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    Clinical Trial Results:
    A standard regimen of dexamethasone in comparison to two dex-sparing regimens in addition to NEPA in preventing CINV in naïve NSCLC patients to be treated with cisplatin based chemotherapy: a three-arm, open-label, randomized study

    Summary
    EudraCT number
    		 2015-005704-29
    Trial protocol
    		 IT  
    Global end of trial date
    16 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LUNG-NEPA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04201769
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Consorzio Oncotech
    Sponsor organisation address
    Via Sergio Pansini, 5, Naples, Italy, 80131
    Public contact
    Clinical Operations, Clinical Research Technology, +39 089301545, lunepa@oncotech.org
    Scientific contact
    Clinical Operations, Clinical Research Technology, +39 089301545, lunepa@oncotech.org
    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
    08 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the possibility to reduce the overall exposure to dexamethasone (DEX), when administered with an oral fixed-dose combination of netupitant and palonosetron (NEPA), to prevent chemotherapy-induced nausea and vomiting in non-small cell lung cancer (NSCLC) patients receiving a cisplatin-based chemotherapy
    Protection of trial subjects
    For women of childbearing potential age: reliable contraceptive measures had to be used during all the planned course of chemotherapy and up to 30 days after last NEPA administration. All patients were allowed to take rescue medication throughout the study period for nausea or vomiting, if necessary. The choice of recommended rescue medicine was either DEX or metoclopramide and was at the discretion of each investigator. No other specific measures to protect trial subjects were required by the study participation.
    Background therapy
    		 Cisplatin-based chemotherapy (cisplatin dose ≥70 mg/m2)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2016
    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
    Italy: 252
    Worldwide total number of subjects
    252
    EEA total number of subjects
    252
    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)
    127
    From 65 to 84 years
    125
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment process for the trial has been conducted from November 2016 to November 2019 in 24 Italian centers. All patients included in this study provided a written informed consent.

    Pre-assignment
    Screening details
    		 Age ≥ 18 years; confirmed diagnosis of NSCLC, chemotherapy-naïve, scheduled to receive the first course of cisplatin (≥70 mg/m2)-based chemotherapy (cisplatin either alone or in combination with antineoplastic agents with low or minimal emetogenic potential), ECOG Performance Status = 0-1; adequate hematologic, hepatic, and renal functions.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (or DEX1 arm)
    Arm description
    		 Treatment arm A: On day 1 oral NEPA and intravenous dexamethasone 12 mg. No further anti-emetic prophylaxis on days 2 thorough 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Akynzeo
    Investigational medicinal product code
    IMP 1
    Other name
    Netupitant/palonosetron, NEPA
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in each arm received oral NEPA (a capsule containing netupitant 300 mg/palonosetron 0.50 mg) 1 hour before the administration of cisplatin on the first day of chemotherapy (day 1).

    Investigational medicinal product name
    Desametasone
    Investigational medicinal product code
    IMP 2
    Other name
    Dexamethasone, DEX
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients in each arm received DEX 12 mg intravenously a maximum of 30 minutes before the administration of cisplatin on day 1.

    Arm title
    		 Arm B (or DEX3 arm)
    Arm description
    		 Treatment arm B: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg once per day in the morning of days 2 and 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Akynzeo
    Investigational medicinal product code
    IMP 1
    Other name
    Netupitant/palonosetron, NEPA
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in each arm received oral NEPA (a capsule containing netupitant 300 mg/palonosetron 0.50 mg) 1 hour before the administration of cisplatin on the first day of chemotherapy (day 1).

    Investigational medicinal product name
    Desametasone
    Investigational medicinal product code
    IMP 2
    Other name
    Dexamethasone, DEX
    Pharmaceutical forms
    Oral drops, Solution for injection
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Patients in each arm received DEX 12 mg intravenously a maximum of 30 minutes before the administration of cisplatin on day 1. In the DEX3 arm, patients received oral DEX 4 mg once per day in the morning of days 2 and 3.

    Arm title
    		 Arm C (or DEX4 arm)
    Arm description
    		 Treatment arm C: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg twice per day on days 2 thorough 4.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Akynzeo
    Investigational medicinal product code
    IMP 1
    Other name
    Netupitant/palonosetron, NEPA
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in each arm received oral NEPA (a capsule containing netupitant 300 mg/palonosetron 0.50 mg) 1 hour before the administration of cisplatin on the first day of chemotherapy (day 1).

    Investigational medicinal product name
    Desametasone
    Investigational medicinal product code
    IMP 2
    Other name
    Dexamethasone, DEX
    Pharmaceutical forms
    Oral drops, Solution for injection
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Patients in each arm received DEX 12 mg intravenously a maximum of 30 minutes before the administration of cisplatin on day 1. In the DEX4 arm, patients received oral DEX 4 mg twice per day on days 2 thorough 4.

    Number of subjects in period 1
    		Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm)
    Started
    84
    85
    83
    Completed
    75
    75
    76
    Not completed
    9
    10
    7
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    1
    -
    -
         Not treated with IMP due to QuantiFERON test value
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    1
         Death
    3
    1
    1
         Not Compliance
    1
    1
    1
         Unknown
    2
    4
    3
         Patient changed chemotherapy scheme
    -
    1
    -
         Hospitalization due to Progressive Disease
    -
    1
    -
         Lost to follow-up
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (or DEX1 arm)
    Reporting group description
    		 Treatment arm A: On day 1 oral NEPA and intravenous dexamethasone 12 mg. No further anti-emetic prophylaxis on days 2 thorough 4.

    Reporting group title
    Arm B (or DEX3 arm)
    Reporting group description
    		 Treatment arm B: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg once per day in the morning of days 2 and 3.

    Reporting group title
    Arm C (or DEX4 arm)
    Reporting group description
    		 Treatment arm C: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg twice per day on days 2 thorough 4.

    Reporting group values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Total
    Number of subjects
    		 84 85 83 252
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Demographic characteristics for the Intention To Treat set appear consistent to those of the standard reference population (namely the target population to which the study therapies are addressed) and homogeneous across the three randomized arms.
    Units: years
        arithmetic mean (standard deviation)
    		 63.94 ( 7.16 ) 62.72 ( 7.98 ) 63.28 ( 8.17 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 34 25 83
        Male
    		 60 51 58 169
    ECOG Performance Status
    Patients were required to have an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work)
    Units: Subjects
        0 - Fully active, able to carry on...
    		 66 70 62 198
        1 - Restricted in physically strenuous activity...
    		 18 15 21 54
    Cisplatin Dose categorical
    In this study, chemotherapy-naïve patients received high-dose cisplatin (≥70 mg/m2) either alone or in combination with antineoplastic agents with low or minimal emetogenic potential. Only one patient (in the Arm C) received cisplatin dose <70 mg/m2.
    Units: Subjects
        Dose = 70 mg/m2
    		 20 21 22 63
        Dose >70 mg/m2
    		 64 64 61 189
    Concomitant Chemotherapy
    Eligible patients were chemotherapy-naïve and scheduled to receive the first course of cisplatin (≥70 mg/m2)-based chemotherapy. Patients could receive cisplatin either alone or in combination with antineoplastic agents with low or minimal emetogenic potential.
    Units: Subjects
        Pemetrexed
    		 37 42 44 123
        Gemcitabine
    		 22 21 22 65
        Vinorelbine
    		 21 18 14 53
        Other
    		 4 4 3 11
    BMI
    Body Mass Index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 24.72 ( 4.22 ) 24.59 ( 4.15 ) 25 ( 4.03 ) -
    Cisplatin Dose
    Units: milligram(s)/square metre
        arithmetic mean (standard deviation)
    		 75.04 ( 4.22 ) 75.27 ( 4.42 ) 74.28 ( 5.89 ) -
    Subject analysis sets

    Subject analysis set title
    Intention To Treat Set (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population contains all the randomized patients. The ITT has been the data set used for producing statistics on disposition, demographic and anamnestic data in addition to the efficacy and safety data. For ITT efficacy analyses, complete analysis sets were obtained by replacing missing efficacy data using the MVTF method whereby missing data are treated as failures.

    Subject analysis set title
    Per Protocol Set (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This population contains all the randomized patients without major protocol violations/deviations as determined by the Principal Investigators. The PP was the dataset used, in addition to the ITT set, for the efficacy analyses

    Subject analysis sets values
    		 Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects
    252
    228
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Demographic characteristics for the Intention To Treat set appear consistent to those of the standard reference population (namely the target population to which the study therapies are addressed) and homogeneous across the three randomized arms.
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    83
        Male
    169
    ECOG Performance Status
    Patients were required to have an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work)
    Units: Subjects
        0 - Fully active, able to carry on...
    198
        1 - Restricted in physically strenuous activity...
    54
    Cisplatin Dose categorical
    In this study, chemotherapy-naïve patients received high-dose cisplatin (≥70 mg/m2) either alone or in combination with antineoplastic agents with low or minimal emetogenic potential. Only one patient (in the Arm C) received cisplatin dose <70 mg/m2.
    Units: Subjects
        Dose = 70 mg/m2
    63
        Dose >70 mg/m2
    189
    Concomitant Chemotherapy
    Eligible patients were chemotherapy-naïve and scheduled to receive the first course of cisplatin (≥70 mg/m2)-based chemotherapy. Patients could receive cisplatin either alone or in combination with antineoplastic agents with low or minimal emetogenic potential.
    Units: Subjects
        Pemetrexed
    123
        Gemcitabine
    65
        Vinorelbine
    53
        Other
    11
    BMI
    Body Mass Index
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    ( )
    ( )
    Cisplatin Dose
    Units: milligram(s)/square metre
        arithmetic mean (standard deviation)
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Arm A (or DEX1 arm)
    Reporting group description
    		 Treatment arm A: On day 1 oral NEPA and intravenous dexamethasone 12 mg. No further anti-emetic prophylaxis on days 2 thorough 4.

    Reporting group title
    Arm B (or DEX3 arm)
    Reporting group description
    		 Treatment arm B: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg once per day in the morning of days 2 and 3.

    Reporting group title
    Arm C (or DEX4 arm)
    Reporting group description
    		 Treatment arm C: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg twice per day on days 2 thorough 4.

    Subject analysis set title
    Intention To Treat Set (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This population contains all the randomized patients. The ITT has been the data set used for producing statistics on disposition, demographic and anamnestic data in addition to the efficacy and safety data. For ITT efficacy analyses, complete analysis sets were obtained by replacing missing efficacy data using the MVTF method whereby missing data are treated as failures.

    Subject analysis set title
    Per Protocol Set (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This population contains all the randomized patients without major protocol violations/deviations as determined by the Principal Investigators. The PP was the dataset used, in addition to the ITT set, for the efficacy analyses

    Primary: Complete Response (CR: no emesis and no rescue medication)

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    End point title
    		 Complete Response (CR: no emesis and no rescue medication)
    End point description
    The primary endpoint was the proportion of patients achieving CR (no emetic episode and no use of rescue medication) in the overall phase (0–120 hours from the initiation ofthe first cycle of cisplatin-based chemotherapy).
    End point type
    Primary
    End point timeframe
    The overall phase (0–120 hours from the initiation of cisplatin).
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    58
    58
    57
    173
    173
    Statistical analysis title
    		 Complete Response Statistical analysis_Arm A vs C
    Statistical analysis description
    For a complete responder during the Overall phase, complete response is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a complete responder during the Acute phase, complete response is expected to occur on day 1 of the first cycle of chemotherapy. For a complete responder during the Delayed phase, complete response is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm A (or DEX1 arm) v Arm C (or DEX4 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 ≤ 0.025 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.137
         upper limit
    		 0.144
    Notes
    [1] - The primary efficacy hypothesis was that NEPA plus 1-day DEX and, in a subordinate position, NEPA plus 3-day DEX (Test treatments) were non-inferior to NEPA plus 4-day DEX (Reference treatment) with respect to the proportion of patients who had a complete response. To accomplish this, the lower boundary of the 2-sided 95% confidence interval (CI) on the difference between the CRs (Risk Difference) must be greater than –15% with 15% used as the prefixed non-inferiority threshold.
    [2] - One-sided
    Statistical analysis title
    		 Complete Response Statistical analysis_Arm B vs C
    Statistical analysis description
    For a complete responder during the Overall phase, complete response is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a complete responder during the Acute phase, complete response is expected to occur on day 1 of the first cycle of chemotherapy. For a complete responder during the Delayed phase, complete response is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 ≤ 0.025 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.145
         upper limit
    		 0.136
    Notes
    [3] - The primary efficacy hypothesis was that NEPA plus 1-day DEX and, in a subordinate position, NEPA plus 3-day DEX (Test treatments) were non-inferior to NEPA plus 4-day DEX (Reference treatment) with respect to the proportion of patients who had a complete response. To accomplish this, the lower boundary of the 2-sided 95% confidence interval (CI) on the difference between the CRs (Risk Difference) must be greater than –15% with 15% used as the prefixed non-inferiority threshold.
    [4] - One-sided

    Secondary: Complete Protection (CP: complete response and none or mild nausea)

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    End point title
    		 Complete Protection (CP: complete response and none or mild nausea)
    End point description
    Secondary endpoints included the proportion of patients who achieved a complete protection (CP; no emetic episode, no use of rescue medication, and no more than mild nausea) during the overall, acute (0–24 hours) and delayed (>24–120 hours) phases.
    End point type
    Secondary
    End point timeframe
    During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    56
    51
    51
    158
    158
    Statistical analysis title
    		 Complete Protection Statistical analysis_ArmA vs C
    Statistical analysis description
    For a patient defined as complete control during the Overall phase, complete control is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a complete control during the Acute phase, complete control is expected to occur on day 1 of the first cycle of chemotherapy. For a complete control during the Delayed phase, complete control is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy
    Comparison groups
    Arm A (or DEX1 arm) v Arm C (or DEX4 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 ≤ 0.025 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.093
         upper limit
    		 0.198
    Notes
    [5] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of complete control were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [6] - One-sided
    Statistical analysis title
    		 Complete Protection Statistical analysis_ArmB vs C
    Statistical analysis description
    For a patient defined as complete control during the Overall phase, complete control is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a complete control during the Acute phase, complete control is expected to occur on day 1 of the first cycle of chemotherapy. For a complete control during the Delayed phase, complete control is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 ≤ 0.025 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.162
         upper limit
    		 0.133
    Notes
    [7] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of complete control were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [8] - One-sided

    Secondary: No emetic episodes

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    End point title
    		 No emetic episodes
    End point description
    Secondary endpoints included the proportion of patients with no emetic episodes during the overall, acute (0–24 hours) and delayed (>24–120 hours) phases.
    End point type
    Secondary
    End point timeframe
    During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    72
    69
    75
    216
    213
    Statistical analysis title
    		 No emetic episodes Statistical analysis_Arm A vs C
    Statistical analysis description
    For a patient defined as emesis-free during the Overall phase, no emesis is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For an emesis-free during the Acute phase, no emesis is expected to occur on day 1 of the first cycle of chemotherapy. For an emesis-free during the Delayed phase, no emesis is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy
    Comparison groups
    Arm A (or DEX1 arm) v Arm C (or DEX4 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 ≤ 0.025 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.145
         upper limit
    		 0.052
    Notes
    [9] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of emesis-free were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [10] - One-sided
    Statistical analysis title
    		 No emetic episodes Statistical analysis_Arm B vs C
    Statistical analysis description
    For a patient defined as emesis-free during the Overall phase, no emesis is expected to occur from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For an emesis-free during the Acute phase, no emesis is expected to occur on day 1 of the first cycle of chemotherapy. For an emesis-free during the Delayed phase, no emesis is expected to occur during days 2 thorough 5 of the first cycle of chemotherapy
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 ≤ 0.025 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.092
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.196
         upper limit
    		 0.013
    Notes
    [11] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of emesis-free were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [12] - One-sided

    Secondary: No nausea

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    End point title
    		 No nausea
    End point description
    Secondary endpoints included the proportion of patients with no nausea during the overall, acute (0–24 hours) and delayed (>24–120 hours) phases.
    End point type
    Secondary
    End point timeframe
    During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    39
    35
    47
    121
    118
    Statistical analysis title
    		 No nausea Statistical analysis_Arm A vs C
    Statistical analysis description
    For a patient defined without nausea during the Overall phase, nausea graded as “none” according to the Likert scale should occur from day 1 thorough day 5 of the 1st cycle of chemotherapy. For a patient defined without nausea during the Acute phase, nausea graded as “none” should occur on day 1 of the 1st cycle of chemotherapy. For a patient defined without nausea during the Delayed phase, nausea graded as “none” should occur during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm A (or DEX1 arm) v Arm C (or DEX4 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 ≤ 0.025 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.102
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.253
         upper limit
    		 0.049
    Notes
    [13] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of patient without nausea were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [14] - One-sided
    Statistical analysis title
    		 No nausea Statistical analysis_Arm B vs C
    Statistical analysis description
    For a patient defined without nausea during the Overall phase, nausea graded as “none” according to the Likert scale should occur from day 1 thorough day 5 of the 1st cycle of chemotherapy. For a patient defined without nausea during the Acute phase, nausea graded as “none” should occur on day 1 of the 1st cycle of chemotherapy. For a patient defined without nausea during the Delayed phase, nausea graded as “none” should occur during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [15]
    P-value
    		 ≤ 0.025 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.304
         upper limit
    		 0.005
    Notes
    [15] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of patient without nausea were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [16] - One-sided

    Secondary: No Significant Nausea (NSN: no more than mild nausea)

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    End point title
    		 No Significant Nausea (NSN: no more than mild nausea)
    End point description
    Secondary endpoints included the proportion of patients with No Significant Nausea (NSN, defined as no more than mild nausea) during the overall, acute (0–24 hours) and delayed (>24–120 hours) phases.
    End point type
    Secondary
    End point timeframe
    During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    61
    56
    59
    176
    173
    Statistical analysis title
    		 No Significant Nausea Statistical analysis_A vs C
    Statistical analysis description
    Patient’s nausea for the Overall phase is computed using the worst patient score recorded from day 1 (first day of chemotherapy) thorough day 5 of the first cycle of chemotherapy. Patient’s nausea for the Acute phase is computed using the worst patient score recorded on day 1 of the first cycle of chemotherapy. Patient’s nausea for the Delayed phase, is computed using the worst patient score recorded during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm A (or DEX1 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    P-value
    		 ≤ 0.025 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 14.7
    Notes
    [17] - Descriptive analyses have been done by tabulating absolute and relative frequency through a three-way contingency table: Treatment x Day (Phase) x Nausea Score. For the ITT set, the relative frequencies were calculated on patients with missing data replaced using the MVTF approach.
    [18] - One-sided
    Statistical analysis title
    		 No Significant Nausea Statistical analysis_B vs C
    Statistical analysis description
    Patient’s nausea for the Overall phase is computed using the worst patient score recorded from day 1 (first day of chemotherapy) thorough day 5 of the first cycle of chemotherapy. Patient’s nausea for the Acute phase is computed using the worst patient score recorded on day 1 of the first cycle of chemotherapy. Patient’s nausea for the Delayed phase, is computed using the worst patient score recorded during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [19]
    P-value
    		 ≤ 0.025 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.4
         upper limit
    		 11.1
    Notes
    [19] - Descriptive analyses have been done by tabulating absolute and relative frequency through a three-way contingency table: Treatment x Day (Phase) x Nausea Score. For the ITT set, the relative frequencies were calculated on patients with missing data replaced using the MVTF approach.
    [20] - One-sided

    Secondary: No use of rescue medications

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    End point title
    		 No use of rescue medications
    End point description
    Secondary endpoints included the proportion of patients with no use of rescue medications during the overall, acute (0–24 hours) and delayed (>24–120 hours) phases.
    End point type
    Secondary
    End point timeframe
    During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy
    End point values
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm) Intention To Treat Set (ITT) Per Protocol Set (PP)
    Number of subjects analysed
    84
    85
    83
    252
    228
    Units: percent
        number (not applicable)
    60
    61
    58
    179
    178
    Statistical analysis title
    		 No use of rescue medications Stat. analysis_A vs C
    Statistical analysis description
    For a patient defined as rescue-free during the Overall phase, no salvage therapy intake occurs from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a rescue-free during the Acute phase, no salvage therapy intake occurs on day 1 of the first cycle of chemotherapy. For a rescue-free during the Delayed phase, no salvage therapy intake occurs during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm A (or DEX1 arm)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    P-value
    		 ≤ 0.025 [22]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.123
         upper limit
    		 0.154
    Notes
    [21] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of rescue-free were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [22] - One-sided
    Statistical analysis title
    		 No use of rescue medications Stat. analysis_B vs C
    Statistical analysis description
    For a patient defined as rescue-free during the Overall phase, no salvage therapy intake occurs from day 1 (first day of chemotherapy) thorough day 5 of the first cycle chemotherapy. For a rescue-free during the Acute phase, no salvage therapy intake occurs on day 1 of the first cycle of chemotherapy. For a rescue-free during the Delayed phase, no salvage therapy intake occurs during days 2 thorough 5 of the first cycle of chemotherapy.
    Comparison groups
    Arm C (or DEX4 arm) v Arm B (or DEX3 arm)
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [23]
    P-value
    		 ≤ 0.025 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.119
         upper limit
    		 0.156
    Notes
    [23] - The two-sided 95% Confidence Limits of the difference in the proportion (Risk Difference) of rescue-free were calculated for the Acute, Delayed and Overall phase by resorting to a generalized linear model with identity link function, binomial distribution and using treatment group as dummy covariate.
    [24] - One-sided

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The overall study period until follow up visit (within 30 days from randomization)
    Adverse event reporting additional description
    Adverse events were evaluated by the investigators according to the Common Terminology Criteria for Adverse Events. Information about every adverse event/reaction have been collected and recorded in the Adverse Event electronic Case Report Form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Arm A (or DEX1 arm)
    Reporting group description
    		 Treatment arm A: On day 1 oral NEPA and intravenous dexamethasone 12 mg. No further anti-emetic prophylaxis on days 2 thorough 4.

    Reporting group title
    Arm B (or DEX3 arm)
    Reporting group description
    		 Treatment arm B: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg once per day in the morning of days 2 and 3.

    Reporting group title
    Arm C (or DEX4 arm)
    Reporting group description
    		 Treatment arm C: On day 1 oral NEPA and intravenous dexamethasone 12 mg. Oral dexamethasone 4 mg twice per day on days 2 thorough 4.

    Serious adverse events
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 80 (7.50%)
    5 / 84 (5.95%)
    3 / 81 (3.70%)
         number of deaths (all causes)
    3
    1
    2
         number of deaths resulting from adverse events
    3
    0
    1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Platelet count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Inflammatory marker increased
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Blood electrolytes abnormal
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Vascular disorders
    Acute coronary syndrome
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Haemoptysis
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Peripheral ischaemia
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Cardiac arrest
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem stroke
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Fatigue
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Pain
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Decreased appetite
    alternative dictionary used: MedDRA 21.0
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Blood and lymphatic system disorders
    Pancytopenia
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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 disorders
    Nausea
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Respiratory, thoracic and mediastinal disorders
    Pneumomediastinum
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Musculoskeletal chest pain
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (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
    Dyspnoea
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (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
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: MedDRA 22.1
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 Arm A (or DEX1 arm) Arm B (or DEX3 arm) Arm C (or DEX4 arm)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 80 (62.50%)
    56 / 84 (66.67%)
    53 / 81 (65.43%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    0
    2
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    0
    2
    1
    Phlebitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Thromboembolic event
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    1
    2
    1
    Fatigue
         subjects affected / exposed
    16 / 80 (20.00%)
    19 / 84 (22.62%)
    22 / 81 (27.16%)
         occurrences all number
    17
    20
    23
    Fever
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    4 / 81 (4.94%)
         occurrences all number
    1
    2
    4
    Allergic reaction to mannitol
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Bilateral hypoacusia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Drowsiness
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Eyestrain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    General decay
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Hiccough
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Pain at right shoulder
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in the right palm
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Scapular pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Surgical site pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Sweating
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    2
    0
    Irritability
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 84 (4.76%)
    2 / 81 (2.47%)
         occurrences all number
    3
    4
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    3
    Cough
         subjects affected / exposed
    2 / 80 (2.50%)
    5 / 84 (5.95%)
    2 / 81 (2.47%)
         occurrences all number
    2
    5
    2
    Dyspnoea
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 84 (4.76%)
    1 / 81 (1.23%)
         occurrences all number
    3
    4
    1
    Hoarseness
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal mucositis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Cooling syndrome
    Additional description: Episode of cooling syndrome
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal discharge
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Sore throat
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    0 / 81 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    0 / 81 (0.00%)
         occurrences all number
    0
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    4 / 81 (4.94%)
         occurrences all number
    1
    1
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    0
    Thrombocytosis
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    2
    2
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Creatinine increased
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    5 / 81 (6.17%)
         occurrences all number
    1
    2
    5
    Weight loss
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    2
    white blood cell decreased
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 84 (3.57%)
    2 / 81 (2.47%)
         occurrences all number
    1
    3
    2
    Neutrophil count decreased
         subjects affected / exposed
    6 / 80 (7.50%)
    4 / 84 (4.76%)
    5 / 81 (6.17%)
         occurrences all number
    6
    5
    5
    Platelet count decreased
         subjects affected / exposed
    4 / 80 (5.00%)
    3 / 84 (3.57%)
    1 / 81 (1.23%)
         occurrences all number
    4
    4
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Worsening of hypertension
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain - cardiac
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    3 / 81 (3.70%)
         occurrences all number
    0
    2
    3
    Headache
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    1
    Confusional state
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Paresthesia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    1
    Tremor
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 84 (2.38%)
    4 / 81 (4.94%)
         occurrences all number
    4
    2
    4
    Neutropenia
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 84 (3.57%)
    1 / 81 (1.23%)
         occurrences all number
    1
    3
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Leukocytosis
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    0
    Ear and labyrinth disorders
    Bilateral hearing loss
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Hearing impaired
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    2
    3
    1
    Vertigo
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    2
    Lachrymation
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Anal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Bloating
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    13 / 80 (16.25%)
    10 / 84 (11.90%)
    21 / 81 (25.93%)
         occurrences all number
    13
    10
    21
    Diarrhoea
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 84 (2.38%)
    4 / 81 (4.94%)
         occurrences all number
    2
    2
    4
    Dyspepsia
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    1
    2
    1
    Esophageal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    2 / 81 (2.47%)
         occurrences all number
    0
    1
    2
    Gastritis
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 84 (2.38%)
    3 / 81 (3.70%)
         occurrences all number
    4
    2
    3
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    0 / 81 (0.00%)
         occurrences all number
    1
    2
    0
    Burning at the throat
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Epigastralgia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Hiccups
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    3 / 81 (3.70%)
         occurrences all number
    1
    1
    3
    Hyporexia
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    0 / 81 (0.00%)
         occurrences all number
    0
    2
    0
    Retching
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Mucositis oral
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 84 (4.76%)
    5 / 81 (6.17%)
         occurrences all number
    1
    4
    5
    Nausea
         subjects affected / exposed
    8 / 80 (10.00%)
    12 / 84 (14.29%)
    7 / 81 (8.64%)
         occurrences all number
    10
    12
    10
    Oral pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 84 (2.38%)
    0 / 81 (0.00%)
         occurrences all number
    3
    2
    0
    Hepatobiliary disorders
    Alkaline phospatase increased
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    1
    Erythema multiforme
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    0
    Rash acneiform
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    0
    2
    1
    Rash
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    1
    Rash pruritic
    Additional description: Pruritic papular erythematous rash
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Renal colic
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    1
    1
    0
    Bone pain
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 84 (3.57%)
    2 / 81 (2.47%)
         occurrences all number
    1
    3
    2
    Chest wall trauma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Cold legs
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Lumbar spinal back pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
    Additional description: Pain in the right-hand parascapular region
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Osteoporosis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    0
    1
    Mucosal infection
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    2 / 81 (2.47%)
         occurrences all number
    1
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    1 / 81 (1.23%)
         occurrences all number
    0
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    0
    Cachexia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    0
    Inappetance
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    1
    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 Oct 2018
    The amendment ("LUNG-NEPA_EM2 del 29.08.2018") regarded these aspects: • extension of the trial duration, with an extension of the enrollment phase from 18 months to 48 months, in order to allow the achievement of the number of patients foreseen by the study protocol; • reformulation of the statistical methodology, on the basis of the new evidence available on the dexamethasone-sparing strategy in the setting of single-day HEC. The LUNG-NEPA study was initially planned with a composite “Study Win Criteria” consisting in declaring study success if non-inferiority will be achieved in at least one of the following two comparisons: “NEPA plus 3-day DEX vs. NEPA plus 4-day DEX” or “NEPA plus 1-day DEX vs. NEPA plus 4-day DEX”. With this amendment: - the “Study Win Criteria” remained unchanged but it was introduced the prioritization between the two comparisons, as suggested by the experts: 1) “NEPA plus 1-day DEX vs. NEPA plus 4-day DEX” and, in a subordinate position, 2) “NEPA plus 3-day DEX vs. NEPA plus 4-day DEX”; - the sample size changed from 588 patients (196 in each arm) to 468 patients (156 in each treatment arm), in order to have 450 enrolled patients (150 in each treatment arm), considering a 4% ineligibility rate. - the primary efficacy hypothesis changed as follows: NEPA plus 1-day DEX and, in a subordinate position, NEPA plus 3-day DEX (Test treatments) were non-inferior to NEPA plus 4-day DEX (Reference treatment) with respect to the proportion of patients who had a complete response (CR; defined as no emetic episodes, and no rescue medication use during the overall phase of the first chemotherapy cycle).
    11 Dec 2019
    The amendment ("LUNG-NEPA_EM3 del 21.11.2019") regarded these aspects: • adaptation of the statistical methodology, in the light of the new evidence available on the dexamethasone-sparing strategy in the CINV (chemotherapy-induced nausea and vomiting) prevention [Ito et al. J Clin Oncol 2018; 36: 1000-1006], The non-inferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4) instead the previous -10%. The study protocol was amended as follows: The primary efficacy hypothesis was that NEPA plus 1-day DEX and, in a subordinate position, NEPA plus 3-day DEX (Test treatments) were non-inferior to NEPA plus 4-day DEX (Reference treatment) with respect to the proportion of patients who had a complete response. To accomplish this, the lower boundary of the 2-sided 95% confidence interval (CI) on the difference between the CRs (Risk Difference) was to be greater than –15% with 15% used as the prefixed non-inferiority threshold. A sample size of 210 eligible and assessable patients when randomized in a 1:1:1 ratio (that is 70 patients in each arm) achieved 80% power to detect a noninferiority margin equal to 15% in the prioritized comparison “DEX1 arm vs. DEX4 arm” assuming that the proportion of CR during the overall phase would be 90% in the reference arm [9] and a one-sided type I error rate equal to 0.025. Assuming an attrition rate of 4%, at least 73 eligible and assessable patients per arm needed.

    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.
    1.Unblinding; however, the consistency of overall findings supports the validity of the study results. 2.Females represented only 33% of study population; however, this is consistent with recent evidence regarding patients undergoing cisplatin chemo

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34101934
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