Study of APD421 as PONV Treatment (Prior Prophylaxis)

• Sponsor: Acacia Pharma Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02646566
• Collaborator: (none)
• Enrollment: 705
• Locations: 8
• Arms: 3
• Actual Duration (Months): 10.1
• Patients Per Site: 88.1
• Patients Per Site Per Month: 8.8

Study Details

Study Description

Brief Summary

Double-blind, randomised, parallel-group, placebo-controlled, adaptive, seamless, dose-selecting study to compare the efficacy of APD421 to placebo as treatment of established PONV, in patients who have had prior PONV prophylaxis.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Nausea and Vomiting	Drug: APD421; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 705 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomised, Double-blind, Placebo-controlled Study of APD421 (Amisulpride for IV Injection) as Treatment of Established Post-operative Nausea and Vomiting, in Patients Who Have Had Prior Prophylaxis
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APD421 standard Single (standard) dose IV APD421	Drug: APD421
Experimental: APD421 high Single (high) dose IV APD421	Drug: APD421
Placebo Comparator: Placebo Single IV placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response (Success of Initial PONV Treatment) [0-24 hours after administration of study medication]

   The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication.

Secondary Outcome Measures

1. Number of Participants With Complete Response 0-2 Hrs [0-2 hours after administration of study medication]

   Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication.

2. Number of Participants With Complete Response 0-4 Hrs [0-4 hours after administration of study medication]

   Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication.

3. Number of Participants With Complete Response 0-6 Hrs [0-6 hours after administration of study medication]

   Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication.

4. Time to Treatment Failure [0-24 hours after study drug administration]

   Time to first violation of the criteria for complete response

5. Number of Patients With Incidence of Emesis [30 mins to 24 hours after study drug administration]

   Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication

6. Number of Patients Receiving Rescue Medication [0-24 hours after study drug administration]

   Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period

7. Number of Patients With an Incidence of Significant Nausea [30 mins to 24 hours after study drug administration]

   Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.

8. Number of Patients With an Incidence of Nausea [30 mins to 24 hours after drug administration]

   Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.

9. Maximum Severity of Nausea [30 mins to 24 hours after study drug administration]

   Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.

10. Evolution Score of Nausea (0-180 Mins) [0-180 minutes after study drug administration]

    The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Male or female patients ≥ 18 years of age

• Provision of written informed consent

• Patients scheduled to undergo elective surgery (open or laparoscopic technique) under general anaesthesia (other than total intravenous anaesthesia with propofol) expected to last at least one hour from induction of anaesthesia to extubation

• Patients judged by the investigator to have a moderate or high risk of experiencing PONV. In forming this judgment, investigators should pay particular attention to risk factors such as a past history of PONV and/or motion sickness; habitual non-smoking status; female sex; and likely use of opioid analgesia post-operatively.

• For females of child-bearing potential: ability and willingness to use a highly effective form of contraception (as defined in ICH M3 guidance, e.g., abstinence from sexual intercourse, surgical sterilisation (of subject or partner), combined oral contraceptive pill, a double-barrier method of contraception such as either an intra-uterine device (IUD) or an occlusive cap with spermicide, in conjunction with partner's use of a condom, or any other method or combination of methods with a failure rate generally considered to be <1% per year) between the date of screening and at least 48 hours after administration of study drug

• In order to be eligible for randomisation, subjects must also:

(i) have experienced a first episode of PONV not more than 24 hours after the end of their operation (wound closure) and prior to discharge from hospital ("qualifying PONV episode"), for which they have not already received any anti-emetic treatment; and (ii) not have received any dopamine-antagonist agent likely to prevent or treat nausea or vomiting (given as prophylaxis or otherwise) in the period from 24 hours prior to the start of their operation up to the time of the qualifying PONV episode.

Exclusion Criteria:

• Patients scheduled to undergo transplant surgery or any surgery where post-operative emesis may pose a significant danger to the patient

• Patients planned to receive only a local anaesthetic and/or regional neuraxial (intrathecal or epidural) block

• Patients who have received APD421 active ingredient for any indication within the last 2 weeks

• Patients who are allergic to APD421 active ingredient or any of the excipients of APD421

• Patients with a significant, ongoing history of vestibular disease or dizziness

• Patients with a known prolactin-dependent tumour (e.g. pituitary gland prolactinoma or breast cancer) or phaeochromocytoma.

• Patients with documented or suspected alcohol or substance abuse within the past 6 months.

• Patients with direct or indirect evidence of clinically significant hypokalaemia, such as a serum potassium level < 3.0 mmol/L.

• Patients who have received in the post-operative period, and prior to receiving study drug, any medication with a substantial risk of inducing torsades de pointes, including Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide; Class III antiarrhythmic agents such as amiodarone and sotalol; and other medications such as bepridil, cisapride, thioridazine, methadone, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin, etc.

• Patients who have a documented, clinically significant cardiac arrhythmia or congenital long QT syndrome.

• Patients who are pregnant or breast feeding.

• Patients being treated with levodopa.

• Patients diagnosed with Parkinson's disease.

• Patients who have received emetogenic anti-cancer chemotherapy in the previous 4 weeks.

• Patients with a history of epilepsy.

• Any other concurrent disease or illness that, in the opinion of the investigator makes the patient unsuitable for the study.

• Patients who have previously participated in this study or who have participated in another interventional clinical study involving pharmacological therapy within the previous 28 days (or longer exclusion period, if required by national or local regulations).

• Where local laws/regulations require: patients under legal protection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jackson Memorial Hospital	Miami	Florida	United States	33136
2	Duke University Medical Center	Durham	North Carolina	United States	27710
3	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157
4	Ohio State University	Columbus	Ohio	United States	43210
5	CHU de Hautepierre	Strasbourg		France
6	HELIOS Klinikum Aue	Aue		Germany	08280
7	Universität Heidelberg	Heidelberg		Germany
8	Philipps University	Marburg		Germany

Sponsors and Collaborators

• Acacia Pharma Ltd

Investigators

• Study Director: Gabriel Fox, MB BChir, Acacia Pharma Ltd

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acacia Pharma Ltd
• ClinicalTrials.gov Identifier: NCT02646566
• Other Study ID Numbers: DP10019
• First Posted: Jan 5, 2016
• Last Update Posted: Jan 22, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Nausea; Vomiting; Postoperative Nausea and Vomiting

Study Results

Participant Flow

Recruitment Details	Estimated recruitment was 700, to deliver 690 evaluable, randomised patients, providing an average of 230 evaluable patients in each of the three groups. The number of randomised patients planned per country was as follows: Germany, 190; France, 15; Canada, 100; and USA, 395
Pre-assignment Detail	Three patients were randomised but not dosed: 2 due to withdrawal of consent, 1 for other reasons.

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single,slow intravenous (IV) push over about two minutes	Matching Placebo administered as a single, slow intravenous (IV) push over about two minutes
Period Title: Overall Study
STARTED	237	230	235
COMPLETED	231	226	230
NOT COMPLETED	6	4	5

Baseline Characteristics

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo	Total
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes	Total of all reporting groups
Overall Participants	237	230	235	702
Age (Count of Participants)
<=18 years	1 0.4%	2 0.9%	1 0.4%	4 0.6%
Between 18 and 65 years	214 90.3%	204 88.7%	216 91.9%	634 90.3%
>=65 years	22 9.3%	24 10.4%	18 7.7%	64 9.1%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.8 (13.12)	46.9 (13.03)	46.0 (13.38)	46.3 (13.17)
Sex: Female, Male (Count of Participants)
Female	213 89.9%	208 90.4%	212 90.2%	633 90.2%
Male	24 10.1%	22 9.6%	23 9.8%	69 9.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	0 0%	0 0%	1 0.1%
Asian	5 2.1%	6 2.6%	8 3.4%	19 2.7%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	0 0%	1 0.1%
Black or African American	19 8%	21 9.1%	22 9.4%	62 8.8%
White	196 82.7%	189 82.2%	193 82.1%	578 82.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	15 6.3%	14 6.1%	12 5.1%	41 5.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response (Success of Initial PONV Treatment)
Description	The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication.
Time Frame	0-24 hours after administration of study medication

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	80 33.8%	96 41.7%	67 28.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments	The primary efficacy analysis was a comparison of the incidence of the primary efficacy variable between the two groups that received APD421 and the group that received placebo, using Pearson's χ2 test. The threshold for determining statistical significance in the comparison of incidence of success between the active and placebo groups (the primary efficacy analysis) was a p-value of 2.5% one-sided.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	One-sided p-value. After adjustment for multiplicity using Hommel's method. (Note: unadjusted p value = 0.003) A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments	The primary efficacy analysis was a comparison of the incidence of the primary efficacy variable between the two groups that received APD421 and the group that received placebo, using Pearson's χ2 test. The threshold for determining statistical significance in the comparison of incidence of success between the active and placebo groups (the primary efficacy analysis) was a p-value of 2.5% one-sided.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.109
	Comments	One-sided p-value. After adjustment for multiplicity using Hommel's method. (Note: unadjusted p value = 0.109) A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Number of Participants With Complete Response 0-2 Hrs
Description	Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication.
Time Frame	0-2 hours after administration of study medication

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	134 56.5%	160 69.6%	116 49.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Number of Participants With Complete Response 0-4 Hrs
Description	Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication.
Time Frame	0-4 hours after administration of study medication

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	105 44.3%	136 59.1%	87 37%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Number of Participants With Complete Response 0-6 Hrs
Description	Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication.
Time Frame	0-6 hours after administration of study medication

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	99 41.8%	121 52.6%	77 32.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	One-sided p-value. No adjustment for multiple comparisons. A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to first violation of the criteria for complete response
Time Frame	0-24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Median (Inter-Quartile Range) [minutes]	188	443	120

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments
	Method	Regression, Cox
	Comments

6. Secondary Outcome

Title	Number of Patients With Incidence of Emesis
Description	Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication
Time Frame	30 mins to 24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	43 18.1%	36 15.7%	67 28.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Number of Patients Receiving Rescue Medication
Description	Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period
Time Frame	0-24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	155 65.4%	127 55.2%	163 69.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.179
	Comments
	Method	Chi-squared
	Comments

8. Secondary Outcome

Title	Number of Patients With an Incidence of Significant Nausea
Description	Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time Frame	30 mins to 24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	135 57%	111 48.3%	139 59.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.315
	Comments
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Number of Patients With an Incidence of Nausea
Description	Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time Frame	30 mins to 24 hours after drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Count of Participants [Participants]	183 77.2%	163 70.9%	181 77%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.520
	Comments
	Method	Chi-squared
	Comments

10. Secondary Outcome

Title	Maximum Severity of Nausea
Description	Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time Frame	30 mins to 24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Mean (Standard Deviation) [Score on a scale]	4.1 (3.08)	3.6 (3.03)	4.2 (3.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.420
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Evolution Score of Nausea (0-180 Mins)
Description	The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome.
Time Frame	0-180 minutes after study drug administration

Outcome Measure Data

Analysis Population Description

Modified ITT population

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes	APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes	Matching placebo administered as a single, slow, IV push over about two minutes
Measure Participants	237	230	235
Mean (Standard Deviation) [Score on a scale*min]	6994.7 (5659.6)	5637.9 (6046.6)	7629.2 (6640.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.258
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	7 days
Adverse Event Reporting Description	Any AE that is serious, occurring during the relevant study period (from study drug administration to 7-day follow-up), irrespective of the treatment received by the subject, must be reported to the Pharmacovigilance provider within 24 hours
Arm/Group Title	APD421 IV 5mg		APD421 IV 10mg		Placebo
Arm/Group Description	IV dose of APD421 5mg (IV dose)- was administered to each patient in a double-blind fashion, by slow IV push over about two minutes into a peripheral or central venous cannula.		IV dose of APD421 10mg (IV dose)- was administered to each patient in a double-blind fashion by slow IV push over about two minutes into a peripheral or central venous cannula.		IV dose of Placebo (IV dose)- was administered to each patient in a double-blind fashion by slow IV push over about two minutes into a peripheral or central venous cannula.
All Cause Mortality
	APD421 IV 5mg		APD421 IV 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/237 (0%)		0/230 (0%)		0/235 (0%)
Serious Adverse Events
	APD421 IV 5mg		APD421 IV 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/237 (2.5%)		3/230 (1.3%)		5/235 (2.1%)
Blood and lymphatic system disorders
Leukocytosis	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Cardiac disorders
Acute Myocardial Infarction	0/237 (0%)	0	1/230 (0.4%)	1	0/235 (0%)	0
Eye disorders
Fatty tissue prolapse at the tempral lobe	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Gastrointestinal disorders
Non-infectious gastroenteritis	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Unspecified Colitis	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Intra-abdominal Hematoma	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Intractable vomiting	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Gastrointestinal bleed	0/237 (0%)	0	1/230 (0.4%)	1	0/235 (0%)	0
Infections and infestations
Abscess Presacral	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Urinary tract infection	0/237 (0%)	0	1/230 (0.4%)	1	0/235 (0%)	0
Injury, poisoning and procedural complications
Anastomosis Insufficiency	0/237 (0%)	0	0/230 (0%)	0	1/235 (0.4%)	1
Post procedural hemorrhage	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Post cholecystectomy bile leak	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Postoperative Ileus	0/237 (0%)	0	1/230 (0.4%)	1	0/235 (0%)	0
Investigations
Postoperative rise in creatinine	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Nervous system disorders
Numbness in the leg	1/237 (0.4%)	1	0/230 (0%)	0	0/235 (0%)	0
Psychiatric disorders
Mental status changes	0/237 (0%)	0	1/230 (0.4%)	1	0/235 (0%)	0
Other (Not Including Serious) Adverse Events
	APD421 IV 5mg		APD421 IV 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/237 (27%)		66/230 (28.7%)		78/235 (33.2%)
Gastrointestinal disorders
Nausea	30/237 (12.7%)	33	27/230 (11.7%)	28	30/235 (12.8%)	32
Flatulence	13/237 (5.5%)	13	13/230 (5.7%)	13	18/235 (7.7%)	18
Constipation	13/237 (5.5%)	13	11/230 (4.8%)	11	17/235 (7.2%)	17
Vomiting	11/237 (4.6%)	14	10/230 (4.3%)	11	13/235 (5.5%)	13
General disorders
Infusion site pain	8/237 (3.4%)	8	12/230 (5.2%)	12	10/235 (4.3%)	10
Pruritus	7/237 (3%)	7	10/230 (4.3%)	10	13/235 (5.5%)	13
Nervous system disorders
Headache	10/237 (4.2%)	10	10/230 (4.3%)	10	17/235 (7.2%)	17

Limitations/Caveats

There were no limitations or caveats with this study

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.