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    Clinical Trial Results:
    Double-blind, randomized, placebo-controlled, phase III study on the efficacy and tolerability of a 48-week treatment with two different doses of budesonide effervescent tablets vs. placebo for maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis

    Summary
    EudraCT number
    		 2014-001485-99
    Trial protocol
    		 DE   BE   GB   ES   NL   DK   IT  
    Global end of trial date
    11 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Feb 2022
    First version publication date
    04 Feb 2022
    Other versions
    Summary report(s)
    		 BUL-2/EER Full paper

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BUL-2/EER
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02493335
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EOS-2: Acronym
    Sponsors
    Sponsor organisation name
    Dr Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, 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
    05 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Double-blind phase: - To assess the efficacy of a 48-week treatment with 2 x 0.5 mg/d or 2 x 1 mg/d budesonide effervescent tablets vs. placebo for the maintenance of clinico-pathological remission in adult patients with eosinophilic esophagitis (EoE).
    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
    29 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 74
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 85
    Country: Number of subjects enrolled
    Switzerland: 33
    Worldwide total number of subjects
    204
    EEA total number of subjects
    171
    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)
    203
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 29 centers randomized patients: 1 center in Belgium (BE), 13 centers in Germany (DE), 8 centers in Spain (ES), 4 centers in Switzerland (CH), 2 centers in The Netherlands (NL), and 1 center in the United Kingdom (UK).

    Pre-assignment
    Screening details
    		 297 patients were screened to fullfill the In-/Exclusion criteria. Of them, 204 patients were randomized and treated with budesonide or placebo.

    Period 1
    Period 1 title
    Double-blind 48-week treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    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
    		 BUL 0.5mg BID
    Arm description
    		 Twice daily 0.5mg budesonide effervescent tablet for orodispersible use
    Arm type
    		 Experimental

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

    Arm title
    		 BUL 1mg BID
    Arm description
    		 Twice daily 1mg budesonide effervescent tablet for orodispersible use
    Arm type
    		 Experimental

    Investigational medicinal product name
    1mg budesonide effervescent tablet for orodispersible use
    Investigational medicinal product code
    BUL 1mg
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take one effervescent tablet each in the morning and in the evening after the meal. The effervescent tablet has to be placed on the tongue which allows disintegration within several minutes. The dissolved parts of the effervescent 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 effervescent tablet for orodispersible use
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo budesonide effervescent tablet for orodispersible use
    Investigational medicinal product code
    BUL Placebo
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Take one effervescent tablet each in the morning and in the evening after the meal. The effervescent tablet has to be placed on the tongue which allows disintegration within several minutes. The dissolved parts of the effervescent 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
    		BUL 0.5mg BID BUL 1mg BID Placebo BID
    Started
    68
    68
    68
    Completed
    59
    59
    23
    Not completed
    9
    9
    45
         Consent withdrawn by subject
    2
    2
    3
         Adverse event, non-fatal
    -
    2
    -
         Lack of efficacy
    7
    5
    42

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BUL 0.5mg BID
    Reporting group description
    		 Twice daily 0.5mg budesonide effervescent tablet for orodispersible use

    Reporting group title
    BUL 1mg BID
    Reporting group description
    		 Twice daily 1mg budesonide effervescent tablet for orodispersible use

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

    Reporting group values
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID Total
    Number of subjects
    		 68 68 68 204
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 67 68 68 203
        From 65-84 years
    		 1 0 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36 ( 10.9 ) 37 ( 11.1 ) 36 ( 9.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11 13 35
        Male
    		 57 57 55 169
    Ethnic Group
    Units: Subjects
        White
    		 68 68 68 204
    Previous PPI trial conducted
    Units: Subjects
        Yes
    		 68 68 68 204
    History of allergic disease
    Units: Subjects
        yes
    		 54 55 50 159
        no
    		 14 13 18 45
    Duration since first symptoms
    Units: years
        arithmetic mean (standard deviation)
    		 12.6 ( 8.5 ) 11.8 ( 9.4 ) 9.6 ( 8.2 ) -
    Duration since diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 4.3 ( 3.5 ) 4.2 ( 4.0 ) 3.3 ( 2.1 ) -
    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 ( 1.4 ) 0 ( 1.7 ) 1 ( 3.6 ) -
    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)
    		 1 ( 1.1 ) 1 ( 1.1 ) 1 ( 1.0 ) -
    '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 ( 0.6 ) 0 ( 0.6 ) 0 ( 0.6 ) -
    '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)
    		 1 ( 0.7 ) 0 ( 0.6 ) 0 ( 0.6 ) -
    Dysphagia Numerical Rating Scale [NRS] (0-10)
    0 = no troubles to swallow 10 = most severe troubles to swallow
    Units: points
        arithmetic mean (standard deviation)
    		 1 ( 0.9 ) 1 ( 0.9 ) 1 ( 0.8 ) -
    Pain during swallowing NRS (0-10)
    0 = no pain during swallowing 10 = most severe pain during swallowing
    Units: points
        arithmetic mean (standard deviation)
    		 1 ( 0.9 ) 1 ( 1.0 ) 0 ( 0.8 ) -
    Patient’s Global Assessment of EoE activity (NRS 0-10)
    0 = no symptoms 10 = most severe symptoms
    Units: points
        arithmetic mean (standard deviation)
    		 1 ( 0.8 ) 1 ( 0.8 ) 1 ( 0.9 ) -
    Physician’s Global Assessment of EoE activity (NRS 0-10)
    considered all findings concerning the severity of the patient’s EoE (clinical, endoscopic, histologic) 0 = inactive EoE 10 = most active EoE
    Units: points
        arithmetic mean (standard deviation)
    		 1 ( 0.8 ) 1 ( 1.0 ) 1 ( 0.9 ) -
    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)
    		 16 ( 14.1 ) 16 ( 15.8 ) 18 ( 16.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    BUL 0.5mg BID
    Reporting group description
    		 Twice daily 0.5mg budesonide effervescent tablet for orodispersible use

    Reporting group title
    BUL 1mg BID
    Reporting group description
    		 Twice daily 1mg budesonide effervescent tablet for orodispersible use

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

    Primary: Primary endpoint: Proportion of patients free of treatment failure (i.e. being in remission) after 48 weeks of double-blind treatment

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    End point title
    		 Primary endpoint: Proportion of patients free of treatment failure (i.e. being in remission) after 48 weeks of double-blind treatment
    End point description
    Proportion of patients free of treatment failure (i.e., being still in remission) after 48 weeks of treatment. Treatment failure after 48 weeks of treatment 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 pain during swallowing in the past seven days (7 day recall period) of a severity of ≥4 points on a 0–10 NRS for dysphagia or pain during swallowing, 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 pain during swallowing (24-hour recall period). - Histological relapse, i.e., a peak of ≥48 eos/mm2 hpf at end-of-treatment, - Experiencing a food impaction which needed endoscopic intervention, - Need for an endoscopic dilation, - Premature withdrawal for any reason.
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID
    Number of subjects analysed
    68
    68
    68
    Units: Patients
    50
    51
    3
    Attachments
    		 Primary endpoint
    Statistical analysis title
    		 Primary endpoint: BUL 0.5mg BID vs placebo
    Statistical analysis description
    For the comparison between the BUL 0.5mg BID group and the Placebo group the difference between rates of patients free of treatment failure was 69.1% with the corresponding 97.5% CI [55.89%; 82.34%]. The one-sided p-value resulting from the normal approximation test was <0.0001. Therefore, the null hypothesis for this comparison could be rejected and statistically significant superiority of BUL 0.5mg BID versus Placebo was successfully shown in a confirmatory manner in the FAS population.
    Comparison groups
    BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    69.1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 55.89
         upper limit
    		 82.34
    Notes
    [1] - The 2 hypotheses of superiority of BUL 0.5mg BID vs placebo and BUL 1mg BID vs placebo were tested each at a one-sided Bonferroni adjusted type I error level of 0.0125 using normal approximation tests for the comparison of rates. For estimating the treatment effect compared to Placebo, two-sided 97.5% (Bonferroni correction) confidence intervals (CI) for the difference of rates were provided.
    Statistical analysis title
    		 Primary endpoint: BUL 1mg BID vs placebo
    Statistical analysis description
    For the comparison between the BUL 1mg BID group and the Placebo group the difference between rates of patients free of treatment failure was 70.6% in the full analysis set (FAS) with corresponding 97.5% CI [57.56%; 83.61%]. The one-sided p-value resulting from the normal approximation test was <0.0001. Therefore, the null hypothesis for this comparison could be rejected and statistically significant superiority of BUL 1mg BID versus Placebo was successfully shown in a confirmatory manner.
    Comparison groups
    Placebo BID v BUL 1mg BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    70.6
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 57.56
         upper limit
    		 83.61
    Notes
    [2] - The 2 hypotheses of superiority of BUL 0.5mg BID vs placebo and BUL 1mg BID vs placebo were tested each at a one-sided Bonferroni adjusted type I error level of 0.0125 using normal approximation tests for the comparison of rates. For estimating the treatment effect compared to Placebo, two-sided 97.5% (Bonferroni correction) confidence intervals (CI) for the difference of rates were provided.

    Secondary: Major secondary endpoint: Proportion of patients with a histological relapse, defined as a peak of ≥48 eos/mm² hpf at end of treatment

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    End point title
    		 Major secondary endpoint: Proportion of patients with a histological relapse, defined as a peak of ≥48 eos/mm² hpf at end of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID
    Number of subjects analysed
    68
    68
    68
    Units: Patients
    9
    7
    61
    Attachments
    		 Major secondary endpoint: Histological relapse
    Statistical analysis title
    		 BUL 0.5mg BID vs placebo
    Comparison groups
    BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -76.5
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -88.8
         upper limit
    		 -64.1
    Statistical analysis title
    		 BUL 1mg BID vs placebo
    Comparison groups
    Placebo BID v BUL 1mg BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -79.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -91.1
         upper limit
    		 -67.7

    Secondary: Major secondary endpoint: Proportion of patients with a clinical relapse, or food impaction which needed endoscopic intervention, or endoscopic dilation during the 48 weeks

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    End point title
    		 Major secondary endpoint: Proportion of patients with a clinical relapse, or food impaction which needed endoscopic intervention, or endoscopic dilation during the 48 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID
    Number of subjects analysed
    68
    68
    68
    Units: patients
    7
    5
    41
    Attachments
    		 Major secondary endpoint: Clinical relapse
    Statistical analysis title
    		 BUL 0.5mg BID vs placebo
    Comparison groups
    BUL 0.5mg BID v Placebo BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -50
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -65.7
         upper limit
    		 -34.3
    Statistical analysis title
    		 BUL 1mg BID vs placebo
    Comparison groups
    BUL 1mg BID v Placebo BID
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Normal approximation test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -52.9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -68
         upper limit
    		 -37.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    BUL 0.5mg BID
    Reporting group description
    		 Twice daily 0.5mg budesonide effervescent tablet for orodispersible use

    Reporting group title
    BUL 1mg BID
    Reporting group description
    		 Twice daily 1mg budesonide effervescent tablet for orodispersible use

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

    Serious adverse events
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Cartilage injury
    Additional description: cartilage damage in ankle joint worsened
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
    0 / 68 (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
    Upper limb fracture
    Additional description: elbow fracture (due to fall)
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
    0 / 68 (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
    Skull fracture
    Additional description: This event was due to a car accident.
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
    0 / 68 (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
    Infections and infestations
    Sinusitis
    Additional description: elective OP of a chronic pansinusitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
    0 / 68 (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: 3%
    Non-serious adverse events
    		 BUL 0.5mg BID BUL 1mg BID Placebo BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 68 (83.82%)
    59 / 68 (86.76%)
    61 / 68 (89.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 68 (20.59%)
    10 / 68 (14.71%)
    5 / 68 (7.35%)
         occurrences all number
    14
    10
    5
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 68 (2.94%)
    1 / 68 (1.47%)
         occurrences all number
    4
    2
    1
    Condition aggravated
    Additional description: Deterioration of underlying disease (i.e, eosinophilic esophagitis)
         subjects affected / exposed
    11 / 68 (16.18%)
    8 / 68 (11.76%)
    44 / 68 (64.71%)
         occurrences all number
    11
    8
    44
    Eye disorders
    Blepharitis
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 68 (2.94%)
    1 / 68 (1.47%)
         occurrences all number
    3
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 68 (2.94%)
    0 / 68 (0.00%)
         occurrences all number
    5
    2
    0
    Dyspepsia
         subjects affected / exposed
    3 / 68 (4.41%)
    7 / 68 (10.29%)
    3 / 68 (4.41%)
         occurrences all number
    3
    7
    3
    Oesophageal food impaction
    Additional description: Self clearing - without the need for endoscopic intervention
         subjects affected / exposed
    0 / 68 (0.00%)
    3 / 68 (4.41%)
    2 / 68 (2.94%)
         occurrences all number
    0
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 68 (5.88%)
    0 / 68 (0.00%)
         occurrences all number
    4
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences all number
    3
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 68 (1.47%)
    1 / 68 (1.47%)
         occurrences all number
    3
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 68 (5.88%)
    0 / 68 (0.00%)
         occurrences all number
    1
    4
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 68 (7.35%)
    1 / 68 (1.47%)
         occurrences all number
    3
    5
    1
    Influenza
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 68 (4.41%)
    2 / 68 (2.94%)
         occurrences all number
    3
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    25 / 68 (36.76%)
    20 / 68 (29.41%)
    19 / 68 (27.94%)
         occurrences all number
    25
    20
    19
    Local fungal infection
    Additional description: In 21/136 patients (15%) under budesonide, a local fungal infection (oral , oropharyngeal, and/or esophageal candidiasis) was suspected. Thereof, only 19 patients (14%) showed clinically mild symptoms with no impact on their daily life.
         subjects affected / exposed
    12 / 68 (17.65%)
    9 / 68 (13.24%)
    0 / 68 (0.00%)
         occurrences all number
    12
    9
    0
    Pharyngitis
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 68 (2.94%)
    1 / 68 (1.47%)
         occurrences all number
    3
    2
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 68 (5.88%)
    0 / 68 (0.00%)
         occurrences all number
    3
    4
    0

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32721437
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