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    Clinical Trial Results:
    Efficacy of erenumab in chronic cluster headache: A 10-week double-blind, randomized, placebo-controlled, multicentric trial

    Summary
    EudraCT number
    		 2020-004399-16
    Trial protocol
    		 DE  
    Global end of trial date
    27 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Nov 2024
    First version publication date
    17 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CHERUB01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04970355
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité- Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Projectmanager, Charité - Universitätsmedizin Berlin, +49 30450 660 139, ma.lorenz@charite.de
    Scientific contact
    Projectmanager, Charité - Universitätsmedizin Berlin, +49 30450 660 139, ma.lorenz@charite.de
    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
    07 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to test the hypothesis that erenumab is superior to placebo in the reduction of weekly CH attacks in weeks 5 and 6 (days 29-42) in the erenumab group compared to placebo versus baseline
    Protection of trial subjects
    The conduct of this study met all legal and regulatory requirements and in accordance with ethical principles of the Declaration of Helsinki.
    Background therapy
    		 About 30% of all cluster headache patients suffer from chronic cluster, i.e.in one year, they are not experiencing more than 3 months without cluster headache attacks. . Erenumab has a marketing authorization for the prophylactic treatment of adult patients with diagnosed migraine (70mg/140mg). It is and was not authorized for the prophylaxis and/or treatment of chronic cluster headache. Two other CGRG monoclonal antibodies (galcanezumab / fremanezumab) were investigated in different double-blind placebo controlled clinical trials, but failed to show any efficacy in the prophylaxis of chronic cluster headache. Only Lithium has a regulatory approval for the prophylaxis of cCH, but other treatments such as Verapamil, Topiramate and Corticosteroids are currently used (off-label) alone or in combination. For treatment of acute headache attacks, treatments such as sumatriptan s.c. or zolmitriptan nasal spray can be used. Furthermore, Oxygen is also used by patients. The pathophysiological similarities between migraine and cluster headache as primarily unilateral trigeminal headache disorders, the role of CGRP in both disorders and the clinical efficacy observed with erenumab to date for the prevention of migraine support the evaluation of erenumab for the treatment of cluster headache. This study was conducted with a CGRP (Calcitonin Gene-Related Peptide) monoclonal antibody named erenumab (Aimovig®). Prophylactic pharmacological treatments of chronic cluster headache (cCH) are limited. Blocking the Calcitonin Gene-Related Peptide (CGRP) receptor might represent a specific new treatment based on pathophysiological evidence. This proof-of-concept study assessed the efficacy and tolerability of the CGRP receptor antibody erenumab in cCH.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Dec 2021
    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
    Germany: 81
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    81
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 11 study centers in Germany, between 02/12/2021 and 27/09/2023.

    Pre-assignment
    Screening details
    		 101 patients were screened according the inclusion criteria (at least 9 cluster attacks as defined by ICHD-3 in 7 days during the baseline epoch (SPII), Attacks must have occurred on more than 50% of days of the baseline epoch, ≥ 90% patient-reported eDiary compliance during the Baseline epoch) 81 of whom were randomized.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum
    Arm description
    		 Erenumab is a monoclonal antibody (mab) that blocks the CGRP receptor. The dosage of 280mg s.c. erenumab as a loading dose and a continuing dosage of 140mg s.c. erenumab after 28 days was based on the pharmacodynamical considerations of the Novartis pharmacological experts. PK-exposure response modelling suggests that with higher doses, a potential additional benefit in terms of efficacy and onset of efficacy might be observed. The estimation was that the cluster headache population obtain an additional benefit from a loading dose with a faster reach of drug steady state.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erenumab
    Investigational medicinal product code
    Other name
    Aimovig®
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    280mg s.c. loading dose at Visit 2 (week 0) in 4x pre-filled syringes of 1 ml each with 70mg Erenumab 140mg s.c. at Visit 3 (4 weeks after first application) with 2x pre-filled syringes á 70mg/1ml 6 weeks, with two dose applications at Visit 2 (week 0) and Visit 4 (week 4)

    Arm title
    		 Placebo
    Arm description
    		 Trial medication (IMP and Placebo) was provided by the Funder Novartis. The pre-filled syringes of IMP and Placebo were completely identical. There were no differences regarding look, smell or other factors.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0mg s.c. loading dose at Visit 2 (week 0) with 4x pre-filled syringes of 1 ml each. 0mg s.c. at Visit 3 (4 weeks after first application) with 2x pre-filled syringes of 1 ml each 6 weeks, with two dose applications at Visit 2 (week 0) and Visit 4 (week 4)

    Number of subjects in period 1
    		Verum Placebo
    Started
    41
    40
    Completed
    35
    35
    Not completed
    6
    5
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    2
    -
         Protocol deviation
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Erenumab is a monoclonal antibody (mab) that blocks the CGRP receptor. The dosage of 280mg s.c. erenumab as a loading dose and a continuing dosage of 140mg s.c. erenumab after 28 days was based on the pharmacodynamical considerations of the Novartis pharmacological experts. PK-exposure response modelling suggests that with higher doses, a potential additional benefit in terms of efficacy and onset of efficacy might be observed. The estimation was that the cluster headache population obtain an additional benefit from a loading dose with a faster reach of drug steady state.

    Reporting group title
    Placebo
    Reporting group description
    		 Trial medication (IMP and Placebo) was provided by the Funder Novartis. The pre-filled syringes of IMP and Placebo were completely identical. There were no differences regarding look, smell or other factors.

    Reporting group values
    		 Verum Placebo Total
    Number of subjects
    		 41 40 81
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.3 ( 10.7 ) 49.6 ( 10.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 10 21
        Male
    		 30 30 60
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 83.8 ( 21.4 ) 78.5 ( 16.6 ) -
    Duration of CH
    Units: years
        arithmetic mean (standard deviation)
    		 7.6 ( 7.0 ) 9.0 ( 7.3 ) -
    Baseline weekly CH attacks
    Units: number
        arithmetic mean (standard deviation)
    		 21.2 ( 8.95 ) 21.7 ( 10.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Erenumab is a monoclonal antibody (mab) that blocks the CGRP receptor. The dosage of 280mg s.c. erenumab as a loading dose and a continuing dosage of 140mg s.c. erenumab after 28 days was based on the pharmacodynamical considerations of the Novartis pharmacological experts. PK-exposure response modelling suggests that with higher doses, a potential additional benefit in terms of efficacy and onset of efficacy might be observed. The estimation was that the cluster headache population obtain an additional benefit from a loading dose with a faster reach of drug steady state.

    Reporting group title
    Placebo
    Reporting group description
    		 Trial medication (IMP and Placebo) was provided by the Funder Novartis. The pre-filled syringes of IMP and Placebo were completely identical. There were no differences regarding look, smell or other factors.

    Primary: Reduction in number of weekly CH attacks

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    End point title
    		 Reduction in number of weekly CH attacks
    End point description
    End point type
    Primary
    End point timeframe
    from baseline up to 42 days (5/6 weeks)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    35
    35
    Units: cluster headache attacks
        arithmetic mean (standard deviation)
    -7.3 ( 8.65 )
    -5.9 ( 10.5 )
    Statistical analysis title
    		 Change of weekly cluster headache attacks
    Statistical analysis description
    Bayesian method used for this Proof of Concept. Methods used was suggested by Fish et al. (Fish et al., 2015); Using non-informative prior distributions, we obtained samples from the posterior distribution of the differences in change from baseline between erenumab and placebo. For sampling from the posterior distribution, we used the STAN software with the default, weakly informative prior.
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.5
    Variability estimate
    Standard deviation
    Notes
    [1] - PerProtocol Effect estimates PE with imputation

    Secondary: participants with a ≥50% reduction of weekly CH attacks

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    End point title
    		 participants with a ≥50% reduction of weekly CH attacks
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to weeks 5/6
    End point values
    		 Verum Placebo
    Number of subjects analysed
    41
    40
    Units: subjects
        Yes
    13
    18
        No
    28
    22
    Statistical analysis title
    		 difference of participants with a ≥50% reduction
    Statistical analysis description
    Percent of participants with a ≥50% reduction of weekly CH attacks from baseline to weeks 5/6
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Bayesian
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.3

    Secondary: PGI-I at 6 week

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    End point title
    		 PGI-I at 6 week
    End point description
    End point type
    Secondary
    End point timeframe
    at week 6
    End point values
    		 Verum Placebo
    Number of subjects analysed
    41
    40
    Units: subjects
        Missing
    1
    4
        PGI-I = 1-2
    15
    14
        PGI-I >2
    25
    22
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial flutter
    Additional description: On admission at hospital sigmoid diverticulitis Type 1b was also diagnosed.
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
    Additional description: worsening of Cluster Headache attacks
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 41 (65.85%)
    15 / 40 (37.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 40 (7.50%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Flu like symptoms
    Additional description: including common cold
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 40 (2.50%)
         occurrences all number
    4
    2
    Pain
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Fatigue
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Mental Tension
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Investigations
    iincreased potassium
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased (ALAT)
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    increased GPT
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Increased GOT
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Increased CK
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Exerbation of Clusterattacks
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences all number
    2
    1
    Dizziness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    Anal stenosis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Vomiting/ Emesis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Simoid Diverticulitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    skin and other subcutaneous tissue disorders-other
    Additional description: Hidradenitis suppurativa in left axilla and Decubitus (Coccyx)
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscular pain in upper body
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Mucosal infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Rhinitis infection
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 40 (5.00%)
         occurrences all number
    2
    3
    Pharyngitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Brochial infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Hepatitis E
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    Hypercholesterteroemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2021
    Update: CT application form, Labelling, Trial protocol (V02, 15-3-2021) Changes in conduct or management of the trial (SARS-CoV-2 Antigen testing, Discontinuation of study treatment by new onset of SARS-CoV-2 Infection as determined at any of the study visits, remote-Site monitoring during pandemic)
    13 Jun 2022
    Update: CT application form, trial protocol and synopsis (V03,30-04-2022), Patient information (ICF V03), SmPc Aimovig 12/21, Changes in safety or integrity of trial subjects, Changes in conduct or management of the trial
    28 Feb 2023
    Update: CT application form, trial protocol and synopsis (V04, 18-01-23); Changes in safety or integrity of trial subjects, Changes in conduct or management of the 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.
    We did not find a sufficient number of patients in the allocated time period and therefore stopped recruitment prematurely. The result is very clearly negative and the addition of the missing subjects would not have changed anything to results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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