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    Clinical Trial Results:
    Interventional, randomized, double-blind, parallel-group, placebo-controlled delayed-start study to evaluate the efficacy and safety of eptinezumab in patients with episodic Cluster Headache

    Summary
    EudraCT number
    		 2020-001969-37
    Trial protocol
    		 NO   DK   DE   SE   CZ   PT   FR   BE   NL   FI   GR   IT  
    Global end of trial date
    05 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Sep 2024
    First version publication date
    29 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    19386A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04688775
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2500
    Public contact
    Email contact via H. Lundbeck A/S, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@Lundbeck.com
    Scientific contact
    Email contact via H. Lundbeck A/S, H. Lundbeck A/S, +45 36301311, LundbeckClinicalTrials@Lundbeck.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
    05 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy of eptinezumab in participants with episodic Cluster Headache (eCH).
    Protection of trial subjects
    This trial was conducted in compliance with Good Clinical Practice and in accordance with the ethical principles described in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2020
    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
    Belgium: 4
    Country: Number of subjects enrolled
    Czechia: 29
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Georgia: 27
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    231
    EEA total number of subjects
    177
    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)
    223
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 231 participants were enrolled in 18 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eptinezumab
    Arm description
    		 Participants received a single intravenous (IV) infusion of eptinezumab 400 milligrams (mg) in 100 milliliters (mL) 0.9% saline solution.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eptinezumab
    Investigational medicinal product code
    Other name
    Vyepti
    Pharmaceutical forms
    Solution for infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eptinezumab was administered per schedule specified in the arm description.

    Arm title
    		 Placebo
    Arm description
    		 Participants received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered per schedule specified in the arm description.

    Number of subjects in period 1
    		Eptinezumab Placebo
    Started
    113
    118
    Received at least 1 dose of study drug
    112
    117
    Completed
    108
    107
    Not completed
    5
    11
         Consent withdrawn by subject
    1
    6
         Adverse event, non-fatal
    2
    -
         Other reasons
    -
    1
         Randomized, not treated
    1
    1
         Lack of efficacy
    1
    2
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Delayed start period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Delayed Start Period: Placebo to Eptinezumab
    Arm description
    		 Participants who received placebo in the placebo-controlled period received a single IV infusion of eptinezumab 400mg in 100 mL 0.9% saline solution.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eptinezumab
    Investigational medicinal product code
    Other name
    Vyepti
    Pharmaceutical forms
    Solution for infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eptinezumab was administered per schedule specified in the arm description.

    Arm title
    		 Delayed Start Period: Eptinezumab to Placebo
    Arm description
    		 Participants who received eptinezumab in the placebo-controlled period received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered per schedule specified in the arm description.

    Number of subjects in period 2
    		Delayed Start Period: Placebo to Eptinezumab Delayed Start Period: Eptinezumab to Placebo
    Started
    107
    108
    Received at least 1 dose of study drug
    107
    108
    Completed
    101
    100
    Not completed
    6
    8
         Consent withdrawn by subject
    2
    4
         Adverse event, non-fatal
    1
    -
         Other reasons
    1
    -
         Lost to follow-up
    2
    1
         Lack of efficacy
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo-controlled period
    Reporting group description
    		 -

    Reporting group values
    		 Placebo-controlled period Total
    Number of subjects
    		 231 231
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 223 223
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Sex: Female, Male
    Units: Participants
        Female
    		 51 51
        Male
    		 180 180
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 8 8
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 202 202
        Other
    		 3 3
        Unknown or Not Reported
    		 17 17
    Number of Weekly Cluster Headache (CH) Attacks
    Units: Number of Weekly Attacks
        arithmetic mean (standard deviation)
    		 15.4 ( 8.17 ) -

    End points

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    End points reporting groups
    Reporting group title
    Eptinezumab
    Reporting group description
    		 Participants received a single intravenous (IV) infusion of eptinezumab 400 milligrams (mg) in 100 milliliters (mL) 0.9% saline solution.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.
    Reporting group title
    Delayed Start Period: Placebo to Eptinezumab
    Reporting group description
    		 Participants who received placebo in the placebo-controlled period received a single IV infusion of eptinezumab 400mg in 100 mL 0.9% saline solution.

    Reporting group title
    Delayed Start Period: Eptinezumab to Placebo
    Reporting group description
    		 Participants who received eptinezumab in the placebo-controlled period received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.

    Primary: Change From Baseline in the Number of Weekly Cluster Headache (CH) Attacks, Averaged Over Weeks 1-2

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    End point title
    		 Change From Baseline in the Number of Weekly Cluster Headache (CH) Attacks, Averaged Over Weeks 1-2
    End point description
    The participant completed a CH eDiary, daily, and recorded for each day/week whether he/she had any CH attacks. For each CH attack, the start date and time was collected. The participant recorded further daily information regarding CH characteristics and intake of acute medication for CH. CH items were assessed with a yes/no response. The APRS included all randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    113
    118
    Units: Number of Weekly Attacks
        least squares mean (standard error)
    -4.0 ( 0.93 )
    -4.6 ( 0.89 )
    Statistical analysis title
    		 Number of Weekly Attacks: Eptinezumab vs. Placebo
    Comparison groups
    Eptinezumab v Placebo
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5048
    Method
    		 Mixed Models Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 2.6

    Secondary: Change From Baseline in the Number of Weekly Times an Abortive Medication Was Used, Averaged Over Weeks 1-2

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    End point title
    		 Change From Baseline in the Number of Weekly Times an Abortive Medication Was Used, Averaged Over Weeks 1-2
    End point description
    Abortive medications included the use of triptans or oxygen (O2). The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: Abortive therapy use per week
        least squares mean (standard error)
    -2.54 ( 0.98 )
    -3.55 ( 0.93 )
    No statistical analyses for this end point

    Secondary: Number of Participants With ≥50% Reduction From Baseline in Number of Weekly Attacks Over Weeks 1-2

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    End point title
    		 Number of Participants With ≥50% Reduction From Baseline in Number of Weekly Attacks Over Weeks 1-2
    End point description
    The APRS included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    113
    118
    Units: participants
    44
    37
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Number of Daily Attacks, Averaged Over Days 1-3

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    End point title
    		 Change From Baseline in the Number of Daily Attacks, Averaged Over Days 1-3
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Days 1-3
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    110
    115
    Units: Attacks per day
        least squares mean (standard error)
    -0.22 ( 0.16 )
    -0.35 ( 0.15 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Number of Days With <3 Attacks Per Day, Averaged Over Weeks 1-2

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    End point title
    		 Change From Baseline in the Number of Days With <3 Attacks Per Day, Averaged Over Weeks 1-2
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: Days
        least squares mean (standard error)
    0.60 ( 0.20 )
    0.82 ( 0.19 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Number of Attacks Starting ≤24 Hours After the Start of the First Infusion of IMP

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    End point title
    		 Change from Baseline in Number of Attacks Starting ≤24 Hours After the Start of the First Infusion of IMP
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From first infusion in the placebo-controlled period (Baseline, Day 0) to 24-hours after the first infusion in the placebo-controlled period
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    104
    110
    Units: Number of attacks
        least squares mean (standard error)
    2.07 ( 0.18 )
    1.96 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Time From First Infusion of IMP to Resolution of Cluster Headache Bout Within the First 4 Weeks

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    End point title
    		 Time From First Infusion of IMP to Resolution of Cluster Headache Bout Within the First 4 Weeks
    End point description
    Presented here is the result of the analysis of time from first infusion of IMP to resolution of cluster headache bout. The hazard ratio estimate is an estimate from the Cox model of time to resolution. The APRS included all randomized participants. "99999" = Data Not Reported. Median and 95% CI could not be calculated due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From first infusion (Baseline, Day 0) to 4 weeks
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    112
    117
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Time From First Infusion to Resolution
    Comparison groups
    Eptinezumab v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0772
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.17

    Secondary: Change From Baseline to Week 1 in the Number of Weekly Attacks

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    End point title
    		 Change From Baseline to Week 1 in the Number of Weekly Attacks
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 1
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: Attacks per week
        least squares mean (standard error)
    -2.62 ( 0.95 )
    -3.71 ( 0.90 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Daily Mean Score on 5-Point Self-Rating Pain Severity Scale, Averaged Over Days 1-3

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    End point title
    		 Change From Baseline in the Daily Mean Score on 5-Point Self-Rating Pain Severity Scale, Averaged Over Days 1-3
    End point description
    The severity of pain was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (headache pain ratings: 0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Days 1-3
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    99
    112
    Units: score on a scale
        least squares mean (standard error)
    -0.30 ( 0.10 )
    -0.18 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 2 in the Number of Weekly Attacks

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    End point title
    		 Change From Baseline to Week 2 in the Number of Weekly Attacks
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    106
    110
    Units: Attacks per week
        least squares mean (standard error)
    -5.44 ( 1.00 )
    -5.64 ( 0.96 )
    No statistical analyses for this end point

    Secondary: Number of Participants With ≥50% Reduction From Baseline in Number of Weekly Attacks in Week 1

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    End point title
    		 Number of Participants With ≥50% Reduction From Baseline in Number of Weekly Attacks in Week 1
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 1
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: participants
    36
    28
    No statistical analyses for this end point

    Secondary: Number of Participants With ≥30% Reduction From Baseline in Number of Weekly Attacks in Week 1

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    End point title
    		 Number of Participants With ≥30% Reduction From Baseline in Number of Weekly Attacks in Week 1
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 1
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: participants
    48
    50
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 1 in Weekly Integrated Measure of Frequency and Intensity of Pain

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    End point title
    		 Change From Baseline to Week 1 in Weekly Integrated Measure of Frequency and Intensity of Pain
    End point description
    The weekly integrated measure of frequency and intensity of pain calculates a singular numerical value for frequency and intensity of pain by adding the intensity rating (Worst pain on a 5-point Self-rating pain severity scale) for each attack during that week. The intensity of pain for each attack was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The total weekly score could range from 0 (no attacks and/or no pain) to no specified upper limit, with lower scores representing better outcomes. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 1
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: score on a scale
        least squares mean (standard error)
    -10.58 ( 2.55 )
    -11.96 ( 2.42 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Integrated Measure of Frequency and Intensity of pain, Averaged Over Weeks 1-2

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    End point title
    		 Change From Baseline in Weekly Integrated Measure of Frequency and Intensity of pain, Averaged Over Weeks 1-2
    End point description
    The weekly integrated measure of frequency and intensity of pain calculates a singular numerical value for frequency and intensity of pain by adding the intensity rating (Worst pain on a 5-point Self-rating pain severity scale) for each attack during that week. The intensity of pain for each attack was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The total weekly score could range from 0 (no attacks and/or no pain) to no specified upper limit, with lower scores representing better outcomes. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: score on a scale
        least squares mean (standard error)
    -13.39 ( 2.56 )
    -14.46 ( 2.43 )
    No statistical analyses for this end point

    Secondary: Number of Participants With ≥30% Reduction from Baseline in Number of Weekly Attacks Over Weeks 1-2

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    End point title
    		 Number of Participants With ≥30% Reduction from Baseline in Number of Weekly Attacks Over Weeks 1-2
    End point description
    The APRS included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    113
    118
    Units: participants
    59
    53
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 2 in Weekly Integrated Measure of Frequency and Intensity of Pain

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    End point title
    		 Change From Baseline to Week 2 in Weekly Integrated Measure of Frequency and Intensity of Pain
    End point description
    The weekly integrated measure of frequency and intensity of pain calculates a singular numerical value for frequency and intensity of pain by adding the intensity rating (Worst pain on a 5-point Self-rating pain severity scale) for each attack during that week. The intensity of pain for each attack was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The total weekly score could range from 0 (no attacks and/or no pain) to no specified upper limit, with lower scores representing better outcomes. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 2
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    106
    110
    Units: score on a scale
        least squares mean (standard error)
    -16.20 ( 2.73 )
    -16.95 ( 2.61 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Mean Score on 5-Point Self-Rating Pain Severity Scale (Average Per Attack Over a Week) for Weeks 1, 2, 3, and 4

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    End point title
    		 Change From Baseline in the Mean Score on 5-Point Self-Rating Pain Severity Scale (Average Per Attack Over a Week) for Weeks 1, 2, 3, and 4
    End point description
    The severity of pain for each attack was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (headache pain ratings: 0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure and "Number Analyzed" is the number of participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1, 2, 3, and 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    101
    116
    Units: score on a scale
    least squares mean (standard error)
        Week 1 (n=101,116)
    -0.33 ( 0.09 )
    -0.24 ( 0.08 )
        Week 2 (n=91,100)
    -0.46 ( 0.10 )
    -0.35 ( 0.09 )
        Week 3 (n=80,97)
    -0.56 ( 0.11 )
    -0.31 ( 0.10 )
        Week 4 (n=70,86)
    -0.51 ( 0.11 )
    -0.42 ( 0.10 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Integrated Measure of Frequency and Intensity of Pain, Averaged Over Weeks 1-4

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    End point title
    		 Change From Baseline in Weekly Integrated Measure of Frequency and Intensity of Pain, Averaged Over Weeks 1-4
    End point description
    The weekly integrated measure of frequency and intensity of pain score calculates a singular numerical value for frequency and intensity of pain by adding the intensity rating (Worst pain on a 5-point Self-rating pain severity scale) for each attack during that week. The intensity of pain for each attack was rated on an ordinal scale that ranged from 0 to 4 with higher scores indicating more headache pain (0 = none/barely any pain; 1 = mild; 2 = moderate; 3 = severe; 4 = excruciating). The total weekly score could range from 0 (no attacks and/or no pain) to no specified upper limit, with lower scores representing better outcomes. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: score on a scale
        least squares mean (standard error)
    -17.81 ( 2.50 )
    -16.81 ( 2.37 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Number of Weekly Attacks, Averaged Over Weeks 1-4

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    End point title
    		 Change From Baseline in the Number of Weekly Attacks, Averaged Over Weeks 1-4
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 1-4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    109
    116
    Units: Attacks per week
        least squares mean (standard error)
    -5.95 ( 0.92 )
    -5.78 ( 0.88 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Number of Weekly Attacks for Each of Weeks 3 and 4

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    End point title
    		 Change from Baseline in the Number of Weekly Attacks for Each of Weeks 3 and 4
    End point description
    The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure and "Number Analyzed" is the number of participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 3-4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    104
    112
    Units: Attacks per week
    least squares mean (standard error)
        Week 3 (n=104,112)
    -7.35 ( 0.98 )
    -6.60 ( 0.94 )
        Week 4 (n=102,107)
    -8.37 ( 1.11 )
    -7.15 ( 1.07 )
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) Score at Weeks 1, 2, and 4

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    End point title
    		 Patient Global Impression of Change (PGIC) Score at Weeks 1, 2, and 4
    End point description
    The PGIC is a patient-reported measure of improvement in pain sensation and quality of life scored on a scale from 1 (very much improved) to 7 (very much worse). Lower scores indicate better health status. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure and "Number Analyzed" is the number of participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, and 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    104
    106
    Units: score on a scale
    least squares mean (standard error)
        Week 1 (n=102,96)
    3.19 ( 0.16 )
    3.55 ( 0.15 )
        Week 2 (n=95,93)
    2.92 ( 0.17 )
    3.44 ( 0.16 )
        Week 4 (n=104,106)
    2.85 ( 0.18 )
    3.23 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Sleep Impact Scale (SIS) Domain Scores at Weeks 2 and 4

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    End point title
    		 Change From Baseline in Sleep Impact Scale (SIS) Domain Scores at Weeks 2 and 4
    End point description
    The SIS is a patient-reported clinical outcome assessment used to assess quality of life resulting from sleep disturbance. The SIS questionnaire includes 35 items belonging to 7 domains to assess sleep impact on: daily activities; emotional well-being; emotional impact; energy/fatigue; social well-being; mental fatigue; and satisfaction with sleep. Each item, for 6 out of the 7 domains, is rated on a 5-point scale ranging from 1 (always or all of the time) to 5 (never or none of the time), whereas satisfaction with sleep is rated on a 5-point scale ranging from 1 (very satisfied) to 5 (very dissatisfied). Each domain yields a score ranging from 0 to 100, which is presented here. A higher score for Daily Activities, Emotional Well-being, Emotional Impact, Energy/Fatigue, Social Well-being, and Mental Fatigue indicates better quality of life. A lower score for Satisfaction with Sleep indicates a higher quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 2 and 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    102
    Units: score on a scale
    least squares mean (standard error)
        Daily Activities - Week 2 (n=91,84)
    16.83 ( 3.08 )
    8.93 ( 3.06 )
        Daily Activities - Week 4 (n=100,102)
    24.82 ( 3.19 )
    13.97 ( 3.08 )
        Emotional Well-being - Week 2 (n=91,84)
    14.85 ( 2.84 )
    6.04 ( 2.81 )
        Emotional Well-being - Week 4 (n=100,102)
    22.77 ( 3.07 )
    12.22 ( 2.97 )
        Energy/Fatigue - Week 2 (n=91,84)
    18.16 ( 3.23 )
    8.03 ( 3.19 )
        Energy/Fatigue - Week 4 (n=100,102)
    24.16 ( 3.47 )
    14.68 ( 3.36 )
        Mental Fatigue - Week 2 (n=91,84)
    9.04 ( 2.66 )
    4.15 ( 2.64 )
        Mental Fatigue - Week 4 (n=100,102)
    15.15 ( 2.91 )
    8.00 ( 2.81 )
        Emotional Impact - Week 2 (n=91,84)
    14.39 ( 3.02 )
    6.00 ( 3.00 )
        Emotional Impact - Week 4 (n=100,102)
    23.09 ( 3.29 )
    13.36 ( 3.18 )
        Social Well-being - Week 2 (n=91,84)
    15.22 ( 3.37 )
    6.92 ( 3.35 )
        Social Well-being - Week 4 (n=100,102)
    23.74 ( 3.46 )
    13.91 ( 3.35 )
        Satisfaction with Sleep - Week 2 (n=91,84)
    -11.41 ( 2.75 )
    -6.06 ( 2.73 )
        Satisfaction with Sleep - Week 4 (n=100,102)
    -19.60 ( 2.88 )
    -9.63 ( 2.78 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Euroqol 5-Dimension 5-Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Weeks 2 and 4

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    End point title
    		 Change From Baseline in Euroqol 5-Dimension 5-Levels (EQ-5D-5L) Visual Analogue Scale (VAS) at Weeks 2 and 4
    End point description
    The EQ-5D-5L VAS is a participant-reported assessment designed to measure the participant's well-being and ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure and "Number Analyzed" is the number of participants evaluable at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Weeks 2 and 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    76
    80
    Units: score on a scale
    least squares mean (standard error)
        Week 2 (n=70,63)
    8.21 ( 2.79 )
    3.47 ( 2.86 )
        Week 4 (n=76,80)
    13.49 ( 2.80 )
    5.73 ( 2.77 )
    No statistical analyses for this end point

    Secondary: Health Care Resource Utilization (HCRU) Score: Number of Visits to a Family Doctor/General Practitioner

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    End point title
    		 Health Care Resource Utilization (HCRU) Score: Number of Visits to a Family Doctor/General Practitioner
    End point description
    Number of participants who visited a family doctor/general practitioner has been reported. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    104
    Units: participants
        0 visits
    85
    85
        1 visit
    9
    10
        2 visits
    1
    6
        3 visits
    3
    1
        5 visits
    1
    1
        6 visits
    1
    1
    No statistical analyses for this end point

    Secondary: HCRU Score: Number of Visits to a Specialist

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    End point title
    		 HCRU Score: Number of Visits to a Specialist
    End point description
    Number of participants who visited a specialist has been reported. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    104
    Units: participants
        0 visits
    77
    68
        1 visit
    11
    18
        2 visits
    6
    14
        3 visits
    4
    2
        4 visits
    2
    2
    No statistical analyses for this end point

    Secondary: HCRU Score: Number of Emergency Department Visits Due to Cluster Headache

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    End point title
    		 HCRU Score: Number of Emergency Department Visits Due to Cluster Headache
    End point description
    Number of participants who visited an emergency department due to CH was reported. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    104
    Units: participants
        0 visits
    98
    99
        1 visit
    1
    2
        2 visits
    1
    2
        3 visits
    0
    1
    No statistical analyses for this end point

    Secondary: HCRU Score: Number of Hospital Admissions Due to Cluster Headache

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    End point title
    		 HCRU Score: Number of Hospital Admissions Due to Cluster Headache
    End point description
    Number of participants who were admitted to a hospital due to CH was reported. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    104
    Units: participants
        0 admissions
    97
    102
        1 admission
    1
    0
        2 admissions
    2
    1
        3 admissions
    0
    1
    No statistical analyses for this end point

    Secondary: HCRU Score: Number of Overnight Hospital Stays Due to Cluster Headache

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    End point title
    		 HCRU Score: Number of Overnight Hospital Stays Due to Cluster Headache
    End point description
    Number of participants who stayed overnight in a hospital due to CH was reported. The APRS included all randomized participants. Here, "Overall Number of Participants Analyzed" is the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    100
    104
    Units: participants
        0 overnight hospital stays
    99
    104
        5 overnight hospital stays
    1
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Work Productivity Activity Impairment (WPAI) Questionnaire Subscores at Week 4

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    End point title
    		 Change From Baseline in the Work Productivity Activity Impairment (WPAI) Questionnaire Subscores at Week 4
    End point description
    The WPAI:GH2.0 is a patient self-rated clinical outcome assessment designed to provide a quantitative measure of the work productivity and activity impairment due to a health condition. The WPAI:GH2.0 assesses activities over the preceding 7 days and consists of 6 items: 1 item assesses employment (yes/no); 3 items assess the number of hours worked, the number of hours missed from work due to the participant’s condition, or due to other reasons; and 2 visual numerical scales assess how much the participant’s condition affects his/her productivity at work and his/her ability to complete normal daily activities. Each item (Absenteeism, Presenteeism, Work Productivity Loss, Activity Impairment) was calculated into an impairment percentage ranging from 0 to 100%, with higher numbers indicating greater impairment and less productivity (i.e. worse outcomes). Change from baseline for each item is shown here.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 4
    End point values
    		 Eptinezumab Placebo
    Number of subjects analysed
    95
    95
    Units: score on a scale
    least squares mean (standard error)
        Absenteeism
    -13.71 ( 3.95 )
    -4.37 ( 3.74 )
        Presenteeism
    -19.29 ( 4.81 )
    -11.03 ( 4.68 )
        Work productivity loss
    -23.59 ( 5.34 )
    -13.68 ( 5.20 )
        Activity impairment
    -25.84 ( 3.70 )
    -15.82 ( 3.58 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose of IMP to 20 weeks after last dose (up to 24 weeks)
    Adverse event reporting additional description
    The APTS included all randomized participants in the who received infusion with double-blind IMP.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo-controlled Period: Eptinezumab
    Reporting group description
    		 Participants received a single IV infusion of eptinezumab 400mg in 100 mL 0.9% saline solution.

    Reporting group title
    Delayed Start Period: Placebo to Eptinezumab
    Reporting group description
    		 Participants who received placebo in the placebo-controlled period received a single IV infusion of eptinezumab 400mg in 100 mL 0.9% saline solution.

    Reporting group title
    Delayed Start Period: Eptinezumab to Placebo
    Reporting group description
    		 Participants who received eptinezumab in the placebo-controlled period received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.

    Reporting group title
    Placebo-controlled Period: Placebo
    Reporting group description
    		 Participants received a single IV infusion of 0.9% saline solution as matching placebo for eptinezumab.

    Serious adverse events
    		 Placebo-controlled Period: Eptinezumab Delayed Start Period: Placebo to Eptinezumab Delayed Start Period: Eptinezumab to Placebo Placebo-controlled Period: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 107 (0.93%)
    2 / 108 (1.85%)
    0 / 117 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 107 (0.00%)
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 107 (0.93%)
    0 / 108 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 107 (0.00%)
    0 / 108 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 107 (0.00%)
    0 / 108 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 107 (0.00%)
    0 / 108 (0.00%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis enteroviral
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 107 (0.00%)
    1 / 108 (0.93%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo-controlled Period: Eptinezumab Delayed Start Period: Placebo to Eptinezumab Delayed Start Period: Eptinezumab to Placebo Placebo-controlled Period: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 112 (8.93%)
    9 / 107 (8.41%)
    13 / 108 (12.04%)
    9 / 117 (7.69%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 112 (3.57%)
    1 / 107 (0.93%)
    0 / 108 (0.00%)
    1 / 117 (0.85%)
         occurrences all number
    4
    1
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 112 (3.57%)
    0 / 107 (0.00%)
    3 / 108 (2.78%)
    2 / 117 (1.71%)
         occurrences all number
    4
    0
    4
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 112 (0.89%)
    2 / 107 (1.87%)
    7 / 108 (6.48%)
    3 / 117 (2.56%)
         occurrences all number
    1
    3
    7
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 107 (5.61%)
    2 / 108 (1.85%)
    3 / 117 (2.56%)
         occurrences all number
    2
    6
    2
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 107 (0.00%)
    3 / 108 (2.78%)
    1 / 117 (0.85%)
         occurrences all number
    0
    0
    3
    1

    More information

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

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

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

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