DISCUSSION
nausea, lip swelling, stomatitis, nausea and vomiting, vomiting, PD
MOUTH ULCERATION, STOMATITIS, INJECTION SITE HEMATOMA, SECONDARY, INJECTION SITE REACTION, BLIND, EVENTS, INJECTION SITE ERYTHEMA
This open-label, randomized, crossover study was designed to meet regulatory requirements as a registrational study in the European Union. The purpose was to compare efficacy, safety, tolerability, and patient preference for SL-APO and SC-APO, with the 90-min primary endpoint chosen based on prior PK studies [Prior studies have demonstrated a rapid onset of effect of SL-APO as early as 15 min postdose, which was chosen as the earliest time point against which differences between SL-APO and SC-APO were measured in this study [The 90-min time point chosen for the primary endpoint was based on differences in PK observed between SL-APO and SC-APO and previous findings from SC-APO studies. In a randomized, open-label, 3-way crossover study, CClinical guidance extrapolated from the results of this study suggest that while dose optimization is highly individualized, generally a factor of 5 to 10 can be used to determine a comparable dose when converting a patient from SC-APO to SL-APO. Based on prior PK studies [An overall preference for SL-APO was observed based on the TPQ. These results are particularly robust considering the crossover design of the study, in which patients were treated with both formulations and provided their response regarding preference for treatment at study end. This finding was supported by a numerically higher level of satisfaction with SL-APO compared with SC-APO on the TSQM for convenience and global satisfaction. Although the TPQ was developed for this study and has not been formally validated, alignment between the TPQ and TSQM findings supports the content validity of the TPQ. These results align with a previous finding that, for OFF treatment modes associated with AEs, patients with PD reported a preference for a hypothetical sublingual film associated with mouth/lip sores versus a hypothetical injectable medication associated with injection site reactions [The safety profiles of SL-APO and SC-APO were generally comparable and well tolerated. During dose optimization, rates of overall AEs, serious AEs, and AEs leading to discontinuation were comparable between SL-APO and SC-APO. The most common AEs were also generally similar. However, higher rates of nausea were observed during dose optimization with SL-APO (31.4%) compared with SC-APO (22.7%). Despite higher rates of nausea for patients treated with SL-APO, the majority of events were mild or moderate in severity and did not lead to discontinuation of treatment, and none were considered serious. Rates of vomiting during dose optimization were relatively low. Daily solicitation of tolerability during SL-APO dose optimization may have contributed to a bias towards higher rates of nausea in patients receiving SL-APO during that study phase, as rates of nausea were comparable during the treatment phase (SL-APO, 14.1%; SC-APO, 15.7%). Although domperidone use could have mitigated nausea and vomiting, its use was not standardized across the study; however, the proportions of patients who did not utilize antiemetics were similar during treatment with SC-APO and SL-APO in both phases of the study. Further, it is not possible to draw conclusions about prophylactic versus reactive antiemetic use as the database did not capture the time or reason an antiemetic was taken. A previously published study demonstrated that among 43.7% of patients who did not use an antiemetic during SL-APO dose optimization, 86.2% achieved an effective and tolerable dose [Expected differences in route of administration AEs were also noted. Among patients treated with SC-APO, 6.2% of patients reported injection site erythema and 2.1% reported injection site hematoma during dose optimization, and 7.1% and 27.1%, respectively, reported these events during the treatment phase. In patients treated with SL-APO, no individual events in the category of oral application-related AEs occurred at a rate >3% during either study phase; the most frequent oral application-related AEs were lip swelling, mouth ulceration, and stomatitis. The combined incidence of all oral AE terms was 1.0% during dose optimization and 9.9% during the treatment phase. The shorter, 4-week duration of exposure in this study may have influenced the occurrence of oral AEs as compared with a previously published SL-APO study that involved an open-label titration phase followed by a 12-week double-blind maintenance phase [There are several limitations to consider. The primary and secondary endpoints were assessed using a statistical hierarchy. As the primary endpoint was not statistically significant, all subsequent endpoints were evaluated descriptively. Efficacy endpoints were assessed by a rater blinded to treatment assignment, and every effort was made to maintain that blind by preventing the rater from witnessing dosing, covering visible evidence of route of administration, and protecting source data and electronic clinical report forms. However, the open-label administration of SL-APO and SC-APO may have introduced bias. As a direct head-to-head study, there was no placebo group and all patients were on active treatment. As previously discussed, there was no specific data collection method for the use of antiemetics; therefore, the impact of antiemetic use on nausea and vomiting rates is confounded. As SL-APO dose optimization was performed at home by patients, investigators may have been more inclined to increase the dose, whereas this bias may not have been evident for SC-APO dosing performed in clinic under supervision. For a dose to be considered optimal, FULL ON had to occur within 30 min, which may have impacted the optimal dose. Furthermore, doses to which patients were optimized may reflect the investigator and patient’s levels of experience with the treatments, as some patients had experience with SC-APO before study enrollment. Similar to previous studies, patients in the current study administered apomorphine approximately 1.6 times per day, despite reporting four OFF episodes per day, demonstrating that patients do not administer treatments at the same frequency at which they experience OFF episodes [In conclusion, SL-APO demonstrated comparable efficacy for the treatment of OFF episodes associated with PD and a similar safety profile to SC-APO, with patients reporting an overall preference for and greater satisfaction with SL-APO.