Aprepitant (aprepitant 80 mg) Dailymed

14.1 Prevention of Nausea and Vomiting Associated with HEC in Adults

Oral administration of aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with HEC including high-dose cisplatin, and nausea and vomiting associated with MEC.

In Studies 1 and 2, both multicenter, randomized, parallel, double-blind, controlled clinical studies in adults, aprepitant in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone alone) in patients receiving a chemotherapy regimen that included cisplatin greater than 50 mg/m² (mean cisplatin dose = 80.2 mg/m²). See Table 13.

In these studies, 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11).

Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. A total of 170 patients were 65 years or older, with 29 patients being 75 years or older.

Table 10: HEC Treatment Regimens – Studies 1 and 2*

	Day 1	Day 2	Day 3	Day 4
CINV Aprepitant Regimen
   Oral Aprepitantâ€	125 mg	80 mg	80 mg	none
   Oral Dexamethasone‡	12 mg	8 mg	8 mg	8 mg
   Ondansetron	5-HT3 antagonist§	none	none	none
CINV Standard Therapy
   Oral Dexamethasone	20 mg	8 mg twice daily	8 mg twice daily	8 mg twice daily
   Ondansetron	5-HT3 antagonist§	none	none	none

^*Aprepitant placebo and dexamethasone placebo were used to maintain blinding.

^†Aprepitant was administered 1 hour prior to chemotherapy treatment on Day 1 and in the morning on Days 2 and 3.

^‡Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the aprepitant regimen [see Clinical Pharmacology (12.3)].

^§Ondansetron 32 mg intravenous was used in the clinical trials of aprepitant. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.

The antiemetic activity of aprepitant was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

•  Primary endpoint:

• •complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries)
•  Other prespecified endpoints:
• •complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score less than 25 mm on a 0 to 100 mm scale)
• •no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• •no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)
• •no significant nausea (maximum VAS less than 25 mm on a 0 to 100 mm scale)

A summary of the key study results from each individual study analysis is shown in Table 14. In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately.

Table 11: Percent of Patients Receiving HEC Responding by Treatment Group and Phase — Cycle 1

	Study 1			Study 2
ENDPOINTS	Aprepitant Regimen (N=260)* %	Standard Therapy (N=261)* %	p-Value	Aprepitant Regimen (N=261)* %	Standard Therapy (N=263)* %	p-Value
PRIMARY ENDPOINT
Complete Response
Overallâ€	73	52	<0.001	63	43	<0.001
OTHER PRESPECIFIED ENDPOINTS
Complete Response
Acute phase‡ Delayed phase§	89 75	78 56	<0.001 <0.001	83 68	68 47	<0.001 <0.001
Complete Protection
Overall Acute phase Delayed phase	63 85 66	49 75 52	0.001 NS¶ <0.001	56 80 61	41 65 44	<0.001 <0.001 <0.001
No Emesis
Overall Acute phase Delayed phase	78 90 81	55 79 59	<0.001 0.001 <0.001	66 84 72	44 69 48	<0.001 <0.001 <0.001
No Nausea
Overall Delayed phase	48 51	44 48	NS# NS#	49 53	39 40	NS¶ NS¶
No Significant Nausea
Overall Delayed phase	73 75	66 69	NS# NS#	71 73	64 65	NS# NS#

Visual analogue scale (VAS) score range: 0 mm=no nausea; 100 mm=nausea as bad as it could be.

^*N: Number of patients (older than 18 years of age) who received cisplatin, study drug, and had at least one post-treatment efficacy evaluation.

^†Overall: 0 to 120 hours post-cisplatin treatment.

^‡Acute phase: 0 to 24 hours post-cisplatin treatment.

^§Delayed phase: 25 to 120 hours post-cisplatin treatment.

^¶Not statistically significant when adjusted for multiple comparisons.

^#Not statistically significant.

In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1.

Figure 1: Percent of Patients Receiving HEC Who Remain Emesis Free Over Time — Cycle 1

p-Value <0.001 based on a log rank test for Study 1 and Study 2; nominal p-values not adjusted for multiplicity.

Additional Patient-Reported Outcomes: The impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 of both studies using the Functional Living Index–Emesis (FLIE), a validated nausea-and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients' daily lives is defined as a FLIE total score greater than 108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%).

Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the aprepitant regimen was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Figure 2: Proportion of Patients Receiving HEC with No Emesis and No Significant Nausea by Treatment Group and Cycle

14.2 Prevention of Nausea and Vomiting Associated with MEC in Adults

Aprepitant was studied in two randomized, double-blind, parallel-group studies (Studies 3 and 4) in adult patients receiving MEC.

In Study 3, in breast cancer patients, aprepitant in combination with ondansetron and dexamethasone was compared with standard therapy (ondansetron and dexamethasone) in patients receiving a MEC regimen that included cyclophosphamide 750 to 1500 mg/m²; or cyclophosphamide 500 to 1500 mg/m² and doxorubicin (less than or equal to 60 mg/m²) or epirubicin (less than or equal to 100 mg/m²). See Table 15.

In this study, the most common combinations were cyclophosphamide + doxorubicin (61%); and cyclophosphamide + epirubicin + fluorouracil (22%).

Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and less than 1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years.

Table 12: MEC Treatment Regimens – Studies 3 and 4^*

	Day 1	Day 2	Day 3
CINV Aprepitant Regimen
  Oral Aprepitantâ€	125 mg	80 mg	80 mg
  Oral Dexamethasone	12 mg‡	none	none
  Oral Ondansetron	8 mg × 2 doses§	none	none
CINV Standard Therapy
  Oral Dexamethasone	20 mg‡	none	none
  Oral Ondansetron	8 mg × 2 doses§	8 mg twice daily	8 mg twice daily

^*Aprepitant placebo and dexamethasone placebo were used to maintain blinding.

^†Aprepitant was administered 1 hour prior to chemotherapy treatment on Day 1 and in the mornings on Days 2 and 3.

^‡Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose of dexamethasone on Day 1 reflects a dosage adjustment to account for a drug interaction with the aprepitant regimen [see Clinical Pharmacology (12.3)].

^§The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.

The antiemetic activity of aprepitant was evaluated based on the following endpoints in which emetic episodes included vomiting, retching, or dry heaves:

•  Primary endpoint:
•  Other prespecified endpoints:

• •complete response (defined as no emetic episodes and no use of rescue therapy as recorded in patient diaries) in the overall phase (0 to 120 hours post-chemotherapy)
•  Other prespecified endpoints:
• •no emesis (defined as no emetic episodes regardless of use of rescue therapy)
• •no nausea (maximum VAS less than 5 mm on a 0 to 100 mm scale)
• •no significant nausea (maximum VAS less than 25 mm on a 0 to 100 mm scale)
• •complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score less than 25 mm on a 0 to 100 mm scale)
• •complete response during the acute and delayed phases.

A summary of the key results from Study 3 is shown in Table 16. In Study 3, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the "No Emesis Endpoint", a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response during the acute (0 to 24 hours) and delayed (25 to 120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments.

Table 13: Percent of Patients Receiving MEC Responding by Treatment Group and Phase — Cycle 1 of Study 3

ENDPOINTS	Aprepitant Regimen (N=433)* %	Standard Therapy (N=424)* %	p-Value
PRIMARY ENDPOINTâ€
  Complete Response	51	42	0.015
OTHER PRESPECIFIED ENDPOINTSâ€
  No Emesis	76	59	NS‡
  No Nausea	33	33	NS
  No Significant Nausea	61	56	NS
  No Rescue Therapy	59	56	NS
  Complete Protection	43	37	NS

^*N: Number of patients included in the primary analysis of complete response.

^†Overall: 0 to 120 hours post-chemotherapy treatment.

^‡NS when adjusted for prespecified multiple comparisons rule; unadjusted p-value <0.001.

Additional Patient-Reported Outcomes: In Study 3, in patients receiving MEC, the impact of nausea and vomiting on patients' daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the "No Vomiting Domain" of this composite endpoint.

Multiple-Cycle Extension: In Study 3, patients receiving MEC were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. The antiemetic effect for patients receiving the aprepitant regimen was maintained during all cycles.

In Study 4, aprepitant in combination with ondansetron and dexamethasone was compared with a standard therapy (ondansetron and dexamethasone alone) in patients receiving a MEC regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenous (less than 1500 mg/m²); or cytarabine intravenous (greater than 1 g/m²). See Table 15. Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers.

Of the 430 patients who were randomized to receive the aprepitant regimen, 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The aprepitant-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years.

The antiemetic activity of aprepitant was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period.

A summary of the key results from Study 4 is shown in Table 17. In Study 4, a statistically significantly higher proportion of patients receiving the aprepitant regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the aprepitant regimen (69%) in Cycle 1 had a complete response in the overall phase (0 to 120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively).

In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For sex, the difference in complete response rates between the aprepitant and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for sex was observed for the no vomiting endpoint.

Table 14: Percent of Patients Receiving MEC Responding by Treatment Group — Cycle 1 of Study 4

ENDPOINTS	Aprepitant Regimen (N=430) * %	Standard Therapy (N=418) * %	p-Value
No Vomiting Overall	76	62	<0.0001
Complete Response Overall	69	56	0.0003

^*N = Number of patients who received chemotherapy treatment, study drug, and had at least one post-treatment efficacy evaluation.

14.3 Prevention of Nausea and Vomiting Associated with HEC or MEC in Pediatric Patients

In a randomized, double-blind, active comparator-controlled clinical study that included 302 pediatric patients aged 6 months to 17 years receiving HEC or MEC, aprepitant in combination with ondansetron was compared to ondansetron alone (control regimen) for the prevention of CINV (Study 5). Intravenous dexamethasone was permitted as part of the antiemetic regimen in both treatment groups, at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the aprepitant group, reflecting a dosage adjustment to account for a drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients who received the control regimen.

Eligible patients had documented malignancy at either an original diagnosis or relapse and were scheduled to receive emetogenic chemotherapy or a chemotherapy regimen not previously tolerated due to vomiting along with ondansetron as part of their antiemetic regimen.

Of the 152 pediatric patients randomized to receive the aprepitant regimen, 55% were male, 45% female, 78% White, 7% Asian, 0% Black, 24% Hispanic, and 13% Multi-Racial. The most common primary malignancies in subjects receiving the aprepitant regimen were osteosarcoma (11%), Ewing’s sarcoma (11%), neuroblastoma (9%) and rhabdomyosarcoma (8%). Other concomitant chemotherapy agents commonly administered and the number of aprepitant patients exposed were: vincristine sulfate (65), etoposide (59), doxorubicin (48), ifosfamide (45), carboplatin (39), and cisplatin (35).

The treatment regimens in Study 5 for pediatric patients are defined in Table 18. Of the pediatric patients, 29% in the aprepitant regimen and 28% in the control regimen used dexamethasone as part of the antiemetic regimen in Cycle 1.

Table 18: HEC and MEC Treatment Regimens* for Pediatric Patients 6 Months to 17 Years of Age— Study 5

	Day 1	Day 2	Day 3
CINV aprepitant Regimen
Pediatric Patients 6 Months to less than 12 Years of Age	3 mg/kg body weight oral suspension	2 mg/kg body weight oral suspension	2 mg/kg body weight oral suspension
Pediatric Patients 12 to 17 Years of Ageâ€	125 mg capsule	80 mg capsule	80 mg capsule
Ondansetron	Per standard of care	none	none
CINV Control Regimen
Ondansetron	Per standard of care‡	none	none

•  *Intravenous dexamethasone was permitted at the discretion of the physician. A 50% dose reduction of dexamethasone was required for patients in the aprepitant group, reflecting a dosage adjustment to account for a drug interaction [see Clinical Pharmacology (12.3)]. No dexamethasone dose reduction was required for patients in the control regimen.
•  †Aprepitant was administered 1 hour prior to chemotherapy treatment on Days 1, 2, and 3. If no chemotherapy was given on Days 2 and 3, aprepitant was administered in the morning.

‡Ondansetron was administered 30 minutes prior to chemotherapy on Day 1^§aprepitant placebo was used to maintain blinding.

The antiemetic activity of aprepitant was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint in Study 5 was complete response in the delayed phase (25 to 120 hours following chemotherapy) in Cycle 1. Patients had the opportunity to receive open-label aprepitant in subsequent cycles (Optional Cycles 2-6); however, efficacy was not assessed in these optional cycles. Overall efficacy was based on the evaluation of the following endpoints:

Primary endpoint:

• •complete response (no vomiting, retching and no use of rescue medication) in the delayed phase (25 to 120 hours following initiation of chemotherapy) Other prespecified endpoints:
• •complete response in the acute phase (0 to 24 hours following initiation of chemotherapy)
• •complete response in the overall phase (up to 120 hours following initiation of chemotherapy)
• •no vomiting (defined as no emesis, retching or dry heaves, regardless of use of rescue medication) in the overall phase
• •safety and tolerability

A summary of the key study results are shown in Table 19.

Table 19: Percent of Patients Who Responded to Treatment by Treatment Group and Phase – Cycle 1 of Study 5

	Aprepitant Regimen n/m (%)	Control Regimen n/m (%)
PRIMARY ENDPOINT
Complete Response - Delayed phase	77/152 (50.7)	39/150 (26.0)
OTHER PRESPECIFIED ENDPOINTS
Complete Response* – Acute phase	101/152 (66.4)	78/150 (52.0)
Complete Response* – Overall phase	61/152 (40.1)â€	30/150 (20.0)

*Complete Response = No vomiting or retching and no use of rescue medication.

†p<0.01 when compared to Control Regimen

‡ p<0.05 when compared to Control Regimen n/m = Number of patients with desired response/number of patients included in time point. Acute Phase: 0 to 24 hours following initiation of chemotherapy. Delayed Phase: 25 to 120 hours following initiation of chemotherapy. Overall Phase: 0 to 120 hours following initiation of chemotherapy.

14.4 Prevention of PONV in Adults

In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (Studies 7 and 8), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. These two studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. Study 7 was a multinational study including the U.S., whereas, Study 8 was conducted entirely in the U.S.

In the two studies, patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron as a single dose. Aprepitant was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the aprepitant 125 mg dose did not demonstrate any additional clinical benefit over the 40 mg dose and is not a recommended dosage regimen [see Dosage and Administration (2.2)].

Of the 564 patients who received 40 mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40 mg aprepitant ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older.

The antiemetic activity of aprepitant was evaluated during the 0 to 48 hour period following the end of surgery.

•  Efficacy measures in Study 7 included:

• •no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• •complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• •no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary)
• •time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory)
• •time to first emesis in the 0 to 48 hours following the end of surgery (exploratory).

A closed testing procedure was applied to control the type I error for the primary endpoints.

The results of the primary and secondary endpoints for 40 mg aprepitant and 4 mg ondansetron are described in Table 20:

Table 20: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat Population) – Study 7

n/m = Number of responders/number of patients in analysis.
Δ Difference (%): Aprepitant 40 mg minus Ondansetron.
Treatment	n/m (%)	Aprepitant vs. Ondansetron
		Δ	Odds ratio *	Analysis
PRIMARY ENDPOINTS
No Vomiting 0 to 24 hours (Superiority)(no emetic episodes)
Aprepitant 40 mg	246/293 (84.0)	12.6%	2.1	P<0.001â€
Ondansetron	200/280 (71.4)
Complete Response (Non-inferiority: If LB‡ >0.65)(no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg	187/293 (63.8)	8.8%	1.4	LB=1.02
Ondansetron	154/280 (55.0)
Complete Response (Superiority: If LB >1.0) (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg	187/293 (63.8)	8.8%	1.4	LB=1.02‡
Ondansetron	154/280 (55.0)
SECONDARY ENDPOINT
No Vomiting 0 to 48 hours (Superiority) (no emetic episodes)
Aprepitant 40 mg	238/292 (81.5)	15.2%	2.3	P<0.001§
Ondansetron	185/279 (66.3)

^*Estimated odds ratio for aprepitant versus Ondansetron. A value of >1 favors aprepitant over Ondansetron.

^†P-value of two-sided test <0.05.

^‡LB = lower bound of 1-sided 97.5% confidence interval for the odds ratio.

^§Based on the prespecified fixed sequence multiplicity strategy, aprepitant 40 mg was not superior to Ondansetron.

In Study 7, the use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3.

Figure 3: Percent of Patients Who Remain Emesis Free During the 48 Hours Following End of Surgery – Study 7

•  Efficacy measures in Study 8 included:

• •complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary)
• •no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary)
• •no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary)
• •no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary).

Study 8 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery.

The study demonstrated that 40 mg aprepitant had a clinically meaningful effect with respect to the secondary endpoint "no vomiting" during the first 24 hours after surgery and was associated with a 16% improvement over ondansetron for the no vomiting endpoint.

Table 21: Response Rates for Select Efficacy Endpoints (Modified-Intention-to-Treat

Population) – Study 8

Treatment	n/m (%)	Aprepitant vs. Ondansetron
		Δ	Odds ratio*	Analysis
PRIMARY ENDPOINT
Complete Response (no emesis and no rescue therapy, 0 to 24 hours)
Aprepitant 40 mg	111/248 (44.8)	2.5%	1.1	0.61
Ondansetron	104/246 (42.3)
SECONDARY ENDPOINTS
No Vomiting (no emetic episodes, 0 to 24 hours)
Aprepitant 40 mg	223/248 (89.9)	16.3%	3.2	<0.001â€
Ondansetron	181/246 (73.6)
No Use of Rescue Medication (for established emesis or nausea, 0 to 24 hours)
Aprepitant 40 mg	112/248 (45.2)	-0.7%	1.0	0.83
Ondansetron	113/246 (45.9)
No Vomiting 0 to 48 hours (Superiority) (no emetic episodes, 0 to 48 hours)
Aprepitant 40 mg	209/247 (84.6)	17.7%	2.7	<0.001*
Ondansetron	164/245 (66.9)

n/m = Number of responders/number of patients in analysis.

Δ Difference (%): Aprepitant 40 mg minus Ondansetron.

^*Estimated odds ratio: Aprepitant 40 mg versus Ondansetron.

^†Not statistically significant after pre-specified multiplicity adjustment.