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    Clinical Trial Results:
    Randomised, double-blind, double-dummy, multicentre study to compare the efficacy and safety of once daily novel 4 mg budesonide suppository versus once daily 2 mg budesonide foam in patients with acute ulcerative proctitis

    Summary
    EudraCT number
    		 2016-001921-15
    Trial protocol
    		 DE   LV   HU   SK   PL  
    Global end of trial date
    30 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 May 2021
    First version publication date
    22 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUS-4/UCA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, Germany, 79215
    Public contact
    Department of Clinical Research, Dr. Falk Pharma GmbH, 49 7611514-0, zentrale@drfalkpharma.de
    Scientific contact
    Department of Clinical Research, Dr. Falk Pharma GmbH, 49 7611514-0, 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
    10 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To prove the non-inferiority of an 8-week treatment with once-daily 4 mg budesonide suppository vs. active comparator 2 mg budesonide foam in patients with acute ulcerative proctitis.
    Protection of trial subjects
    Close supervision of patients by regular intermin visits, safety and wellbeing guarantied. Patient documents e.g. ICF - according to Declaration of Helsinki, ICH-GCP, local laws/regulations - submitted to ECs and approved prior to recruiting any patient. Upfront enrollent of a patient he/she a) was well informed about the trial, b) consented to participate in writing, c) and therefore, participation in trial was voluntary. Withdrawal of study always given without fear about loss of medical care. Patient consented to follow the instructions of the protocol/study team.
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 84
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Latvia: 29
    Country: Number of subjects enrolled
    Russian Federation: 166
    Country: Number of subjects enrolled
    Ukraine: 241
    Worldwide total number of subjects
    577
    EEA total number of subjects
    170
    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)
    532
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total 577 patients were included in 7 countries (Germany, Russia, Slovakia, Latvia, Hungary, Poland and Ukraine) from June 2017 to March 2020.

    Pre-assignment
    Screening details
    		 Screening criteria: Signed informed consent • Man or woman between 18 and 75 years of age • Active ulcerative proctitis. In total, 695 patients were screened. Thereof 577 patients were randomised, received at least one dose of study medication and were included in the safety analysis set (SAF).

    Period 1
    Period 1 title
    Treatment Phase (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Budesonide 4 mg Suppository
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide 4mg Suppository
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suppository
    Routes of administration
    Rectal use
    Dosage and administration details
    1 Budesonide 4 mg suppository OD, in the morning or evening (stratified)

    Investigational medicinal product name
    Budesonide Placebo Foam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal foam
    Routes of administration
    Rectal use
    Dosage and administration details
    1 actuation of Budesonide placebo foam OD, in the morning or evening (stratified)

    Arm title
    		 Arm B
    Arm description
    		 Budesonide 2 mg Foam
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide Placebo Suppository
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suppository
    Routes of administration
    Rectal use
    Dosage and administration details
    1 Budesonide placebo suppository OD, in the morning or evening (stratified)

    Investigational medicinal product name
    Budesonide 2 mg Foam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Rectal foam
    Routes of administration
    Rectal use
    Dosage and administration details
    1 actuation of Budesonide 2 mg foam OD, in the morning or evening (stratified)

    Number of subjects in period 1
    		Arm A Arm B
    Started
    286
    291
    Completed
    267
    276
    Not completed
    19
    15
         Adverse event, non-fatal
    4
    5
         lack of patient´s cooperation
    3
    3
         Delayed exclusion
    5
    -
         Supsected Chickenpox/herpes zoster/measles infect
    1
    -
         Lack of efficacy
    5
    5
         other reason
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Budesonide 4 mg Suppository

    Reporting group title
    Arm B
    Reporting group description
    		 Budesonide 2 mg Foam

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 286 291 577
    Age categorical
    577 patients were randomized into the trial aged between the age groups ≥ 18 to ≤ 64 years and > 64 to ≤ 75 years
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 260 272 532
        From 65-84 years
    		 26 19 45
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ± 14.0 43.4 ± 13.4 -
    Gender categorical
    Units: Subjects
        Female
    		 135 156 291
        Male
    		 151 135 286

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Budesonide 4 mg Suppository

    Reporting group title
    Arm B
    Reporting group description
    		 Budesonide 2 mg Foam

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis was performed on 577 patients treated with at least one dose of IMP. None of the patients randomised was to be excluded from the safety analysis set.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomised patients who received at least one dose of IMP. Moreover, all patients identified as not fulfilling the entry criteria shortly after randomisation (delayed exclusions: 6 in this study) were excluded from the FAS. Accordingly, the ITT analysis was performed on 571 randomised patients included in the FAS.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP analysis, representing the primary analysis set was performed on 511 patients.

    Primary: Co-primary efficacy endpoint: Clinical Remission

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    End point title
    		 Co-primary efficacy endpoint: Clinical Remission
    End point description
    0 or 1 for UC-DAI stool frequency subscore and 0 for rectal bleeding subscore
    End point type
    Primary
    End point timeframe
    Within 8 weeks starting with Baseline and with EoT Visit.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    250
    261
    Units: Patients
    197
    194
    Statistical analysis title
    		 Per Protocol Analysis Set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.00007
    Method
    		 Farrington-Manning
    Confidence interval

    Primary: Co-primary efficacy endpoint: Mucosal healing

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    End point title
    		 Co-primary efficacy endpoint: Mucosal healing
    End point description
    mucosal appearance of 0 or 1
    End point type
    Primary
    End point timeframe
    Within 8 weeks starting with Baseline and with EoT Visit.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    250
    261
    Units: Patients
    203
    212
    Statistical analysis title
    		 Per Protocol Analysis Set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00224
    Method
    		 Farrington-Manning
    Confidence interval

    Secondary: Time to resolution of the hallmark symptoms of UC

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    End point title
    		 Time to resolution of the hallmark symptoms of UC
    End point description
    Time in days from Baseline visit to the date of the first day with a number of stools not higher than normal (stool frequency in remission) and with no rectal bleeding.
    End point type
    Secondary
    End point timeframe
    Within 8 weeks starting with Baseline and with EoT Visit.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    281
    290
    Units: Days
        median (confidence interval 95%)
    17.0 (15.0 to 22.0)
    21.0 (16.0 to 27.0)
    Statistical analysis title
    		 Full analysis set (FAS)
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4552
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were assessed at V1 (Baseline), V2,V3, V4, V5 (EOT) and V6 (FU)
    Adverse event reporting additional description
    Treatment emergent adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Budesonide 4mg suppository

    Reporting group title
    Arm B
    Reporting group description
    		 Budesonide 2mg Foam

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 286 (0.70%)
    3 / 291 (1.03%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 286 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 286 (0.35%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endocervical curettage
         subjects affected / exposed
    1 / 286 (0.35%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 286 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 286 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 286 (0.35%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 286 (0.35%)
    0 / 291 (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
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 286 (49.30%)
    119 / 291 (40.89%)
    Injury, poisoning and procedural complications
    Cortisol decreased
         subjects affected / exposed
    69 / 286 (24.13%)
    39 / 291 (13.40%)
         occurrences all number
    71
    40
    ALT increased
         subjects affected / exposed
    5 / 286 (1.75%)
    9 / 291 (3.09%)
         occurrences all number
    5
    9
    Lipase increased
         subjects affected / exposed
    5 / 286 (1.75%)
    8 / 291 (2.75%)
         occurrences all number
    5
    8
    AST increased
         subjects affected / exposed
    3 / 286 (1.05%)
    6 / 291 (2.06%)
         occurrences all number
    3
    6
    Blood ALP increased
         subjects affected / exposed
    2 / 286 (0.70%)
    5 / 291 (1.72%)
         occurrences all number
    2
    5
    GGT increased
         subjects affected / exposed
    3 / 286 (1.05%)
    3 / 291 (1.03%)
         occurrences all number
    3
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 286 (1.40%)
    3 / 291 (1.03%)
         occurrences all number
    4
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 286 (6.64%)
    17 / 291 (5.84%)
         occurrences all number
    29
    27
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 286 (1.40%)
    4 / 291 (1.37%)
         occurrences all number
    4
    4
    Leukocytosis
         subjects affected / exposed
    4 / 286 (1.40%)
    1 / 291 (0.34%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    12 / 286 (4.20%)
    9 / 291 (3.09%)
         occurrences all number
    12
    9
    Abdominal pain
         subjects affected / exposed
    3 / 286 (1.05%)
    4 / 291 (1.37%)
         occurrences all number
    5
    5
    Dyspepsia
         subjects affected / exposed
    5 / 286 (1.75%)
    0 / 291 (0.00%)
         occurrences all number
    5
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 286 (0.00%)
    3 / 291 (1.03%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    0 / 286 (0.00%)
    3 / 291 (1.03%)
         occurrences all number
    0
    3
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    3 / 286 (1.05%)
    0 / 291 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 286 (2.10%)
    10 / 291 (3.44%)
         occurrences all number
    7
    11
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    5 / 286 (1.75%)
    3 / 291 (1.03%)
         occurrences all number
    5
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2017
    Amendment 01 has been made to take into account the objections of the Competent Authorities (CAs) and the competent Ethics Committees (ECs).
    11 Aug 2017
    Amendment 02 includes revisions to Section 6.1 Reference Safety Information (RSI) in the current version of the IMP's Investigator's Brochure (IB; Version 8.0 F, dated 12/07/2017).
    23 Jan 2018
    Amendment 03 became necessary in reason of a procedural change regarding the nomenclature of batch numbers used to identify different packaging campaigns of the investigational medicinal products.

    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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