To shorten the time required to obtain the data from the two Phase 3 clinical studies of the Amikacin Inhale program (BAY 41 6551/13084 [Inhale I] and BAY 41-6551/13085 [Inhale II]) to sustain regulatory submission, the Sponsor, Bayer AG, decided that the results of both studies should be consolidated into a single integrated report. As there will be no second study to corroborate the findings in the consolidated report it was considered necessary to review the endpoints to ensure optimal clinical relevance. During a blinded review of the data from 106 patients entered into the Phase 3 program it was found that there was an artificially high failure rate occasioned by the original antibiotic use rules. These failures did not correspond with data that are used as medical management tools and were considered spurious. Certain other elements of the original endpoint were also considered not to accurately reflect clinical benefit. This required modifications a priori of the statistical analysis plan, but did not require any alterations to patient management, modifications to data collection tools, or changes to clinical/laboratory evaluations being performed at the ICU to assess Clinical Failure or Success. The aim was that the patient population recruited into the study and the management of the patients would be the same after the implementation of this amendment as it was before. Recruitment continued in the two studies until a total of approximately 724 patients had been enrolled. Enrollment was competitive and both studies were planned to stop once the number was reached. The primary efficacy endpoint had been modified to allow antibiotic rules to better reflect Clinical Success or Failure and the other variables to be more clearly aligned with clinical response. The secondary variables, Days in hospital and relapses rates were removed, pneumonia-related mortality added and speed of response based on CPIS success or failure added.

A correction was made in the temperature criterion for the calculation of CPIS points. This correction accurately reflects the programming that has been used in the electronic case report form by the investigators to calculate the CPIS score throughout the study, i.e., it did not represent a change in the conduct of the study. Note: This was an error in the original protocol that was carried forward in other amendments.

The amendment date was 29-Aug-2017. During a blinded review of the data from 454 mITT patients entered into the Phase III program it was found that there was an artificially high failure rate due to the antibiotic criteria. These failures did not correspond with data that are used as medical management tools and were considered spurious. Certain other elements of the endpoint related to the TOC date were also considered not to accurately reflect clinical benefit. These data necessitated a change in the primary endpoint. It was decided to narrow the primary endpoint to all-cause mortality alone through the LFU visit (Days 28-32). This primary endpoint is in alignment with current FDA draft guidance for ventilated pneumonia. All-cause mortality through the LFU visit was the sole criterion for evaluation. Survival was the new primary endpoint.