Clinical Trial Result Information

Title of Study:
A prospective, randomized, double-blind, noninferiority study of granisetron plus dexamethasone vs ondansetron plus dexamethasone in the prevention of post-operative nausea and vomiting in patients undergoing abdominal hysterectomy

Fast Facts:

Protocol number:	ML17517
Sponsor:	Roche Laboratories Inc.
Company division:	Pharmaceutical
Product name:	Kytril
Generic name:	granisetron
Phase of development:	IV
Therapeutic area, approved indication:	Post-Operative Nausea and Vomiting
Date of report:	6/30/2004

Clinical study summary:
This multicenter, randomized, double-blind, parallel-group, active-control study compared the effect of granisetron (Kytril) plus dexamethasone and ondansetron plus dexamethasone in the prevention of post-operative nausea and vomiting (PONV) in patients undergoing abdominal hysterectomy.

Study center(s) :
19 study centers in the United States.

Objectives:
Primary: To determine if Kytril 0.1 mg plus dexamethasone 8 mg was noninferior to ondansetron 4 mg plus dexamethasone 8 mg with respect to no vomiting during the 0–2 hour interval following end of surgery (time of extubation).

Secondary: (1) (1) To report the difference between the 2 treatment groups in the proportion of patients who experienced nausea and/or vomiting during the 0-24 hour interval following time of extubation; (2) To determine the difference between the 2 treatment groups in the proportion of patients who required rescue medication during the 24 hours following time of extubation; (3) To determine the difference between the 2 treatment groups over the 0–24 hour interval in time to first vomiting episode, first moderate/severe nausea episode, first use of rescue medication; and (4) To determine the proportion of patients who experienced improvement or resolution of PONV symptoms during the 30 minutes after administration of the rescue medication Kytril 0.1 mg.

Safety: To examine the safety profile of combination therapy iv Kytril plus dexamethasone and iv ondansetron plus dexamethasone in patients undergoing abdominal hysterectomy

Methodology:
Patients who fulfilled the entry criteria were randomized to 1 of 2 treatment groups (Group 1: Kytril 0.1mg iv plus dexamethasone 8mg; Group 2: odansetron 4mg iv plus dexamethasone 8mg) On the day of the scheduled surgery, all patients received a single prophylactic iv dose of dexamethasone 8 mg immediately after induction of anesthesia, and also received a single prophylactic iv dose of either Kytril 0.1 mg or ondansetron 4 mg approximately 15 minutes prior to the end of surgery (time of extubation).

The time of each vomiting episode and the time and severity of each nausea episode were recorded. If the patient failed prophylaxis with Kytril 0.1 mg plus dexamethasone 8 mg or ondansetron 4 mg plus dexamethasone 8 mg during the 0–24 hour interval following time of extubation, Kytril 0.1 mg was administered as rescue. The patient was monitored for improvement or resolution of PONV symptoms during the 30 minutes after administration of rescue medication. Adverse events (AEs) were determined by the investigator and recorded. Vital signs were recorded at baseline and at 24 hours post-dosing.

Number of patients (planned/analyzed):
Planned: 200 enrolled and 170 evaluable; Actual: 210 enrolled, 176 evaluable for efficacy, and 194 evaluable for safety.

Diagnosis and main criteria for inclusion:
Adult female patients ≥18 years of age undergoing abdominal hysterectomy requiring general anesthesia.

Test product, dose and mode of administration or test procedure:
Dexamethasone 8mg iv single dose immediately after induction of anesthesia followed by either Kytril 0.1 mg iv or Zofran 4 mg iv approximately 15 minutes before the end of surgery (time of extubation).

Duration of treatment:
Single dose.

Reference therapy, dose and mode of administration or reference procedure:
Dexamethasone 8 mg iv single dose immediately after induction of anesthesia plus ondansetron 4 mg iv single dose approximately 15 minutes before the end of surgery (time of extubation).

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: (1) Proportion of patients who experience no vomiting during the 0–2 hour time interval following end of surgery (time of extubation).

Secondary efficacy parameters: (1) Proportion of patients who experience no vomiting; (2) Proportion of patients who experience no moderate/severe nausea; (3) Proportion of patients who require rescue medication; (4) Proportion of patients who experience complete response; (5) Proportion of patients who experience total control; (6) Time to onset of the first vomiting episode; (7) Time to onset of the first moderate/severe nausea episode; (8) Time to first use of rescue antiemetics; (9) Proportion of patients who experience improvement or resolution of PONV symptoms during the 30 minutes after administration of the rescue medication Kytril 0.1 mg.

Primary safety parameter: Adverse events.

Statistical methods:
The proportion of patients who experience no vomiting during the 0–2 hour interval was expected to be approximately 96.7% for both treatments groups, based on a previous study with iv 5 HT3 receptor antagonists used in combination with dexamethasone. A 95% confidence interval (CI) around the difference between the 2 treatment groups (Kytril minus ondansetron) was to be calculated for the primary efficacy variable (proportion of patients who experience no vomiting during the first 2 hours following time of extubation after surgery). Noninferiority of Kytril was to be declared if the lower limit was greater than –15%. An evaluable population of 85 patients per group (170 evaluable patients overall) assured this assertion with a power of approximately 90%.

With the exception of time-to-event measures, secondary efficacy variables were analyzed using the same methodology as the primary efficacy variable (with no emphasis on the lower bounds of the 95% CI). Time-to-event secondary efficacy variables were analyzed using survival analysis methodology, and a Cox proportional hazards regression was conducted. As a measure of treatment difference, the estimated hazard ratio and the 95% CI for the hazard ratio were provided.

Adverse events were summarized, and vital signs were presented with descriptive statistics.

Summary (efficacy, safety, other results):
Efficacy – Eighty-two patients (94%) given Kytril and 86 patients (97%) given ondansetron did not experience a vomiting episode in the 0–2 hour time interval following the end of surgery (time of extubation). The treatment difference (Kytril minus ondansetron) was –2.4% with a 95% CI of –8.5% to 3.8%. Because the lower bound of the 2 sided 95% CI (–8.5%) was > –15%, the test for noninferiority was satisfied and it was concluded that Kytril 0.1 mg plus dexamethasone 8 mg was noninferior to ondansetron 4 mg plus dexamethasone 8 mg in preventing vomiting during the first 2 hours following surgery. Analysis of all the secondary efficacy parameters indicated that results were similar across the 2 treatment groups at all time intervals (see table below).

Safety – Both Kytril and ondansetron were well tolerated in the study. The proportion of patients with AEs was similar in the 2 treatment groups (Kytril 37%; ondansetron 41%). Most AEs were judged by the investigator to be unrelated to study medication and mild or moderate in intensity. There was no evidence of corticosteroid-related AEs in either treatment group. Two patients in the Kytril group and 4 patients in the ondansetron group experienced SAEs. All SAEs were judged by the investigator to be unrelated to study medication. One patient in the Kytril group was withdrawn from the study due to an AE (vaginal hemorrhage), which was also judged by the investigator as unrelated to study medication. There were no clinically meaningful mean changes in vital signs during the study.

Conclusions:
The results of this study demonstrated that Kytril 0.1 mg plus dexamethasone 8 mg is noninferior to ondansetron 4 mg plus dexamethasone 8 mg in controlling postoperative vomiting in the 0–2 hour interval following extubation in patients undergoing abdominal hysterectomy requiring general anesthesia. The treatment groups were similar in preventing vomiting in the 0–6 hour and 0–24 hour intervals following extubation. Furthermore, the secondary efficacy measures—moderate/severe nausea, use of rescue medication, complete response, and total control—showed similar results in the 2 treatment groups. Both Kytril and ondansetron were well tolerated in this study. There were no unusual or unexpected safety results.

Publications (references, if available):
Gan TJ, Coop A, Philip B and the Kytril Study Group. A randomized double-blind study of granisetron plus dexamethasone, versus ondansetron plus dexamethasone, to prevent postoperative nausea and vomiting in patients undergoing abdominal hysterectomy. Anasthesia Analgesia, November 2005