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    Clinical Trial Results:
    A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of MK-0517/Fosaprepitant and Ondansetron Versus Ondansetron for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Pediatric Subjects Receiving Emetogenic Chemotherapy

    Summary
    EudraCT number
    		 2014-001783-34
    Trial protocol
    		 SE   NO   ES   LT   FI   PT   EE   HU   GB   NL   GR   Outside EU/EEA  
    Global end of trial date
    24 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Sep 2017
    First version publication date
    03 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0517-044
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02519842
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration Number: MK-0517-044, IND Number: 48,924
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and safety of fosaprepitant (MK-0517) plus ondansetron versus ondansetron alone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric participants scheduled to receive chemotherapeutic agent(s) associated with moderate or high risk of causing emesis (vomiting), or chemotherapy agent(s) not previously tolerated due to vomiting. The primary hypothesis was that a single dose of fosaprepitant in combination with ondansetron provided superior control of CINV compared to ondansetron alone as measured by the percentage of participants with a Complete Response (no vomiting, no retching, and no use of rescue medications) in the delayed phase (>24 to 120 hours) following initiation of emetogenic chemotherapy in Cycle 1.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. Participants <12 years of age were not permitted to participate in the current study until Pharmacokinetic/Pharmacodynamic and safety data were evaluated from an earlier study to confirm the planned dose adjustments for subjects <12 years of age.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Sep 2015
    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
    Chile: 6
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    75
    EEA total number of subjects
    45
    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)
    37
    Adolescents (12-17 years)
    38
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants for chemotherapy Cycles 1-6 were 0-17 years old and had documented malignancies and were scheduled to receive chemotherapeutic agent(s) associated with moderate or high risk of emetogenicity. Participants entering Cycles 2-6 must have completed Cycle 1 and had no unresolved drug related adverse events.

    Pre-assignment
    Screening details
    		 Participants received double-blinded fosaprepitant+ondansetron with/without dexamethasone OR placebo+ondansetron with/without dexamethasone in Cycle 1. Upon completion of Cycle 1, participants from both Cycle 1 arms had the option to continue for up to 5 cycles of open-label fosaprepitant+5-hydroxytryptamine 3 antagonist with/without dexamethasone.

    Period 1
    Period 1 title
    Base Study-Cycle 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fosaprepitant Regimen Cycle 1
    Arm description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fosaprepitant
    Investigational medicinal product code
    Other name
    Emend® for injection fosaprepitant dimeglumine MK-0517
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose of fosaprepitant 150 mg (or age-based adjustment) administered IV on Day 1 prior to chemotherapy

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dexamethasone administered IV, as specified by local labeling and/or local standard of care, at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Investigational medicinal product name
    Ondansetron
    Investigational medicinal product code
    Other name
    Ondansetron hydrochloride Zofran® Injection
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ondansetron administered IV, as specified by local labeling and/or local standard of care, on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Arm title
    		 Control Regimen Cycle 1
    Arm description
    		 Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for fosaprepitant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose of Placebo for fosaprepitant administered IV on Day 1 prior to chemotherapy

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dexamethasone administered IV, as specified by local labeling and/or local standard of care, at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Investigational medicinal product name
    Ondansetron
    Investigational medicinal product code
    Other name
    Ondansetron hydrochloride Zofran® Injection
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ondansetron administered IV, as specified by local labeling and/or local standard of care, on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Number of subjects in period 1
    		Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1
    Started
    38
    37
    Treated
    37
    34
    Completed
    36
    34
    Not completed
    2
    3
         Non-Compliance with Study Drug
    -
    1
         Adverse event, non-fatal
    1
    -
         Screening Failure
    1
    1
         Withdrawn By Parent/Guardian
    -
    1
    Period 2
    Period 2 title
    Optional Extension-Cycles 2-6
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Fosaprepitant Regimen Cycles 2-6
    Arm description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5-hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fosaprepitant
    Investigational medicinal product code
    Other name
    Emend® for injection fosaprepitant dimeglumine MK-0517
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose of fosaprepitant 150 mg (or age-based adjustment) administered IV on Day 1 prior to chemotherapy

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dexamethasone administered by a route of administration determined by the investigator, as specified by local labeling and/or local standard of care, at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Investigational medicinal product name
    5-hydroxytryptamine 3 antagonist
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-HT3 antagonist administered by a route of administration determined by the investigator, as specified by local labeling and/or local standard of care, on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy

    Number of subjects in period 2 [1]
    		Fosaprepitant Regimen Cycles 2-6
    Started
    55
    Completed
    26
    Not completed
    29
         Consent withdrawn by subject
    1
         Physician decision
    5
         Did not respond to chemotherapy
    2
         Completed chemotherapy
    13
         Enrollment Terminated at Site
    1
         Adverse event, non-fatal
    1
         Death
    1
         Withdrawn By Parent/Guardian
    3
         Cycle Inclusion/Exclusion Criteria Not Met
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Upon completion of Cycle 1, participants from the fosaprepitant and control arms of Cycle 1 had the option to continue in the fosaprepitant arm in Cycles 2-6.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fosaprepitant Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Reporting group title
    Control Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Reporting group values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1 Total
    Number of subjects
    		 38 37 75
    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)
    		 19 18 37
        Adolescents (12-17 years)
    		 19 19 38
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.8 ( 4.2 ) 10.9 ( 4.4 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 14 16 30
        Male
    		 24 21 45

    End points

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    End points reporting groups
    Reporting group title
    Fosaprepitant Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Reporting group title
    Control Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.
    Reporting group title
    Fosaprepitant Regimen Cycles 2-6
    Reporting group description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5-hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Subject analysis set title
    Fosaprepitant Regimen Cycle 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Analysis was in the intent-to-treat population which consists of all randomized participants who received any study drug.

    Subject analysis set title
    Control Regimen Cycle 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Analysis was in the intent-to-treat population which consists of all randomized participants who received any study placebo.

    Subject analysis set title
    Fosaprepitant Regimen Cycle 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Analysis was in the all subjects as treated population which consists of all randomized participants who received at least one dose of study drug.

    Subject analysis set title
    Control Regimen Cycle 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Analysis was in the all subjects as treated population which consists of all randomized participants who received at least one dose of study drug.

    Subject analysis set title
    Fosaprepitant Regimen Cycles 2-6
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5-hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Analysis was in the all subjects as treated population which consists of all randomized participants who received at least one dose of study drug.

    Primary: Percentage of Participants Who Experience a Complete Response During the Delayed Phase (>24 to 120 hours post initiation of chemotherapy) in Cycle 1

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    End point title
    		 Percentage of Participants Who Experience a Complete Response During the Delayed Phase (>24 to 120 hours post initiation of chemotherapy) in Cycle 1 [1]
    End point description
    Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the delayed phase, defined as the time period of >24 to120 hours post initiation of chemotherapy in Cycle 1, was calculated. The endpoint was based on all participants who received at least 1 dose of study drug during Cycle 1.
    End point type
    Primary
    End point timeframe
    >24 to 120 hours post initiation of chemotherapy (1 to 15 days after the dose of study drug)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Early termination of the study limited the data for efficacy and statistical analyses were not performed for this endpoint.
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1
    Number of subjects analysed
    37
    34
    Units: percentage of participants
        number (not applicable)
    48.6
    41.2
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experience One or More Adverse Events

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    End point title
    		 Percentage of Participants Who Experience One or More Adverse Events
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. The endpoint was based on all participants who received at least 1 dose of study drug during Cycles 1 through 6. An analysis was performed on Tier 2 AEs in Cycle 1 to compare the percentage of participants who received fosaprepitant regimen and experienced at least 1 Tier 2 AE compared with the percentage of participants in the control regimen. The Tier 2 endpoint included broad clinical and laboratory AE categories consisting of the percentage of participants with any AE, drug-related AE, serious AE, and AEs that are both drug-related and serious. Tier 2 AEs were not pre-specified as events of interest and inclusion in the Tier 2 analysis required that at least 4 participants in any treatment group exhibited the AE.
    End point type
    Primary
    End point timeframe
    Up to 6.5 months (Up to 2 weeks after last dose of study drug)
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1 Fosaprepitant Regimen Cycles 2-6
    Number of subjects analysed
    37
    34
    55
    Units: percentage of participants
        number (not applicable)
    89.2
    79.4
    78.2
    Statistical analysis title
    		 Difference in Percentage of Participants
    Statistical analysis description
    Mean difference in percentage of participants who experienced at least 1 tier 2 AE and received fosaprepitant regimen compared with participants who received control regimen. Estimates were based on the Miettinen & Nurminen method.
    Comparison groups
    Fosaprepitant Regimen Cycle 1 v Control Regimen Cycle 1
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 27.9

    Primary: Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug. The endpoint was based on all participants who received at least 1 dose of study drug during Cycles 1 through 6. An analysis was performed to compare the percentage of participants who discontinued in Cycle 1 due to an AE and received fosaprepitant regimen compared with the percentage of participants who received control regimen.
    End point type
    Primary
    End point timeframe
    Up to 6 months (Up to last dose of study drug)
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1 Fosaprepitant Regimen Cycles 2-6
    Number of subjects analysed
    37
    34
    55
    Units: percentage of participants
        number (not applicable)
    5.4
    0
    0
    Statistical analysis title
    		 Difference in Percentage of Participants
    Statistical analysis description
    Mean difference in percentage of participants who discontinued due to an AE and received fosaprepitant regimen compared with participants who received control regimen. Estimates were based on the Miettinen & Nurminen method.
    Comparison groups
    Fosaprepitant Regimen Cycle 1 v Control Regimen Cycle 1
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 17.8

    Secondary: Percentage of Participants Who Experience a Complete Response During the Acute Phase (0 to 24 hours post initiation of chemotherapy) in Cycle 1

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    End point title
    		 Percentage of Participants Who Experience a Complete Response During the Acute Phase (0 to 24 hours post initiation of chemotherapy) in Cycle 1
    End point description
    Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the acute phase, defined as the time period of 0 to 24 hours post initiation of chemotherapy in Cycle 1, was calculated. The endpoint was based on all participants who received at least 1 dose of study drug during Cycle 1.
    End point type
    Secondary
    End point timeframe
    0 to 24 hours post initiation of chemotherapy (up to 1 day after the dose of study drug)
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1
    Number of subjects analysed
    37
    34
    Units: percentage of participants
        number (not applicable)
    70.3
    58.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experience a Complete Response During the Overall Phase (0 to 120 hours post initiation of chemotherapy) in Cycle 1

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    End point title
    		 Percentage of Participants Who Experience a Complete Response During the Overall Phase (0 to 120 hours post initiation of chemotherapy) in Cycle 1
    End point description
    Complete Response was defined as no vomiting, no retching, and no use of rescue medication following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. The percentage of participants with no vomiting and no retching episodes in the overall phase, defined as the time period of 0 to 120 hours post initiation of chemotherapy in Cycle 1, was calculated. The endpoint was based on all participants who received at least 1 dose of study drug during Cycle 1.
    End point type
    Secondary
    End point timeframe
    0 to 120 hours post initiation of chemotherapy (up to 15 days after the dose of study drug)
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1
    Number of subjects analysed
    37
    34
    Units: percentage of participants
        number (not applicable)
    40.5
    32.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experience No Vomiting, Regardless of Rescue Medication Use, During the Overall Phase (0 to 120 hours post initiation of chemotherapy) in Cycle 1

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    End point title
    		 Percentage of Participants Who Experience No Vomiting, Regardless of Rescue Medication Use, During the Overall Phase (0 to 120 hours post initiation of chemotherapy) in Cycle 1
    End point description
    Vomiting was assessed, regardless of rescue medicine use, following the initiation of emetogenic chemotherapy in Cycle 1. A vomiting episode was specified as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retching/dry heaves (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were separated by the absence of emesis and retching for at least one minute. The date and time of each vomiting episode was recorded by participants in diaries at the time of occurrence. Rescue medication was permitted to alleviate symptoms of established nausea or vomiting; but not as preventive medication. The percentage of participants with no vomiting and no retching episodes in the overall phase, defined as the time period of 0 to 120 hours post initiation of chemotherapy in Cycle 1, was calculated. The endpoint was based on all participants who received at least 1 dose of study drug during Cycle 1.
    End point type
    Secondary
    End point timeframe
    0 to 120 hours post initiation of chemotherapy (up to 15 days after the dose of study drug)
    End point values
    		 Fosaprepitant Regimen Cycle 1 Control Regimen Cycle 1
    Number of subjects analysed
    37
    34
    Units: percentage of participants
        number (not applicable)
    40.5
    32.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events data were collected up to 6.5 months (from start of study drug and up to 14 days after the last dose for each cycle in Cycles 1-6).
    Adverse event reporting additional description
    This safety analysis was based on all participants who received at least 1 dose of study drug during Cycles 1 through 6.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Fosaprepitant Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) administered intravenously (IV) on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Reporting group title
    Fosaprepitant Regimen Cycles 2-6
    Reporting group description
    		 Participants received a single dose of fosaprepitant 150 mg (or age-based adjustment) IV on Day 1 prior to chemotherapy plus a 5- hydroxytryptamine 3 (5-HT3) antagonist on Day 1 prior to chemotherapy and per product label or standard of care. Participants may also have received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Reporting group title
    Control Regimen Cycle 1
    Reporting group description
    		 Participants received a single dose of matched placebo for fosaprepitant IV on Day 1 prior to chemotherapy plus ondansetron IV on Day 1 prior to chemotherapy and at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy. Participants may have also received dexamethasone IV at investigator's discretion on day(s) of chemotherapy and up to 24 hours after chemotherapy.

    Serious adverse events
    		 Fosaprepitant Regimen Cycle 1 Fosaprepitant Regimen Cycles 2-6 Control Regimen Cycle 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 37 (29.73%)
    28 / 55 (50.91%)
    8 / 34 (23.53%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 37 (10.81%)
    19 / 55 (34.55%)
    5 / 34 (14.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 32
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Thrombocytopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    General physical health deterioration
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Mucosal inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Soft tissue inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Proctalgia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Musculoskeletal and connective tissue disorders
    Soft tissue mass
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Bacteraemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Catheter site infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Otitis media chronic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 55 (0.00%)
    0 / 34 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Dehydration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Diet refusal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fosaprepitant Regimen Cycle 1 Fosaprepitant Regimen Cycles 2-6 Control Regimen Cycle 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 37 (75.68%)
    30 / 55 (54.55%)
    18 / 34 (52.94%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 55 (5.45%)
    3 / 34 (8.82%)
         occurrences all number
    2
    3
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    2
    3
    2
    Neutrophil count decreased
         subjects affected / exposed
    6 / 37 (16.22%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    6
    2
    3
    Platelet count decreased
         subjects affected / exposed
    4 / 37 (10.81%)
    5 / 55 (9.09%)
    3 / 34 (8.82%)
         occurrences all number
    4
    32
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 37 (29.73%)
    11 / 55 (20.00%)
    3 / 34 (8.82%)
         occurrences all number
    11
    20
    3
    Febrile neutropenia
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    2
    Leukopenia
         subjects affected / exposed
    5 / 37 (13.51%)
    7 / 55 (12.73%)
    0 / 34 (0.00%)
         occurrences all number
    5
    15
    0
    Neutropenia
         subjects affected / exposed
    5 / 37 (13.51%)
    4 / 55 (7.27%)
    3 / 34 (8.82%)
         occurrences all number
    6
    5
    3
    Thrombocytopenia
         subjects affected / exposed
    8 / 37 (21.62%)
    7 / 55 (12.73%)
    2 / 34 (5.88%)
         occurrences all number
    8
    14
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Mucosal inflammation
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 55 (7.27%)
    0 / 34 (0.00%)
         occurrences all number
    4
    6
    0
    Pyrexia
         subjects affected / exposed
    4 / 37 (10.81%)
    7 / 55 (12.73%)
    0 / 34 (0.00%)
         occurrences all number
    5
    8
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 37 (10.81%)
    6 / 55 (10.91%)
    1 / 34 (2.94%)
         occurrences all number
    4
    9
    1
    Constipation
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    3
    6
    3
    Diarrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    9 / 55 (16.36%)
    1 / 34 (2.94%)
         occurrences all number
    1
    14
    1
    Proctalgia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    1
    3
    0
    Stomatitis
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    1
    3
    0
    Vomiting
         subjects affected / exposed
    4 / 37 (10.81%)
    11 / 55 (20.00%)
    1 / 34 (2.94%)
         occurrences all number
    4
    24
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    2
    3
    0
    Hiccups
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    1
    Bone pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Pain in extremity
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 55 (7.27%)
    1 / 34 (2.94%)
         occurrences all number
    2
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Enrollment was terminated early because it was determined that data were not necessary to support a claim in pediatric participants. The last participant was enrolled on 2016-08-05. Enrolled participants were allowed to remain active in the study.
    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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