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    Clinical Trial Results:
    Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia The RAPID Study (NODE-301 Part 2) and RAPID Extension (NODE-301 Part 3)

    Summary
    EudraCT number
    		 2018-000308-41
    Trial protocol
    		 NL   BE   PL   FR   DE  
    Global end of trial date
    20 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2025
    First version publication date
    28 Mar 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MSP-2017-1138
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03464019
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Milestone Pharmaceuticals Inc.
    Sponsor organisation address
    1111 Dr. Frederik-Philips Blvd, Suite 420, Montreal, Canada, H4M 2X6
    Public contact
    Guy Rousseau, Milestone Pharmaceuticals Inc., +1 514803-2668, grousseau@milestonepharma.com
    Scientific contact
    Guy Rousseau, Milestone Pharmaceuticals Inc., +1 514803-2668, grousseau@milestonepharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the RAPID study is to determine whether Etripamil nasal spray (NS) self-administered by patients is superior to placebo at terminating episodes of paroxysmal ventricular tachycardia (PSVT) in an at-home setting.
    Protection of trial subjects
    The study protocol, all study protocol amendments, written study participant information, informed consent form (ICF), Investigator's Brochure (IB) and any other relevant documents were reviewed and approved by an independent ethics committee (IEC) or institutional review board (IRB) at each study center. The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation (ICH)/Good Clinical Practice (GCP) and other Guidelines, and applicable laws and regulations. An ICF approved by each study center's IEC/IRB was signed by the participant or their legally authorized representative and the authorized person obtaining the ICF before the participant was entered in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 178
    Country: Number of subjects enrolled
    United States: 192
    Country: Number of subjects enrolled
    Spain: 114
    Country: Number of subjects enrolled
    Netherlands: 110
    Country: Number of subjects enrolled
    Poland: 112
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 5
    Worldwide total number of subjects
    748
    EEA total number of subjects
    378
    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)
    575
    From 65 to 84 years
    173
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were screened & recruited at sites in France, Spain, the Netherlands, Belgium, Poland, Germany, Hungary. The Efficacy Population included all modified Intent to Treat-mITT patients who took study drug to treat an episode of PSVT confirmed by the Adjudication Committee. The disposition described here is for the Efficacy Population.

    Pre-assignment
    Screening details
    		 At the end of the RAPID extension study, the disposition was: Patients screened = 877; Patients with screen failure = 130; Patients who had a test dose = 748; Patients randomized = 735. Patients in Test Dose (TD) only population = 445 Patients in the mITT and Safety population = 303 Patients in the Efficacy population = 214

    Period 1
    Period 1 title
    RAPID (Part 2) plus RAPID Ext (Part 3) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomization and double-blinding were used to minimize bias arising from the assignment of participants to treatment groups and the expectations of participants, investigators and individuals collecting data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Etripamil
    Arm description
    		 Self-administration of etripamil for a perceived episode of PSVT during the randomized treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etripamil
    Investigational medicinal product code
    MSP-2017
    Other name
    Pharmaceutical forms
    Nasal/oromucosal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    The dose of etripamil to be evaluated in the RAPID study is 70 mg per nasal spray device. Each nasal spray device delivers a total of 200µL of etripamil.

    Arm title
    		 Placebo
    Arm description
    		 Self-administration of placebo for a perceived episode of PSVT during the randomized treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal/oromucosal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    Each nasal spray device delivers a total of 200 μL of placebo

    Arm title
    		 Test Dose Only
    Arm description
    		 Single Test Dose of Etripamil in sinus rhythm before randomization
    Arm type
    		 Pre-Randomization

    Investigational medicinal product name
    Etripamil
    Investigational medicinal product code
    MSP-2017
    Other name
    Pharmaceutical forms
    Nasal/oromucosal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    The dose of etripamil to be evaluated in the RAPID study is 70 mg per nasal spray device. Each nasal spray device delivers a total of 200µL of etripamil.

    Number of subjects in period 1
    		Etripamil Placebo Test Dose Only
    Started
    160
    143
    445
    Participants randomized
    160
    143
    0
    Participants in Efficacy Population
    114
    100
    0
    Completed
    81
    76
    0
    Not completed
    79
    67
    445
         Consent withdrawn by subject
    1
    5
    32
         Physician decision
    -
    -
    2
         Ablation
    11
    8
    46
         Adverse event, non-fatal
    3
    1
    14
         Other
    1
    5
    -
         Pregnancy
    -
    -
    1
         Study terminated by sponsor
    61
    46
    314
         Reason not provided by participant
    -
    -
    15
         Test Dose Failure
    -
    -
    8
         Lost to follow-up
    -
    1
    7
         Protocol deviation
    1
    -
    2
         Prohibited Medication
    1
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Etripamil
    Reporting group description
    		 Self-administration of etripamil for a perceived episode of PSVT during the randomized treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Self-administration of placebo for a perceived episode of PSVT during the randomized treatment period.

    Reporting group title
    Test Dose Only
    Reporting group description
    		 Single Test Dose of Etripamil in sinus rhythm before randomization

    Reporting group values
    		 Etripamil Placebo Test Dose Only Total
    Number of subjects
    		 160 143 445 748
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 129 109 337 575
        From 65-84 years
    		 31 34 108 173
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ( 13.9 ) 55.9 ( 12.5 ) 53.9 ( 14.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 112 100 268 480
        Male
    		 48 43 177 268
    Subject analysis sets

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The data presented here summarizes demographic and patient-history characteristics for patients who were included in the Efficacy Population.

    Subject analysis sets values
    		 Efficacy Population
    Number of subjects
    214
    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)
    175
        From 65-84 years
    39
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.0 ( 13.0 )
    Gender categorical
    Units: Subjects
        Female
    155
        Male
    59

    End points

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    End points reporting groups
    Reporting group title
    Etripamil
    Reporting group description
    		 Self-administration of etripamil for a perceived episode of PSVT during the randomized treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Self-administration of placebo for a perceived episode of PSVT during the randomized treatment period.

    Reporting group title
    Test Dose Only
    Reporting group description
    		 Single Test Dose of Etripamil in sinus rhythm before randomization

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The data presented here summarizes demographic and patient-history characteristics for patients who were included in the Efficacy Population.

    Primary: Primary endpoint: The time to conversion of an episode of PSVT to sinus rhythm (SR) after study drug administration. (Kaplan Meier Analysis)

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    End point title
    		 Primary endpoint: The time to conversion of an episode of PSVT to sinus rhythm (SR) after study drug administration. (Kaplan Meier Analysis) [1]
    End point description
    The primary efficacy endpoint is defined as an adjudicated termination of a positively adjudicated episode of PSVT (atrioventricular (AV) nodal reentrant tachycardia or atrioventricular (AV) reentrant tachycardia determination if possible) and conversion to sinus rhythm (SR) for at least 30 seconds within 30 minutes of start of study drug dosing.
    End point type
    Primary
    End point timeframe
    Within 30 minutes of start of study drug dosing.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: minute
        median (confidence interval 95%)
    17.0 (12.8 to 21.7)
    51.6 (36.9 to 86.1)
    Statistical analysis title
    		 Kaplan-Meier Analyses - 30min
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 10 minutes

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    End point title
    		 Time to conversion of PSVT at 10 minutes [2]
    End point description
    Time to Conversion Analyses by Additional Specified Time Point
    End point type
    Secondary
    End point timeframe
    Within 10 minutes of start of study drug dosing
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan Meier Estimate (%)
        number (not applicable)
    34.5
    20.2
    Statistical analysis title
    		 Kaplan-Meier Analyses - 10min
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0119
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Use of Study Drug Among Patients in Repeat-Dose Regimen Groups

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    End point title
    		 Use of Study Drug Among Patients in Repeat-Dose Regimen Groups [3]
    End point description
    The RAPID study was designed to assess the efficacy and safety of a treatment regimen of a repeat dose of etripamil to be administered 10 minutes after a first dose if PSVT symptoms persisted, by comparing this etripamil regimen to a placebo one.
    End point type
    Secondary
    End point timeframe
    After the first dose administration
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    98
    87
    Units: patients
        number (not applicable)
    64
    68
    Statistical analysis title
    		 patients chose to take a repeat dose of study drug
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0536
    Method
    		 Chi-squared
    Confidence interval

    Secondary: The percentage of patients that required additional medical intervention in an emergency department to terminate an episode of PSVT.

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    End point title
    		 The percentage of patients that required additional medical intervention in an emergency department to terminate an episode of PSVT. [4]
    End point description
    The percentage of patients requiring additional medical intervention in an emergency department to terminate an episode of PSVT.
    End point type
    Secondary
    End point timeframe
    After an episode of PSVT
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patient number
    16
    25
    Statistical analysis title
    		 Analysis of Additional Medical Intervention
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Relief of specific symptom: rapid pulse potentially associated with an episode of PSVT.

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    End point title
    		 Relief of specific symptom: rapid pulse potentially associated with an episode of PSVT. [5]
    End point description
    Impact of Study Drug on Patient-Reported Symptom: rapid pulse during Double-Blind Treated PSVT Episodes
    End point type
    Secondary
    End point timeframe
    During double blind study drug administration
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patients
        number (not applicable)
    53
    26
    Statistical analysis title
    		 Relief of rapid pulse
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9) Global Satisfaction

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    End point title
    		 Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9) Global Satisfaction [6]
    End point description
    Treatment satisfaction was analyzed by comparing the TSQM-9 score for the Global Satisfaction domain in the 2 treatment groups
    End point type
    Secondary
    End point timeframe
    Completed as soon as possible after termination of the treated PSVT episode
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: point
        arithmetic mean (standard deviation)
    59.4 ( 29.0 )
    52.7 ( 31.3 )
    Statistical analysis title
    		 Analysis of Treatment Satisfaction Questionnaire
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.109
    Method
    		 ANOVA
    Confidence interval

    Secondary: Relief of specific symptom: palpitations during Double-Blind Treated PSVT Episodes

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    End point title
    		 Relief of specific symptom: palpitations during Double-Blind Treated PSVT Episodes [7]
    End point description
    End point type
    Secondary
    End point timeframe
    During double blind study drug administration
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Patients
        number (not applicable)
    50
    25
    Statistical analysis title
    		 Relief of palpitations
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Relief of feeling dizzy or lightheaded

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    End point title
    		 Relief of feeling dizzy or lightheaded [8]
    End point description
    End point type
    Secondary
    End point timeframe
    During double blind study drug administration
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patients
        number (not applicable)
    28
    11
    Statistical analysis title
    		 Relief of feeling dizzy or lightheaded
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Relief of shortness of breath

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    End point title
    		 Relief of shortness of breath [9]
    End point description
    End point type
    Secondary
    End point timeframe
    During double-blind study drug administration
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patients
        number (not applicable)
    19
    4
    Statistical analysis title
    		 Relief of shortness of breath
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Relief of anxiety potentially associated with an episode of PSVT

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    End point title
    		 Relief of anxiety potentially associated with an episode of PSVT [10]
    End point description
    End point type
    Secondary
    End point timeframe
    During double blind study drug administration
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patients
        number (not applicable)
    20
    9
    Statistical analysis title
    		 Relief of anxiety
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Relief of Chest tightness, pain or pressure

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    End point title
    		 Relief of Chest tightness, pain or pressure [11]
    End point description
    End point type
    Secondary
    End point timeframe
    During double blind study drug administration
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Patients
        number (not applicable)
    13
    7
    Statistical analysis title
    		 Relief of chest tightness, pain or pressure
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to conversion of PSVT at 15 minutes

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    End point title
    		 Time to conversion of PSVT at 15 minutes [12]
    End point description
    End point type
    Secondary
    End point timeframe
    at 15 minutes
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan Meier Estimate (%)
        number (not applicable)
    45.1
    22.2
    Statistical analysis title
    		 Kaplan-Meier Analyses - 15 min
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 45 minutes

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    End point title
    		 Time to conversion of PSVT at 45 minutes [13]
    End point description
    End point type
    Secondary
    End point timeframe
    At 45 minutes
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    71.7
    47.1
    Statistical analysis title
    		 Kaplan-Meier Analyses - 45min
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 60 minutes

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    End point title
    		 Time to conversion of PSVT at 60 minutes [14]
    End point description
    End point type
    Secondary
    End point timeframe
    At 60 minutes
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    74.3
    56.4
    Statistical analysis title
    		 Kaplan-Meier Analyses - 60 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 90 minutes

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    End point title
    		 Time to conversion of PSVT at 90 minutes [15]
    End point description
    End point type
    Secondary
    End point timeframe
    At 90 minutes
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    80.5
    61.6
    Statistical analysis title
    		 Kaplan-Meier Analyses - 90 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 120 minutes

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    End point title
    		 Time to conversion of PSVT at 120 minutes [16]
    End point description
    End point type
    Secondary
    End point timeframe
    At 120 minutes
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    81.4
    66.8
    Statistical analysis title
    		 Kaplan-Meier Analyses - 120 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 180 minutes

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    End point title
    		 Time to conversion of PSVT at 180 minutes [17]
    End point description
    End point type
    Secondary
    End point timeframe
    At 180 minutes
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    81.4
    70.0
    Statistical analysis title
    		 Kaplan-Meier Analyses - 180 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 240 minutes

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    End point title
    		 Time to conversion of PSVT at 240 minutes [18]
    End point description
    End point type
    Secondary
    End point timeframe
    At 240 minutes
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    82.3
    70.0
    Statistical analysis title
    		 Kaplan-Meier Analyses - 240 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to conversion of PSVT at 300 minutes

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    End point title
    		 Time to conversion of PSVT at 300 minutes [19]
    End point description
    End point type
    Secondary
    End point timeframe
    At 300 minutes
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: Kaplan-Meier Estimate (%)
        number (not applicable)
    83.2
    72.3
    Statistical analysis title
    		 Kaplan-Meier Analyses - 300 minutes
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9): Effectiveness

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    End point title
    		 Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9): Effectiveness [20]
    End point description
    End point type
    Secondary
    End point timeframe
    Completed as soon as possible after termination of the treated PSVT episode
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: point
        arithmetic mean (standard deviation)
    62.3 ( 29.9 )
    44.9 ( 33.6 )
    Statistical analysis title
    		 Analysis of Treatment Satisfaction Questionnaire
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Confidence interval

    Secondary: Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9): Convenience

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    End point title
    		 Rating of Treatment Satisfaction Questionnaire for Medication®-9 (TSQM-9): Convenience [21]
    End point description
    End point type
    Secondary
    End point timeframe
    Completed as soon as possible after termination of the treated PSVT episode
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: point
        arithmetic mean (standard deviation)
    72.6 ( 17.6 )
    70.6 ( 17.7 )
    Statistical analysis title
    		 Analysis of Treatment Satisfaction Questionnaire
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.414
    Method
    		 ANOVA
    Confidence interval

    Secondary: Durability of Conversion/Reoccurrence of PSVT

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    End point title
    		 Durability of Conversion/Reoccurrence of PSVT [22]
    End point description
    End point type
    Secondary
    End point timeframe
    within the 5-hour observation window after conversion to SR for more than 30 seconds
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The relevant statistics for comparing Etripamil vs Placebo is presented here.
    End point values
    		 Etripamil Placebo
    Number of subjects analysed
    114
    100
    Units: patient
        number (not applicable)
    5
    5
    Statistical analysis title
    		 Durability of Conversion of Adjudicated PSVT to SR
    Comparison groups
    Etripamil v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.832
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomized Treatment Emergent Adverse Events (RTEAEs) were defined as treatment-emergent adverse events that occurred within 24 hours after, or 12 hours prior to, or 25 hours prior to and were drug-related to, taking randomized study drug.
    Adverse event reporting additional description
    The data presented here are the treatment-emergent adverse events (RTEAEs) for the Safety Population (N=303). 143 were randomized to Placebo vs 160 randomized to Etripamil.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Etripamil
    Reporting group description
    		 Self Administration of Etripamil following an episode of PSVT.

    Reporting group title
    Placebo
    Reporting group description
    		 Self Administration of Placebo following an episode of PSVT.

    Serious adverse events
    		 Etripamil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 143 (0.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Etripamil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 160 (51.88%)
    27 / 143 (18.88%)
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    4 / 160 (2.50%)
    2 / 143 (1.40%)
         occurrences all number
    4
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 160 (2.50%)
    2 / 143 (1.40%)
         occurrences all number
    4
    2
    Dysgeusia
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 143 (0.70%)
         occurrences all number
    2
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    6 / 160 (3.75%)
    2 / 143 (1.40%)
         occurrences all number
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    39 / 160 (24.38%)
    10 / 143 (6.99%)
         occurrences all number
    39
    10
    Nasal congestion
         subjects affected / exposed
    23 / 160 (14.38%)
    1 / 143 (0.70%)
         occurrences all number
    23
    1
    Rhinorrhoea
         subjects affected / exposed
    17 / 160 (10.63%)
    4 / 143 (2.80%)
         occurrences all number
    17
    4
    Epistaxis
         subjects affected / exposed
    9 / 160 (5.63%)
    3 / 143 (2.10%)
         occurrences all number
    9
    3
    Sneezing
         subjects affected / exposed
    7 / 160 (4.38%)
    1 / 143 (0.70%)
         occurrences all number
    7
    1
    Throat irritation
         subjects affected / exposed
    6 / 160 (3.75%)
    0 / 143 (0.00%)
         occurrences all number
    6
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 160 (1.88%)
    1 / 143 (0.70%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jul 2020
    Defined the separation between NODE 301 Part 2 (RAPID) and NODE-301 Part 1 (conducted under Protocol Versions 5.0 and earlier). Introduced changes into RAPID, including study design changes affecting patient dosing and treatment periods, refinement of the eligibility criteria, and changes to the primary efficacy endpoint and to the statistical methods.
    01 Mar 2021
    Allowed all Screening Visit procedures and Test Dose Randomization Visits to be conducted on the same day.
    14 Jan 2022
    Modified requirements after questions raised by the BfArM: The following updates were made to the amended protocol: Procedures in Case of Emergency or Serious Adverse Event Reporting was revised with updated contact information Study Description and Site Study Procedures were revised to add precision related to when the Test Dose Randomization Visit could not be performed within 28 days of the Screening visit, that missing Follow-up visits was considered a protocol deviation, and to the window for the final study visit. Selection and Withdrawal of Patients was updated to revise one inclusion criterion, clarify one exclusion criterion, and revise one exclusion criterion. Study Treatments was revised to correct the emergency unblinding procedure. Safety Assessments was revised to clarify the reporting of AESIs, clarify procedures for SAEs related to PSVT, to align the reporting language with the German law, to update the contact information for the Medical Monitors Statistics was revised to clarify the definition of the Test Dose Only population and remove the estimators related to safety assessments from the primary efficacy section. Investigator Requirements and Quality Control was updated with a statement related to the obligation to publish the results of the clinical trial.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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