Study of APD421 as PONV Treatment (no Prior Prophylaxis)

• Sponsor: Acacia Pharma Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02449291
• Collaborator: (none)
• Enrollment: 568
• Locations: 4
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 142
• Patients Per Site Per Month: 14.2

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 not 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: 568 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 no Prior Prophylaxis
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2016

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. Complete Response (Success of Initial PONV Treatment) [0-24 hours after treatment]

   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 2-24 Hrs [2-24 hours after administration of study medication]

   Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) and no administration of anti-emetic rescue medication from 2 to 24 hours after administration of study medication.

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

   Time to first violation of the criteria for complete response

4. Number of Patients Experiencing 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

5. Number of Participants Using Rescue Medication [0-24 hours after study drug administration]

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

6. Incidence of Significant Nausea [30 mins to 24 hours after study drug administration]

   Proportion 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.

7. Incidence of Nausea [30 mins to 24 hours after study drug administration]

   Proportion 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.

8. 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.

9. Evolution Score of Nausea (0-30 Mins) [0-30 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 four pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes 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 low to moderate 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 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 agent likely to prevent or treat nausea or vomiting (given as prophylaxis or otherwise) in the period from 12 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 being treated with regular anti-emetic therapy (dosed at least three times per week), which is still ongoing within one week prior to surgery

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

• Patients being treated with levodopa

• Patients who are pregnant or breast feeding

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

• Patients with a documented, clinically significant cardiac arrhythmia

• 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	Ohio State University	Columbus	Ohio	United States	43210
3	CHU de Hautepierre	Strasbourg		France
4	Universität Heidelberg	Heidelberg		Germany

Sponsors and Collaborators

• Acacia Pharma Ltd

Investigators

• Principal Investigator: Keith Candiotti, MD, University of Miami

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acacia Pharma Ltd
• ClinicalTrials.gov Identifier: NCT02449291
• Other Study ID Numbers: DP10018
• First Posted: May 20, 2015
• 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

Arm/Group Title	APD421 Standard	APD421 High	Placebo
Arm/Group Description	Single (standard) dose IV APD421	Single (high) dose IV APD421	Single IV placebo
Period Title: Overall Study
STARTED	191	188	181
COMPLETED	186	186	180
NOT COMPLETED	5	2	1

Baseline Characteristics

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo	Total
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181	560
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	44.2	47.4	46.5	46.1
Sex: Female, Male (Count of Participants)
Female	146 76.4%	145 77.1%	136 75.1%	427 76.3%
Male	45 23.6%	43 22.9%	45 24.9%	133 23.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	0 0%	0 0%	1 0.2%
Asian	7 3.7%	4 2.1%	3 1.7%	14 2.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	14 7.3%	17 9%	13 7.2%	44 7.9%
White	153 80.1%	152 80.9%	151 83.4%	456 81.4%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	16 8.4%	15 8%	14 7.7%	45 8%

Outcome Measures

1. Primary Outcome

Title	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 treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg IV	APD421 10mg IV	Placebo
Arm/Group Description	APD421 (amisulpride) at 5mg administered as a single, slow, intravenous (IV) push over about two minutes.	APD421 (amisulpride) at 10 mg administered as a single, slow, intravenous (IV) push over about two minutes.	Single IV placebo administered as a single, slow, intravenous (IV) push over about two minutes.
Measure Participants	191	188	181
Count of Participants [Participants]	60 31.4%	59 31.4%	39 21.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, 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	0.016
	Comments	One-sided p-value. After adjustment for multiplicity using Hommel's method. (Note: unadjusted p value = 0.016) A priori threshold for statistical significance = 0.025.
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, 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	0.016
	Comments	One-sided p-value. After adjustment for multiplicity using Hommel's method. (Note: unadjusted p value = 0.015) 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

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	112 58.6%	105 55.9%	79 43.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	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 IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	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 2-24 Hrs
Description	Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) and no administration of anti-emetic rescue medication from 2 to 24 hours after administration of study medication.
Time Frame	2-24 hours after administration of study medication

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	100 52.4%	109 58%	96 53%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.170
	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 IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.552
	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	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

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Median (Inter-Quartile Range) [minutes]	159	177	79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Regression, Cox
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Cox
	Comments

5. Secondary Outcome

Title	Number of Patients Experiencing 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 dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	64 33.5%	57 30.3%	62 34.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.209
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.440
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Number of Participants Using Rescue Medication
Description	Proportion 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

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	121 63.4%	119 63.3%	135 74.6%

Statistical Analysis 1

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

7. Secondary Outcome

Title	Incidence of Significant Nausea
Description	Proportion 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

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	114 59.7%	108 57.4%	115 63.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.222
	Comments
	Method	Chi-squared
	Comments

8. Secondary Outcome

Title	Incidence of Nausea
Description	Proportion 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 study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Count of Participants [Participants]	151 79.1%	148 78.7%	143 79%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.474
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.505
	Comments
	Method	Chi-squared
	Comments

9. 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

[Not Specified]

Arm/Group Title	APD421 5mg	APD421 10mg	Placebo
Arm/Group Description	APD421 5mg dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Mean (Standard Deviation) [score on a scale]	4.3 (3.24)	4.2 (3.34)	4.7 (3.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.103
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.166
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Evolution Score of Nausea (0-30 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 four pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes 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	0-30 minutes 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 dose administered as a single, slow, intravenous (IV) push over about two minutes	APD421 10mg dose 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	191	188	181
Mean (Full Range) [Score on a scale*min]	1440.79	1502.55	1661.25

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 10mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg IV, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	7 days
Arm/Group Title	APD421 5 mg		APD421 10 mg		Placebo
Arm/Group Description	Single 5 mg dose IV APD421		Single 10 mg dose IV APD421		Single IV placebo
All Cause Mortality
	APD421 5 mg		APD421 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/191 (0%)		0/188 (0%)		0/181 (0%)
Serious Adverse Events
	APD421 5 mg		APD421 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/191 (2.6%)		4/188 (2.1%)		5/181 (2.8%)
Cardiac disorders
Tachyarrhythmia	0/191 (0%)	0	1/188 (0.5%)	1	0/181 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Vomiting	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Hepatobiliary disorders
Biliary colic	0/191 (0%)	0	1/188 (0.5%)	1	0/181 (0%)	0
Infections and infestations
Abdominal abscess	1/191 (0.5%)	1	0/188 (0%)	0	0/181 (0%)	0
Peritonitis	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Injury, poisoning and procedural complications
Postoperative ileus	1/191 (0.5%)	1	1/188 (0.5%)	1	0/181 (0%)	0
Gastrointestinal anastomotic leak	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Post procedural bile leak	0/191 (0%)	0	1/188 (0.5%)	1	0/181 (0%)	0
Post procedural haematoma	1/191 (0.5%)	1	0/188 (0%)	0	0/181 (0%)	0
Procedural pain	1/191 (0.5%)	1	0/188 (0%)	0	0/181 (0%)	0
Nervous system disorders
Cerebellar infarction	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Renal and urinary disorders
Renal haemorrhage	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Reproductive system and breast disorders
Endometriosis	1/191 (0.5%)	1	0/188 (0%)	0	0/181 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/191 (0%)	0	0/188 (0%)	0	1/181 (0.6%)	1
Pulmonary embolism	1/191 (0.5%)	1	0/188 (0%)	0	0/181 (0%)	0
Other (Not Including Serious) Adverse Events
	APD421 5 mg		APD421 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/191 (22.5%)		45/188 (23.9%)		49/181 (27.1%)
Gastrointestinal disorders
Flatulence	24/191 (12.6%)	25	17/188 (9%)	17	21/181 (11.6%)	21
Nausea	15/191 (7.9%)	17	18/188 (9.6%)	18	19/181 (10.5%)	22
Constipation	14/191 (7.3%)	14	13/188 (6.9%)	13	16/181 (8.8%)	16
General disorders
Infusion site pain	8/191 (4.2%)	8	13/188 (6.9%)	13	7/181 (3.9%)	7

Limitations/Caveats

There were no limitations or caveats associated 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.