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    Clinical Trial Results:
    Double-blind, randomized phase III trial in adult and adolescent patients with eosinophilic esophagitis to prove superiority compared to placebo of an episodic and/or a continuous 48-week treatment with budesonide orodispersible tablets for maintaining clinico-histological remission

    Summary
    EudraCT number
    		 2017-003516-39
    Trial protocol
    		 DE   ES   IT  
    Global end of trial date
    29 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2026
    First version publication date
    15 Aug 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BUL-3/EER
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EOS-3: Acronym
    Sponsors
    Sponsor organisation name
    Dr Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg im Breisgau, Germany, 79108
    Public contact
    Dept. of Clinic. Res. & Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.de
    Scientific contact
    Dept. of Clinic. Res. & Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.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
    29 Nov 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To prove superiority compared to placebo of episodic treatment with 4 cycles of budesonide 0.5 mg orodispersible tablets twice daily (BID) for 4 weeks followed by 8 weeks placebo BID over a total of 48 weeks and/or of continuous 48-week treatment with budesonide 0.5 mg orodispersible tablets BID in adult and adolescent eosinophilic esophagitis (EoE) patients in maintaining clinico-histological remission.
    Protection of trial subjects
    Prior to recruitment of patients, all relevant documents of the clinical study were submitted and approved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient’s personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial. For endoscopy and biopsy sampling to be performed for confirmation of diagnosis of eosinophilic esophagitis by the central pathologist, the patients received the standard preparation for sedation during the endoscopy as routinely performed at the study sites.
    Background therapy
    		 No concomitant background therapy, except stable diets and/or stable treatment with protonpumpinhibitors was allowed during the trial.
    Evidence for comparator
    		 Using a placebo arm in this clinical trial was ethically justified as there were compelling and scientifically sound methodological reasons for the use of a placebo control in this trial, since there were no comparator products with a marketing authorization for the treatment of EoE available. Moreover, the use of a placebo group was also justified, as it allowed to control for all other potential influences on the actual or apparent course of the disease other than those arising from the pharmacological action of budesonide (including but not limited to influences such as, spontaneous change in the disease, subject and investigator expectations, the effect of participating in this trial, or subjective elements of diagnosis or assessments), as stated in the “ICH Topic E10: Note for guidance on choice of control group in clinical trials” (CPMP/ICH/364/96).
    Actual start date of recruitment
    22 Jul 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
    Spain: 57
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Switzerland: 4
    Worldwide total number of subjects
    112
    EEA total number of subjects
    108
    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)
    2
    Adults (18-64 years)
    108
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total 112 patients were recruited from August 2021 to October 2023. 21 centers randomized patients: 2 centers in Switzerland (CH), 9 centers in Germany (DE), 6 centers in Spain (ES), and 4 centers in Italy (IT).

    Pre-assignment
    Screening details
    		 158 patients were screened to fullfill the In-/Exclusion criteria for this study. Of them, 112 patients were randomized and treated with budesonide or placebo.

    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, Carer, Assessor
    Blinding implementation details
    The appearance and taste of the placebo effervescent tablet for orodispersible use was indistinguishable from the verum effervescent tablet for orodispersible use.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 episodic BUL 0.5mg BID
    Arm description
    		 4 cycles of 3 months each with one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening for 4 weeks followed by 8 weeks of Placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.5mg budesonide tablet for orodispersible use
    Investigational medicinal product code
    BUL 0.5mg
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take one orodispersible tablet each in the morning and in the evening after the meal. The orodispersible tablet has to be placed on the tongue which allows disintegration within several minutes. The dissolved parts of the orodispersible tablet will be swallowed with saliva little by little. Do not drink or eat during 30 minutes after study drug administration.

    Arm title
    		 continuous BUL 0.5mg BID
    Arm description
    		 one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening continuously
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.5mg budesonide tablet for orodispersible use
    Investigational medicinal product code
    BUL 0.5mg
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take one orodispersible tablet each in the morning and in the evening after the meal. The orodispersible tablet has to be placed on the tongue which allows disintegration within several minutes. The dissolved parts of the orodispersible tablet will be swallowed with saliva little by little. Do not drink or eat during 30 minutes after study drug administration.

    Arm title
    		 Placebo BID
    Arm description
    		 Twice daily Placebo tablet for orodispersible use
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo budesonide tablet for orodispersible use
    Investigational medicinal product code
    BUL Placebo
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take one orodispersible tablet each in the morning and in the evening after the meal. The orodispersible tablet has to be placed on the tongue which allows disintegration within several minutes. The dissolved parts of the orodispersible tablet will be swallowed with saliva little by little. Do not drink or eat during 30 minutes after study drug administration.

    Number of subjects in period 1
    		episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Started
    45
    45
    22
    Completed
    28
    41
    11
    Not completed
    17
    4
    11
         Consent withdrawn by subject
    1
    1
    -
         Adverse event, non-fatal
    1
    1
    -
         Protocol-specified withdrawl criteria met
    -
    1
    -
         Intended pregnancy of patient’s wife
    -
    -
    1
         Lack of efficacy
    15
    1
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    episodic BUL 0.5mg BID
    Reporting group description
    		 4 cycles of 3 months each with one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening for 4 weeks followed by 8 weeks of Placebo

    Reporting group title
    continuous BUL 0.5mg BID
    Reporting group description
    		 one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening continuously

    Reporting group title
    Placebo BID
    Reporting group description
    		 Twice daily Placebo tablet for orodispersible use

    Reporting group values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID Total
    Number of subjects
    		 45 45 22 112
    Age categorical
    Units: Subjects
        Adolescent (16 - <18)
    		 0 1 1 2
        Adults (18-75)
    		 45 44 21 110
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.6 ( 2.0 ) 41.1 ( 1.9 ) 36.6 ( 2.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 16 5 31
        Male
    		 35 29 17 81
    Smoking status at screening
    Units: Subjects
        Current smoker
    		 1 3 1 5
        Former smoker
    		 6 6 5 17
        Never smoker
    		 38 35 16 89
        Missing status
    		 0 1 0 1
    Ethnic Group
    Units: Subjects
        White
    		 45 45 21 111
        Black or African American
    		 0 0 1 1
    Patient global impression of severity (PGI-S)
    Units: Subjects
        None
    		 35 36 18 89
        Mild
    		 8 8 4 20
        Moderate
    		 2 0 0 2
        Severe
    		 0 1 0 1
    History of allergic disease
    Units: Subjects
        yes
    		 34 23 21 78
        no
    		 11 22 1 34
    Concomitant use of PPIs
    Units: Subjects
        yes
    		 3 8 2 13
        no
    		 42 37 20 99
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 73.09 ( 2.12 ) 75.24 ( 2.05 ) 73.62 ( 3.12 ) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 23.44 ( 0.59 ) 25.21 ( 0.65 ) 24.01 ( 0.68 ) -
    EEsAI PRO at baseline
    Units: points
        arithmetic mean (standard deviation)
    		 7.5 ( 1.47 ) 7.4 ( 1.83 ) 6.0 ( 2.5 ) -
    Total Modified Endoscopic Reference Score (EREFS; range: 0-9)
    Worst case assessment from all parts of the esophagus. Lower values reflect lower total endoscopic disease activity.
    Units: points
        arithmetic mean (standard deviation)
    		 0.6 ( 0.2 ) 0.6 ( 0.1 ) 0.6 ( 0.2 ) -
    'Inflammatory signs' subscore - Modified Endoscopic Reference Score (EREFS; range: 0-4)
    Worst case assessment from all parts of the esophagus. Lower values reflect lower endoscopic inflammatory disease activity.
    Units: points
        arithmetic mean (standard deviation)
    		 0.4 ( 0.1 ) 0.3 ( 0.1 ) 0.2 ( 0.1 ) -
    'Fibrotic signs' subscore - Modified Endoscopic Reference Score (EREFS, range: 0-4)
    Worst case assessment from all parts of the esophagus. Lower values reflect lower endoscopic fibrotic disease activity.
    Units: points
        arithmetic mean (standard deviation)
    		 0.2 ( 0.1 ) 0.3 ( 0.1 ) 0.4 ( 0.1 ) -
    Overall peak eos/mm2 hpf
    Overall peak eosinophil count (eos)/mm2 high power field (hpf) derived from 6 biopsies (2 each from the proximal, mid, and distal esophageal segment).
    Units: eos/mm2 hpf
        arithmetic mean (standard deviation)
    		 0 ( 0.0 ) 0 ( 0.0 ) 0 ( 0.0 ) -
    Total weekly EEsAI-PRO (0-100)
    Eosinophilic Esophagitis Activity Index Patient Reported Outcome (EEsAI-PRO) score: The relevant items for the EEsAI-PRO Score were: - Frequency of trouble swallowing (with 4 increments ranging from never to daily) - Duration of dysphagia episodes (≤ 5 / > 5 minutes) - Presence / absence of pain during swallowing - Visual Dysphagia Questions (VDQ) on 8 foods of 8 different consistencies (hypothetical test meal; grades 0 to 3) resulting in a VDQ score - Behavioural change strategies on specific foods with 8 different consistencies: Range: 0 (no EoE activity) to 100 (most severe EoE)
    Units: points
        arithmetic mean (standard deviation)
    		 7.5 ( 1.47 ) 7.4 ( 1.83 ) 6.0 ( 2.5 ) -
    Adult Eosinophilic Esophagitis Quality of Life (range of weighted average scores: 0-4)
    Higher scores denote better quality of life.
    Units: points
        arithmetic mean (standard deviation)
    		 2.96 ( 0.16 ) 3.32 ( 0.10 ) 3.33 ( 0.21 ) -
    Dysphagia Numerical Rating Scale [NRS] (0-10)
    0 = no troubles to swallow 10 = most severe troubles to swallow
    Units: points
        arithmetic mean (standard deviation)
    		 0.5 ( 0.1 ) 0.4 ( 0.1 ) 0.1 ( 0.1 ) -
    Odynophagia Numerical Rating Scale [NRS] (0-10)
    0 = no troubles to swallow 10 = most severe troubles to swallow
    Units: points
        arithmetic mean (standard deviation)
    		 0.1 ( 0.1 ) 0.2 ( 0.1 ) 0 ( 0.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    episodic BUL 0.5mg BID
    Reporting group description
    		 4 cycles of 3 months each with one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening for 4 weeks followed by 8 weeks of Placebo

    Reporting group title
    continuous BUL 0.5mg BID
    Reporting group description
    		 one budesonide 0.5 mg orodispersible tablet each in the morning and in the evening continuously

    Reporting group title
    Placebo BID
    Reporting group description
    		 Twice daily Placebo tablet for orodispersible use

    Primary: Proportion of patients free of treatment failure after a 48-week DB treatment phase

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    End point title
    		 Proportion of patients free of treatment failure after a 48-week DB treatment phase
    End point description
    Treatment failure was “yes”, if at least one of the following criteria was met at any time during the DB treatment phase: Clinical relapse, i.e., experiencing dysphagia or odynophagia in the past 7 days of a severity of ≥ 4 points on a 0–10 NRS for dysphagia or odynophagia, respectively, confirmed by a severity of ≥ 4 points on at least 1 day during the subsequent week on the respective 0-10 NRS for dysphagia or odynophagia, Clinical relapse [EEsAI PRO] defined as a > 20-point increase compared to DB baseline in EEsAI PRO score, confirmed one week later, whereby DB baseline was defined as screening visit or OLI EOT visit, unless an assessment from visit DB V1 was available, Histological relapse, i.e., a peak of ≥ 48 eos/mm2 hpf at DB week 48/EOT, Experiencing a food impaction which needed endoscopic intervention, Presence of fixed ring/stricture, which prevented the passage of an adult standard endoscope (9-10 mm), Need for an endoscopic dilation, Premature withdrawal for any reason
    End point type
    Primary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    5
    28
    2
    Statistical analysis title
    		 episodic BUL 0.5 mg BID vs placebo
    Comparison groups
    Placebo BID v episodic BUL 0.5mg BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.3245 [2]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - The difference between proportions of patients free of treatment failure in the BUL 0.5 mg BID episodic group and the Placebo group was -0.0202 (97.5% CI [-0.1931, 0.1527]). The one-sided p-value resulting from the Fisher’s exact test was 0.3245. Therefore, the null hypothesis for this comparison could not be rejected and BUL 0.5 mg BID episodic was not superior to Placebo.
    [2] - Testing of H0 (πPla ≥ πEff) by means of the Fisher’s exact test test, Bonferroni adjusted alpha = 0.0125
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Statistical analysis description
    The difference between proportions of patients free of treatment failure in the BUL 0.5 mg BID continuous group and the Placebo was -0.5313 in the FAS-DB (97.5% CI [-0.7437, -0.3189]). The one-sided p-value resulting from the Fisher’s exact test was <0.0001. All pre-specified subgroup analyses of the primary endpoint were in line with the primary outcome and showed the robustness of the observed superiority of BUL 0.5mg BID continuous over Placebo.
    Comparison groups
    Placebo BID v continuous BUL 0.5mg BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - Testing of H0 (πPla ≥ πEff) by means of the Fisher’s exact test test, Bonferroni adjusted alpha = 0.0125

    Secondary: Proportion of patients with histological relapse at DB Week 48/EOT

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    End point title
    		 Proportion of patients with histological relapse at DB Week 48/EOT
    End point description
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    30
    1
    18
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    episodic BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1045 [4]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [4] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [5] - Testing of H0 (BUL vs. Placebo)

    Secondary: Change in the peak eos/mm2 hpf from screening or OLI V2/EOT to DB Week 48/EOT

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    End point title
    		 Change in the peak eos/mm2 hpf from screening or OLI V2/EOT to DB Week 48/EOT
    End point description
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    42
    42
    21
    Units: eos/mm2 hpf
        arithmetic mean (standard deviation)
    233 ( 30.3 )
    9 ( 8.5 )
    305 ( 53.5 )
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    Placebo BID v episodic BUL 0.5mg BID
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2115 [6]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [6] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [7] - Testing of H0 (BUL vs. Placebo)

    Secondary: Proportion of patients with a clinical relapse during the 48-week DB treatment phase

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    End point title
    		 Proportion of patients with a clinical relapse during the 48-week DB treatment phase
    End point description
    End point type
    Secondary
    End point timeframe
    during a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    35
    18
    17
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    Placebo BID v episodic BUL 0.5mg BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.243 [8]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [8] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    Placebo BID v continuous BUL 0.5mg BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0034
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [9] - Testing of H0 (BUL vs. Placebo)

    Secondary: Proportion of patients with clinical relapse EEsAI PRO increase of >20 points at DB Week 48/EOT

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    End point title
    		 Proportion of patients with clinical relapse EEsAI PRO increase of >20 points at DB Week 48/EOT
    End point description
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    16
    2
    12
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    episodic BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0713 [10]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [10] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [11] - Testing of H0 (BUL vs. Placebo)

    Secondary: Proportion of patients in clinico-histological remission, at DB Week 48/EOT

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    End point title
    		 Proportion of patients in clinico-histological remission, at DB Week 48/EOT
    End point description
    Clinico-histological remission = defined as clinical remission (with clinical remission based on EEsAI PRO score ≤ 20 and NRS(D-O)7d ≤ 2 points) and histological remission (based on the peak number of eos per hpf, i.e. <16 eos/hpf).
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    8
    33
    2
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    episodic BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2008 [12]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [12] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [13] - Testing of H0 (BUL vs. Placebo)

    Secondary: Proportion of patients in deep disease remission I at DB Week 48/EOT

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    End point title
    		 Proportion of patients in deep disease remission I at DB Week 48/EOT
    End point description
    Deep disease remission I = being in deep clinical [i.e., EEsAI PRO score of 0], AND deep endoscopic [modified EREFS subscores: fixed rings = 'Grade 0: none' or 'Grade 1: mild', exudates = 'Grade 0: none', furrows = 'Grade 0: absent', and edema = 'Grade 0: absent’], AND deep histological remission [0 eos/hpf]).
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    4
    22
    1
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    episodic BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3444 [14]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [14] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [15]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [15] - Testing of H0 (BUL vs. Placebo)

    Secondary: Proportion of patients in deep disease remission II at DB Week 48/EOT

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    End point title
    		 Proportion of patients in deep disease remission II at DB Week 48/EOT
    End point description
    Deep disease remission II = being in deep clinical [i.e., EEsAI PRO score of 0], AND deep endoscopic [total modified EREFS score of 0], AND deep histological remission [0 eos/hpf]).
    End point type
    Secondary
    End point timeframe
    after a 48-week DB treatment phase, identified at the latest at visit DB V5/EOT (either after 48 weeks of treatment or earlier)
    End point values
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID Placebo BID
    Number of subjects analysed
    45
    45
    22
    Units: Patients
    4
    20
    1
    Statistical analysis title
    		 episodic BUL 0.5mg BID vs placebo
    Comparison groups
    episodic BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3444 [16]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [16] - Testing of H0 (BUL vs. Placebo)
    Statistical analysis title
    		 continuous BUL 0.5mg BID vs placebo
    Comparison groups
    continuous BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [17]
    Method
    		 Fisher exact
    Confidence interval
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [17] - Testing of H0 (BUL vs. Placebo)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48-week double-blinded phase
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    episodic BUL 0.5mg BID
    Reporting group description
    		 -

    Reporting group title
    continuous BUL 0.5mg BID
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Pneumonia
    Additional description: Aspergillus fumigatus and Pseudomonas aeruginosa lung infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 episodic BUL 0.5mg BID continuous BUL 0.5mg BID placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 45 (77.78%)
    32 / 45 (71.11%)
    18 / 22 (81.82%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 45 (11.11%)
    5 / 45 (11.11%)
    0 / 22 (0.00%)
         occurrences all number
    24
    30
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    Condition aggravated
         subjects affected / exposed
    15 / 45 (33.33%)
    3 / 45 (6.67%)
    8 / 22 (36.36%)
         occurrences all number
    16
    3
    8
    Influenza-like illness
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    6
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
    2 / 22 (9.09%)
         occurrences all number
    2
    3
    2
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    0
    Oesophageal food impaction
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    0
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    0
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    3
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    0
    Back pain
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    Neck pain
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
         occurrences all number
    15
    1
    1
    Pain in extremity
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    6 / 45 (13.33%)
    8 / 45 (17.78%)
    1 / 22 (4.55%)
         occurrences all number
    6
    8
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    1
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 45 (17.78%)
    11 / 45 (24.44%)
    6 / 22 (27.27%)
         occurrences all number
    13
    19
    13
    Influenza
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 45 (6.67%)
    0 / 22 (0.00%)
         occurrences all number
    2
    4
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 45 (8.89%)
    0 / 22 (0.00%)
         occurrences all number
    1
    5
    0
    Oropharyngeal candidiasis
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 45 (8.89%)
    1 / 22 (4.55%)
         occurrences all number
    2
    7
    1
    Pharyngitis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    Tonsilitis
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    5 / 45 (11.11%)
    1 / 45 (2.22%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2021
    CSP Amendment 01, version 2.0 18 Mar 2021 (all countries), including eligibility for DB-phase, OLI phase, specifications of exclusion criteria for DB and OLI phase.
    28 Jun 2021
    CSP Local Amendment 1 (ES), version 2.1 of 28 Jun 2021 (ES only), including pregnancy of patient as a separate withdrawal reason, risk minimization process clarification, and informed consent during Coronavirus disease 2019 (COVID19).

    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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