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    Clinical Trial Results:
    Open-label, ascending-dose, Phase II study to determine the minimum effective dose of APD421 (intravenous amisulpride) in the prevention of cisplatin-induced nausea and vomiting

    Summary
    EudraCT number
    		 2010-022170-14
    Trial protocol
    		 GB   DK  
    Global end of trial date
    10 Jul 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2016
    First version publication date
    19 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DN10007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01303978
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Acacia Pharma Ltd
    Sponsor organisation address
    Harston Mill,, Cambridge, United Kingdom, CB22 7GG
    Public contact
    Dr Gabriel Fox, Acacia Pharma Ltd , 441223 875130, ITHelpdesk@acaciapharma.com
    Scientific contact
    Dr Gabriel Fox, Acacia Pharma Ltd , 441223 875130, ITHelpdesk@acaciapharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Apr 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the lowest dose of APD421 which shows an adequate level of effectiveness at preventing sickness in patients given cisplatin chemotherapy (compared to what would be expected based on historical data on other known anti-emetics).
    Protection of trial subjects
    Before commencing the conduct of any of the pre-study procedures, the investigator or medical delegate explained the study fully to each patient. If the patient was willing to participate in the study they were requested to give written informed consent and sufficient time was given to consider their participation and the opportunity to ask further details.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    10 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Denmark: 31
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    29
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Planned: up to 54 Enrolled: 51 Analysed (intent-to-treat): 51 Analysed (per protocol): 51 Analysed (safety): 51 Per cohort: Cohort 1 (2.5 mg APD421): 5 patients Cohort 2 (7.5 mg APD421): 5 patients Cohort 3 (20 mg APD421): 18 patients Cohort 4 (20 mg APD421 + ondansetron): 23 patients

    Pre-assignment
    Screening details
    		 Patients were screened up to 14 days before the planned date of their operation and admitted to hospital on the day before or morning of their operation.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 APD421 (2.5mg)
    Arm description
    		 Arm 1(Experimental): APD421 at 2.5mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amisulpride
    Investigational medicinal product code
    APD421
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    APD421 (amisulpride) for intravenous administration, given over 1-2minutes, 30 minutes prior to the administration of cisplatin.

    Arm title
    		 APD421 (7.5mg)
    Arm description
    		 Arm 2 (Experimental): APD421 IV at 7.5mg
    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
    7.5mg dosage Amisulpride(APD421) given via intravenous(IV) administration over 1-2 minutes, 30 mins prior to administration of cisplatin.

    Arm title
    		 APD421 (20mg)
    Arm description
    		 Arm 3 (Experimental): APD421 IV at 20mg
    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
    20mg dosage Amisulpride(APD421) given via intravenous(IV) administration over 1-2 minutes,30 mins prior to administration of cisplatin.

    Arm title
    		 APD421 Combo with Ondansteron
    Arm description
    		 Arm 4: APD421 IV at 20mg in combination with a standard dose of IV ondansteron
    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
    20mg dosage Amisulpride(APD421) given via intravenous(IV) administration over 1-2 minutes,30 mins prior to administration of cisplatin.

    Investigational medicinal product name
    Ondansetron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ondansetron give at a dose of 8-16mg according to usual site procedures

    Number of subjects in period 1
    		APD421 (2.5mg) APD421 (7.5mg) APD421 (20mg) APD421 Combo with Ondansteron
    Started
    5
    5
    18
    23
    Completed
    5
    5
    18
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 -

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 51 51
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 26 26
        From 65-84 years
    		 25 25
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (42 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 30 30
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who signed informed consent, enrolled into the study and received study drug were included in the ITT analysis.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who received the study medication and adhered to the protocol with no major protocol violations, as decided and documented by the sponsor‟s Chief Medical Officer, were included in a per protocol analysis. The reason for exclusion of any cases was documented.

    Subject analysis set title
    Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This is identical to the ITT population, in the sense that all subjects who signed the informed consent and received study drug were included in the Safety Analysis.

    Subject analysis sets values
    		 ITT Per Protocol Safety Analysis
    Number of subjects
    51
    51
    51
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    26
    26
    26
        From 65-84 years
    25
    25
    25
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    64 (42 to 77)
    64 (42 to 77)
    64 (42 to 77)
    Gender categorical
    Units: Subjects
        Female
    21
    21
    21
        Male
    30
    30
    30

    End points

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    End points reporting groups
    Reporting group title
    APD421 (2.5mg)
    Reporting group description
    		 Arm 1(Experimental): APD421 at 2.5mg

    Reporting group title
    APD421 (7.5mg)
    Reporting group description
    		 Arm 2 (Experimental): APD421 IV at 7.5mg

    Reporting group title
    APD421 (20mg)
    Reporting group description
    		 Arm 3 (Experimental): APD421 IV at 20mg

    Reporting group title
    APD421 Combo with Ondansteron
    Reporting group description
    		 Arm 4: APD421 IV at 20mg in combination with a standard dose of IV ondansteron

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who signed informed consent, enrolled into the study and received study drug were included in the ITT analysis.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who received the study medication and adhered to the protocol with no major protocol violations, as decided and documented by the sponsor‟s Chief Medical Officer, were included in a per protocol analysis. The reason for exclusion of any cases was documented.

    Subject analysis set title
    Safety Analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This is identical to the ITT population, in the sense that all subjects who signed the informed consent and received study drug were included in the Safety Analysis.

    Primary: Incidence of emesis in the 24-hour period post Cisplatin

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    End point title
    		 Incidence of emesis in the 24-hour period post Cisplatin
    End point description
    End point type
    Primary
    End point timeframe
    24 hours
    End point values
    		 APD421 (2.5mg) APD421 (7.5mg) APD421 (20mg) APD421 Combo with Ondansteron ITT Per Protocol Safety Analysis
    Number of subjects analysed
    5
    5
    18
    23
    51
    51
    51
    Units: Whole numbers
    5
    5
    15
    4
    29
    29
    29
    Statistical analysis title
    		 Primary Efficacy Analysis
    Statistical analysis description
    The primary efficacy analysis was a description of the rate of complete response with a 90% confidence intervals at each dose of APD421 and in the combination therapy cohort adjusted with the possibility of stopping at the end of the first stage.
    Comparison groups
    APD421 (2.5mg) v APD421 (7.5mg) v APD421 (20mg) v APD421 Combo with Ondansteron
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AE encountered during the study will be reported in detail in the source documents and noted in the AE section of the CRF from the date of subject consent, throughout the clinical conduct and up to the follow-up visit.
    Adverse event reporting additional description
    The nature and frequency of AEs in the study were recorded on the CRF by the investigator and were standardised by assigning terminology according to the Medical Dictionary for Drug Regulatory Affairs(MedDRA)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    2.5mg APD421
    Reporting group description
    		 -

    Reporting group title
    7.5mg APD421
    Reporting group description
    		 -

    Reporting group title
    20mg APD421
    Reporting group description
    		 -

    Reporting group title
    20mg APD421 + Ondasetron
    Reporting group description
    		 -

    Serious adverse events
    		 2.5mg APD421 7.5mg APD421 20mg APD421 20mg APD421 + Ondasetron
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    5 / 18 (27.78%)
    1 / 23 (4.35%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension, Irregular heart beat, Renal disorder, Sepsis and Spinal Cord Compression
    Additional description: Hypotension, Irregular heart beat, Renal disorder, Sepsis and Spinal Cord Compression
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
    Additional description: The patient experienced moderate pain while taking part in the study.
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia Obstructive
    Additional description: Patient experienced incarcerated hernia whist participating in the study.
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: Pulmonary embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Dehydration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 2.5mg APD421 7.5mg APD421 20mg APD421 20mg APD421 + Ondasetron
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    18 / 18 (100.00%)
    7 / 23 (30.43%)
    Vascular disorders
    Increased Hypertension
    Additional description: Increased Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Chills
    Additional description: Chills
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infusion site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    6 / 23 (26.09%)
         occurrences all number
    1
    0
    2
    6
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 5 (80.00%)
    4 / 5 (80.00%)
    15 / 18 (83.33%)
    5 / 23 (21.74%)
         occurrences all number
    4
    4
    15
    5
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    14 / 18 (77.78%)
    7 / 23 (30.43%)
         occurrences all number
    5
    5
    14
    7
    Dry Mouth
    Additional description: Dry Mouth
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Retching
    Additional description: Retching
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    4
    2
    Constipation
    Additional description: Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 23 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Bronchospasm
    Additional description: Bronchospasm
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash around eyes-puritus
    Additional description: Rash around eyes-puritus
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema of chest and upper back
    Additional description: Erythema of chest and upper back
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
    Additional description: Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2011
    A substantial amendment to the protocol was approved on 02 June 2011 to enrol a further cohort of subjects to be given APD421 at the highest dose level showing signs of efficacy, in combination with a single dose of IV ondansetron (given according to its marketing authorisation),
    14 Jun 2011
    A substantial amendment to the protocol was approved on 14 June 2011 to allow the proactive collection of nausea data at 2, 4, 8, and 24 hours post-cisplatin in addition to reactively, when nausea was reported by the patient.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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