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Clinical Trial Results:
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.

Summary
EudraCT number	2015-002041-59
Trial protocol	DE
Global end of trial date	18 Jul 2016

Results information
Results version number	v1(current)
This version publication date	15 Jul 2018
First version publication date	15 Jul 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

DP10018

ISRCTN number

US NCT number

NCT02449291

WHO universal trial number (UTN)

Sponsor organisation name

Acacia Pharma Ltd

Sponsor organisation address

Harston Mill, Cambridge, United Kingdom, CB22 7GG

Public contact

Dr Gabriel Fox, Acacia Pharma Ltd, 01223 875149, medinfo@acaciapharma.com

Scientific contact

Dr Gabriel Fox, Acacia Pharma Ltd, 01223 875149, medinfo@acaciapharma.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

17 Mar 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Jul 2016

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of 5 mg and 10 mg APD421 to placebo as treatment of established PONV, in adults who have had no prior PONV prophylaxis

Protection of trial subjects

The investigator or individuals designated by the investigator(where acceptable by regulations) was responsible for ensuring that each patient provided signed and dated written informed consent before participating in the study. Each patient who attended a pre-study visit was provided with a written explanation of the study giving details of the investigational drug,study procedures and objectives, potential hazards involved and overall requirements for study subjects.

Background therapy

N/A

Evidence for comparator

Placebo

Actual start date of recruitment

20 Jul 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 95

Country: Number of subjects enrolled

United States: 266

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Germany: 183

Worldwide total number of subjects

560

EEA total number of subjects

199

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

505

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Planned (Consent):-2,500 Planned (Randomised):- 580 Analysed (Safety):-560 Intent-To-Treat:-560 Per Protocol:-542 Enrolled:- 1,988 Randomised and did not receive treatment and discontinued the study:- 8 Randomised and received treatment and completed the study:-552

Screening details

The study consisted of a screening period from days –28 to 0 (day of operation)

Period 1 title

Overall Trial ( Overall Period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

The randomisation information was not available to the sponsor or to any personnel at any study site or at the CRO. The randomisation list was made available to the appropriate Qualified Person at the clinical packaging contractor for the study labeling purpose.

Are arms mutually exclusive

Yes

APD421 at 5mg

Arm description

APD421 (Amisulpride) at 5mg is administered as a single slow intravenous (IV) push over a period of two minutes.

Arm type

Experimental

Investigational medicinal product name

Amisulpride

Investigational medicinal product code

APD421

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

APD421 (Amisulpride) at 5mg administered as a single, slow intravenous (IV) push over a period of two minutes.

APD421 at 10mg

Arm description

APD421 (Amisulpride) at 10mg is administered as single slow intravenous push over a period of two minutes.

Arm type

Experimental

Investigational medicinal product name

Amisulpride

Investigational medicinal product code

ADP421

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

APD421 (Amisulpride) at 10mg administered as a single, slow intravenous (IV) push over a period of two minutes.

APD421 IV Placebo

Arm description

APD421 Placebo administered as a single dose, slow IV push over a period of two minutes.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

APD421 Placebo administered as a single, slow IV push over a period of two minutes

Number of subjects in period 1	APD421 at 5mg	APD421 at 10mg	APD421 IV Placebo
Started	191	188	181
Completed	186	186	180
Not completed	5	2	1
Major Protocol Deviation	1	-	-
Lost to follow-up	4	2	1

Baseline characteristics

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Reporting group title

APD421 at 5mg

Reporting group description

APD421 (Amisulpride) at 5mg is administered as a single slow intravenous (IV) push over a period of two minutes.

Reporting group title

APD421 at 10mg

Reporting group description

APD421 (Amisulpride) at 10mg is administered as single slow intravenous push over a period of two minutes.

Reporting group title

APD421 IV Placebo

Reporting group description

APD421 Placebo administered as a single dose, slow IV push over a period of two minutes.

Reporting group values	APD421 at 5mg	APD421 at 10mg	APD421 IV Placebo	Total
Number of subjects	191	188	181	560
Age categorical
Units: Subjects
Adults (18-64 years)	178	168	159	505
From 65-84 years	13	20	22	55
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	44.3 ± 13.24	47.4 ± 14.42	46.5 ± 14.13	-
Gender categorical
Units: Subjects
Female	146	145	136	427
Male	45	43	45	133

Subject analysis set title

mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who have signed the informed consent form and been randomised into the study by virtue of receiving a dose of APD421 or placebo study medication.

Subject analysis sets values	mITT
Number of subjects	560
Age categorical
Units: Subjects
Adults (18-64 years)	505
From 65-84 years	55
85 years and over	0
Age continuous
Units: years
arithmetic mean (standard deviation)	±
Gender categorical
Units: Subjects
Female	427
Male	133

End points

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Reporting group title

APD421 at 5mg

Reporting group description

APD421 (Amisulpride) at 5mg is administered as a single slow intravenous (IV) push over a period of two minutes.

Reporting group title

APD421 at 10mg

Reporting group description

APD421 (Amisulpride) at 10mg is administered as single slow intravenous push over a period of two minutes.

Reporting group title

APD421 IV Placebo

Reporting group description

APD421 Placebo administered as a single dose, slow IV push over a period of two minutes.

Subject analysis set title

mITT

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

All subjects who have signed the informed consent form and been randomised into the study by virtue of receiving a dose of APD421 or placebo study medication.

Primary: Incidence of complete response in the 24-hour period after treatment

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End point title

Incidence of complete response in the 24-hour period after treatment

End point description

The primary efficacy variable is 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 study medication

End point type

Primary

End point timeframe

24hr period after study drug administration.

End point values	APD421 at 5mg	APD421 at 10mg	APD421 IV Placebo	mITT
Number of subjects analysed	191	188	181	560
Units: Comparison of the incidence of CR	60	59	39	560

5 mg APD421 v placebo

Statistical analysis description

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 chi-square test.

Comparison groups

APD421 at 5mg v APD421 IV Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016 ^[1]

Method

Chi-squared

Confidence interval

Notes
[1] - One-sided p-value,adjusted for multiplicity using the Hommel procedure.

10 mg APD421 v placebo

Comparison groups

APD421 at 10mg v APD421 IV Placebo

Number of subjects included in analysis

369

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016 ^[2]

Method

Chi-squared

Confidence interval

Notes
[2] - One-sided p-value,adjusted for multiplicity using the Hommel procedure.

Adverse events

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Timeframe for reporting adverse events

Any AE from randomisation, throughout the clinical conduct and up to the follow-up visit.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

APD421 at 5mg

Reporting group description

APD421 at 5mg administered as a single slow intravenous (IV) push over a period of two minutes.

Reporting group title

APD421 at 10mg

Reporting group description

APD421 at 10mg is administered as a single slow intravenous IV push over a period of two minutes.

Reporting group title

APD421 IV Placebo

Reporting group description

Serious adverse events	APD421 at 5mg	APD421 at 10mg	APD421 IV Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 191 (2.62%)	4 / 188 (2.13%)	5 / 181 (2.76%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Pulmonary embolism
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative ileus
subjects affected / exposed	1 / 191 (0.52%)	1 / 188 (0.53%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural Pain
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-procedural bile leak
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal anastomotic leak
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Tachyarrhythmia
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebellar infarction
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometriosis
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary Colic
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dysponea
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal haemorrhage
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Peritonitis
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal Abscess
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	APD421 at 5mg	APD421 at 10mg	APD421 IV Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	61 / 191 (31.94%)	61 / 188 (32.45%)	63 / 181 (34.81%)
General disorders and administration site conditions
Infusion site pain
subjects affected / exposed	8 / 191 (4.19%)	13 / 188 (6.91%)	7 / 181 (3.87%)
occurrences all number	8	13	7
Gastrointestinal disorders
Flatulence
subjects affected / exposed	24 / 191 (12.57%)	17 / 188 (9.04%)	21 / 181 (11.60%)
occurrences all number	25	17	21
Nausea
subjects affected / exposed	15 / 191 (7.85%)	18 / 188 (9.57%)	19 / 181 (10.50%)
occurrences all number	17	18	22
Constipation
subjects affected / exposed	14 / 191 (7.33%)	13 / 188 (6.91%)	16 / 181 (8.84%)
occurrences all number	14	13	16

More information

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Were there any global substantial amendments to the protocol? Yes

21 Aug 2015

Non-substantial amendment was made specifically to only the French protocol (Version 1.1)- Three exclusion criteria was added.

07 Sep 2015

A non-substantial amendment was made specifically on the German Protocol (version 1.2)- one exclusion criteria was added.

23 Sep 2015

Protocol version 1.3 was developed for UK sites but not implemented as UK sites were not initiated.

29 Oct 2015

A non-substantial amendment was made for French specific protocol ( version 1.4)- A change to laboratory tests/ assessments.

18 Dec 2015

A substantial amendment was made to all sites version 2.0- Amendments made to version 1.0 incorporated those made to country specific versions 1.1, 1.2 and 1.4. Changes made include the following:- Changes were made to study design Number of subjects and estimated recruitment Addition if the definition of randomisation and the change to randomisation for the drop dose selection Changes made to study centres Changes to exclusion criteria Redefinition of the primary study period Changes to laboratory tests/ assessments. Flexibilty around nominal study time points Change to labelling information Change to definitions Redefinition of primary efficacy analysis Redefinition of ITT analysis population Change to only one blinded data review at the end of the study Appendix 3 deleted Changes to the wording for the anti-emetic agents in appendix 4

04 Feb 2016

A non-substantial amendment was made to the German country specific protocol ( version 2.1)- Changes were made to the one of the exclusion criteria of the protocol.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None Reported

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Clinical trials

Clinical Trial Results:
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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of complete response in the 24-hour period after treatment

Primary: Incidence of complete response in the 24-hour period after treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: 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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of complete response in the 24-hour period after treatment

Primary: Incidence of complete response in the 24-hour period after treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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.