Phase IIIb Study of APD421 in Combination as PONV Prophylaxis

• Sponsor: Acacia Pharma Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02337062
• Collaborator: (none)
• Enrollment: 1,147
• Locations: 25
• Arms: 2
• Duration (Months): 7
• Patients Per Site: 45.9
• Patients Per Site Per Month: 6.6

Study Details

Study Description

Brief Summary

A comparison of the efficacy of APD421 and placebo when combined with a standard anti-emetic in the prevention of PONV in patients at high risk of Post-operative Nausea and Vomiting (PONV).

Condition or Disease	Intervention/Treatment	Phase
PONV	Drug: APD421; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1147 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomised, Double-blind, Placebo-controlled Phase III Study of APD421 (Amisulpride for IV Injection) as Combination Prophylaxis Against Post-operative Nausea and Vomiting in High-risk Patients
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APD421 + standard anti-emetic Single dose of IV APD421	Drug: APD421
Placebo Comparator: Placebo + standard anti-emetic Single dose of IV placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response [24 hours after the end of surgery]

   Complete response defined as no emesis and no use of rescue medication in the 24 hour period after end of surgery (defined as wound closure)

Secondary Outcome Measures

1. Number of Participants With Emesis [24 hours after the end of surgery]

   Emesis is defined as vomiting (production of even the smallest amount of stomach contents) or retching (muscular movements of vomiting but without expulsion of stomach contents, usually because of an empty stomach)

2. Number of Participants Receiving Rescue Medication [24 hours after the end of surgery]

   Rescue medication defined as an antiemetic (or other medication) given with the intention of relieving nausea and/or emesis, or any incidental use of a drug known to have antiemetic potential

3. Number of Participants With Any Nausea [24 hours after the end of surgery]

   Nausea (defined as the desire to vomit without the presence of expulsive muscular movements) measured on a 0-10 verbal response scale, where 0=no nausea at all and 10=the worst nausea imaginable. "Any nausea" means a score ≥ 1.

4. Number of Participants With Significant Nausea [24 hours after end of surgery]

   Nausea (defined as the desire to vomit without the presence of expulsive muscular movements) measured on a 0-10 verbal response scale, where 0=no nausea at all and 10=the worst nausea imaginable. "Significant nausea" means a score ≥ 4.

5. Time to First Violation of Criteria for PONV [24 hours after end of surgery]

   Criteria for PONV are any episode of emesis or use of rescue medication in the 24 hours after the end of surgery

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

• Patients undergoing elective surgery (open or laparoscopic technique) under general anaesthesia, expected to last at least one hour from induction of anaesthesia to wound closure

• Patients with at least 3 "Apfel" risk factors for PONV

Exclusion Criteria:

• Patients scheduled to undergo transplant surgery

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

• Patients who are expected to remain ventilated for a period after surgery

• Patients who are expected to need a naso- or orogastric tube in situ after surgery is completed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Helen Keller Hospital	Sheffield	Alabama	United States	35660
2	UCSF School of Medicine	San Francisco	California	United States	94143
3	Jackson Memorial Hospital	Miami	Florida	United States	33136
4	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
5	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
6	Albany Medical Center Hospital	Albany	New York	United States	12208
7	Stony Brook Medicine	Stony Brook	New York	United States	11794
8	Duke University Medical Center	Durham	North Carolina	United States	27710
9	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157
10	Cleveland Clinic	Cleveland	Ohio	United States	44195
11	Ohio State University	Columbus	Ohio	United States	43210
12	First Street Surgical Center	Bellaire	Texas	United States	77401
13	Victory Medical Center Houston	Houston	Texas	United States	77004
14	Memorial Hermann-Memorial City Hospital	Houston	Texas	United States	77024
15	University Hospital	Besançon		France	25030
16	Centre Hospitalier Lyon-Sud	Lyon		France	69495
17	Centre Hospitalier de Mulhouse	Mulhouse		France	68051
18	Hopital Foch	Paris		France
19	CHU de Hautepierre	Strasbourg		France
20	HELIOS Klinikum Aue	Aue		Germany	08280
21	Universitätsklinikum Bonn	Bonn		Germany	53127
22	Klinikum Ludwigshafen	Ludwigshafen		Germany	67063
23	Universitätsmedizin Mainz	Mainz		Germany	55131
24	Philipps University	Marburg		Germany	35033
25	University Hospitals of Würzburg	Würzburg		Germany

Sponsors and Collaborators

• Acacia Pharma Ltd

Investigators

• Principal Investigator: Peter Kranke, MD, Würzburg University Hospitals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Acacia Pharma Ltd
• ClinicalTrials.gov Identifier: NCT02337062
• Other Study ID Numbers: DP10017
• First Posted: Jan 13, 2015
• Last Update Posted: Mar 20, 2019
• Last Verified: Mar 1, 2019

Study Results

Participant Flow

Recruitment Details	Study start date:- 12th February 2015 (first patient in) Study completion date:- 28th September 2015 (last patient last visit) Location:-France, Germany and the USA.

Arm/Group Title	APD421 + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	APD421 (amisulpride) at 5 mg administered as a single, slow, intravenous (IV) push over one minute at the time of induction of anaesthesia; given in combination with standard anti-emetic.	Matching Placebo administered as a single, slow push, IV push over one minute at the time of induction anaesthesia given in combination with standard anti-emetic
Period Title: Overall Study
STARTED	572	575
COMPLETED	555	556
NOT COMPLETED	17	19

Baseline Characteristics

Arm/Group Title	APD421 + Standard Anti-emetic	Placebo + Standard Anti-emetic	Total
Arm/Group Description	Single dose of IV APD421 APD421	Single dose of IV placebo Placebo	Total of all reporting groups
Overall Participants	572	575	1147
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	48.8 (14.24)	48.3 (13.98)	48.5 (14.10)
Sex: Female, Male (Count of Participants)
Female	552 96.5%	557 96.9%	1109 96.7%
Male	20 3.5%	18 3.1%	38 3.3%
Region of Enrollment (Count of Participants)
United States	353 61.7%	351 61%	704 61.4%
France	79 13.8%	85 14.8%	164 14.3%
Germany	140 24.5%	139 24.2%	279 24.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response
Description	Complete response defined as no emesis and no use of rescue medication in the 24 hour period after end of surgery (defined as wound closure)
Time Frame	24 hours after the end of surgery

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	APD421 (amisulpride) at 5 mg administered as a single, slow, intravenous (IV) push over one minute at the time of induction of anaesthesia; given in combination with standard anti-emetic.	Matching placebo administered as a single, slow, IV push over one minute, at the time of induction of anaesthesia; given in combination with standard anti-emetic
Measure Participants	572	575
Count of Participants [Participants]	330 57.7%	268 46.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Number of Participants With Emesis
Description	Emesis is defined as vomiting (production of even the smallest amount of stomach contents) or retching (muscular movements of vomiting but without expulsion of stomach contents, usually because of an empty stomach)
Time Frame	24 hours after the end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	Single IV dose of 5 mg APD421 administered in combination with standard anti-emetic	Single dose of IV placebo administered in combination with standard anti-emetic
Measure Participants	572	575
Count of Participants [Participants]	79 13.8%	115 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	Number of Participants Receiving Rescue Medication
Description	Rescue medication defined as an antiemetic (or other medication) given with the intention of relieving nausea and/or emesis, or any incidental use of a drug known to have antiemetic potential
Time Frame	24 hours after the end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	Single IV dose of 5 mg APD421 administered in combination with standard anti-emetic	Single dose of IV placebo administered in combination with standard anti-emetic
Measure Participants	572	575
Count of Participants [Participants]	234 40.9%	284 49.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Number of Participants With Any Nausea
Description	Nausea (defined as the desire to vomit without the presence of expulsive muscular movements) measured on a 0-10 verbal response scale, where 0=no nausea at all and 10=the worst nausea imaginable. "Any nausea" means a score ≥ 1.
Time Frame	24 hours after the end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	Single IV dose of 5 mg APD421 administered in combination with standard anti-emetic	Single dose of IV placebo administered in combination with standard anti-emetic
Measure Participants	572	575
Count of Participants [Participants]	286 50%	335 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Number of Participants With Significant Nausea
Description	Nausea (defined as the desire to vomit without the presence of expulsive muscular movements) measured on a 0-10 verbal response scale, where 0=no nausea at all and 10=the worst nausea imaginable. "Significant nausea" means a score ≥ 4.
Time Frame	24 hours after end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	Single IV dose of 5 mg APD421 administered in combination with standard anti-emetic	Single dose of IV placebo administered in combination with standard anti-emetic
Measure Participants	572	575
Count of Participants [Participants]	212 37.1%	274 47.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Time to First Violation of Criteria for PONV
Description	Criteria for PONV are any episode of emesis or use of rescue medication in the 24 hours after the end of surgery
Time Frame	24 hours after end of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	APD421 5mg + Standard Anti-emetic	Placebo + Standard Anti-emetic
Arm/Group Description	APD421 (amisulpride) at 5 mg administered as a single, slow, intravenous (IV) push over one minute at the time of induction of anaesthesia; given in combination with standard anti-emetic.	Matching placebo administered as a single, slow, IV push over one minute, at the time of induction of anaesthesia; given in combination with standard anti-emetic
Measure Participants	572	575
Median (Inter-Quartile Range) [minutes]	NA	821.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD421 5mg + Standard Anti-emetic, Placebo + Standard Anti-emetic
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	For the 7 day period after study drug administration
Arm/Group Title	APD421 + Standard Anti-emetic		Placebo + Standard Anti-emetic
Arm/Group Description	Single dose of IV APD421 APD421		Single dose of IV placebo Placebo
All Cause Mortality
	APD421 + Standard Anti-emetic		Placebo + Standard Anti-emetic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/572 (0.2%)		0/575 (0%)
Serious Adverse Events
	APD421 + Standard Anti-emetic		Placebo + Standard Anti-emetic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/572 (2.4%)		14/575 (2.4%)
Gastrointestinal disorders
Small intestinal Obstruction	1/572 (0.2%)	1	2/575 (0.3%)	2
Intra-abdominal haemorrhage	1/572 (0.2%)	1	0/575 (0%)	0
Nausea	0/572 (0%)	0	1/575 (0.2%)	1
Vomiting	0/572 (0%)	0	1/575 (0.2%)	1
Infections and infestations
Peritonitis	2/572 (0.3%)	2	0/575 (0%)	0
Pneumonia	1/572 (0.2%)	1	1/575 (0.2%)	1
Post Operative wound infections	2/572 (0.3%)	2	0/575 (0%)	0
Gastroenteritis viral	1/572 (0.2%)	1	0/575 (0%)	0
Sepsis	1/572 (0.2%)	1	0/575 (0%)	0
Staphylococcal infections	0/572 (0%)	0	1/575 (0.2%)	1
Urinary Tract Infection	0/572 (0%)	0	1/575 (0.2%)	1
Wound infection	0/572 (0%)	0	1/575 (0.2%)	1
Injury, poisoning and procedural complications
Post Procedural haemorrhage	2/572 (0.3%)	2	2/575 (0.3%)	2
Wound Secretion	1/572 (0.2%)	1	1/575 (0.2%)	1
Herpatic Haematoma	0/572 (0%)	0	1/575 (0.2%)	1
Pelvic Organ Injury	1/572 (0.2%)	1	0/575 (0%)	0
Postoerative ileus	0/572 (0%)	0	1/575 (0.2%)	1
Procedural Haemorrhage	0/572 (0%)	0	1/575 (0.2%)	1
Procedural Pain	1/572 (0.2%)	1	0/575 (0%)	0
Other (Not Including Serious) Adverse Events
	APD421 + Standard Anti-emetic		Placebo + Standard Anti-emetic
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/572 (19.4%)		120/575 (20.9%)
Gastrointestinal disorders
Nausea	62/572 (10.8%)	62	70/575 (12.2%)	70
Injury, poisoning and procedural complications
Procedural Pain	53/572 (9.3%)	53	58/575 (10.1%)	58

Limitations/Caveats

There were no limitations and caveats that occurred during the duration of this study.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.