was started the same day (Day -4 prior to allogeneic HSCT). Moreover, the follow-up period of transplanted patients was extended from 1 year to 2 years after Transplantation, the sample size increased and the statistical planning revised. Due to the substantial changes, previously enrolled patients (part 1) were not included in the statistical analysis. Thus, the modified new part of the study reported here (part 2) has to be considered an independent study.

The responsibilities for planned statistical interim analyses and DMC reports were transferred to an independent contract research organisation. A new pharmacokinetic sub-study was to be implemented and conducted at one German site due to dose reduction of Treosulfan after amendment 03 and newly available bioanalytical methods for Treosulfan and epoxide detection. Further minor changes were made to promote future study conduct, monitoring and documentation, including the reduction of protocol appendices. For a better comprehensibility, all paragraphs related to protocol versions prior to amendment 03 were deleted. The patient information was revised to include an update of the Summary of product characteristic (SmPC) of the comparator Busilvex®. An additional patient information and informed consent form was provided for the site that was to perform the pharmacokinetic sub-study.

The CRO contracted for trial conduct was replaced with another CRO. Textual changes were made to country specific clinical trial protocols in order to provide one integrated protocol for all countries. It was clarified that the DMC was to meet on a yearly basis after the trial is open to patient enrolment until the last patient enrolled had been treated. Thereafter, no changes in trial conduct could result from DMC recommendations. In addition the DMC was to meet at the pre-specified time points of confirmatory efficacy analyses. The range of permissible IMP dose deviation (previously < 10%) was aligned with the exclusion criteria of patients from the Per Protocol Set (PPS) (deviation of at most plus/minus 20%). For the initial examinations it was clarified that it is sufficient to measure either diffusing capacity of the lung for carbon monoxide (DLCOS) Hb-adjusted or forced expiratory volume 1 second (FEV1). Mucositis was considered a significant adverse event in trial MC-FludT.14/L. Although differently described in the Clinical Trial Protocol, confirmatory superiority testing was not planned for the event ‘mucositis’. Relevant sections of the Clinical Trial Protocol were revised. The definition of engraftment after HSCT was clarified in order to avoid misinterpretations. The Investigational Medicinal Product Dossier (IMPD) was updated and submitted.