The oral NK1 antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials
Introduction
Two identically designed Phase III trials have been previously reported describing the addition of the NK1 antagonist aprepitant to a control regimen (a 5HT3 antagonist and dexamethasone) for the prevention of cisplatin-based chemotherapy induced nausea and vomiting (CINV) [1], [2]. The aprepitant regimen was significantly superior to the control regimen in the overall 5-day study period, the first 24 h postchemotherapy (day 1, the acute phase of CINV), and particularly days 2–5 (the delayed phase). The reports of the individual phase III studies established that aprepitant was generally well tolerated and made a large impact on the likelihood of vomiting following high dose cisplatin. The impact of NK1 receptor antagonists on the important symptom of nausea, however, was less clear. There was a statistically significant difference in the proportion of patients with no nausea in only one of the two phase III trials. Non-statistically significant trends were reported for the proportion of patients with nausea visual analog scores less than 25 mm. No tests of statistical significance were reported for the functional living index emesis (FLIE) questionnaire, nor were the results for the nausea and vomiting domains of that questionnaire reported separately. This paper aims to expand upon the results for the nausea outcomes in the pooled dataset.
Another topic that appears in the antiemetic literature is the relationship between acute and delayed emesis. Consistent with current belief that the most important risk factor for delayed emesis is poor control of acute emesis [3], in both phase III studies, the likelihood of delayed emesis was lower in patients who had not experienced acute emesis [1], [2]. It has been suggested that the pharmacologic benefit of aprepitant in the delayed phase is not strictly a carryover effect from the acute phase [4], [5]. In this study, we have analysed data pooled from the Phase III studies to determine the extent to which the results in the first 24 h predict the results in the delayed phase.
Section snippets
Design
Two identically designed multicenter, randomised, double-blind, parallel-group, placebo-controlled trials were conducted. Written informed consent to participate was obtained from every patient, and was approved by the Institutional Review Board of each participating site. Detailed descriptions of the design (including enrollment criteria), as well as the primary efficacy and tolerability results of the individual studies, are published elsewhere [1], [2].
Patients
The studies enrolled cisplatin-naı¨ve
Patients
Details of patient accounting for the individual studies are published elsewhere [1], [2]. Combined data from 1099 patients were assessed for baseline characteristics (Table 1). As shown in the table, baseline characteristics were similar between the treatment groups. A total of 1043 patients (520 in the aprepitant group and 523 in the control group) were included in the efficacy analyses.
Efficacy
Fig. 1 and Table 2 show results of the efficacy analyses. No statistically significant interaction between
Discussion
The efficacy of currently recommended therapeutic regimens, which include a 5HT3 antagonist combined with a corticosteroid, has been well established for the acute phase of CINV (especially up to about 16 h post cisplatin), but these agents have not been nearly as effective in the delayed phase [3], [13], [14].
As anticipated, based on the consistency of results between the individual studies [1], [2], the present efficacy findings based on the pooled Phase III data confirmed that the aprepitant
Conflict of interest statement
Drs. Carides, Evans, and Horgan are employees of Merck Research Laboratories. Drs. Warr, Grunberg, Gralla, Hesketh, Roila, and de Wit have received funding from Merck Research Laboratories for the conduct of clinical studies of aprepitant. The studies described in this paper were funded by Merck Research Laboratories, manufacturers of aprepitant.
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